ESC/EAS GUIDELINES
2016 ESC/EAS Guidelines for the Management
of Dyslipidaemias
The Task Force for the Management of Dyslipidaemias of the
European Society of Cardiology (ESC) and European Atherosclerosis
Society (EAS)
Developed with the special contribution of the European Assocciation
for Cardiovascular Prevention & Rehabilitation (EACPR)
Authors/Task Force Members: Alberico L. Catapano* (Chairperson) (Italy),
Ian Graham* (Chairperson) (Ireland), Guy De Backer (Belgium), Olov Wiklund
(Sweden), M. John Chapman (France), Heinz Drexel (Austria), Arno W. Hoes
(The Netherlands), Catriona S. Jennings (UK), Ulf Landmesser (Germany),
Terje R. Pedersen (Norway), Zˇ eljko Reiner (Croatia), Gabriele Riccardi (Italy),
Marja-Riita Taskinen (Finland), Lale Tokgozoglu (Turkey), W. M. Monique
Verschuren (The Netherlands), Charalambos Vlachopoulos (Greece), David A. Wood
(UK), Jose Luis Zamorano (Spain)
Additional Contributor: Marie-Therese Cooney (Ireland)
Document Reviewers: Lina Badimon (CPG Review Coordinator) (Spain), Christian Funck-Brentano (CPG Review
Coordinator) (France), Stefan Agewall (Norway), Gonzalo Baro´n-Esquivias (Spain), Jan Bore´n (Sweden),
Eric Bruckert (France), Alberto Cordero (Spain), Alberto Corsini (Italy), Pantaleo Giannuzzi (Italy),
* Corresponding authors: Alberico L. Catapano, Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, and Multimedica IRCCS
(MI) Italy. Tel: +39 02 5031 8401, Fax: +39 02 5031 8386, E-mail: alberico.catapano@unimi.it; Ian Graham, Cardiology Department, Hermitage Medical Clinic, Old Lucan Road, Dublin
20, Dublin, Ireland. Tel: +353 1 6459715, Fax: +353 1 6459714, E-mail: ian@grahams.net
ESC Committee for Practice Guidelines (CPG) and National Cardiac Society Reviewers can be found in the Appendix.
ESC entities having participated in the development of this document:
Associations: Acute Cardiovascular Care Association (ACCA), European Association for Cardiovascular Prevention & Rehabilitation (EACPR), European Association of Cardiovascular
Imaging (EACVI), European Association of Percutaneous Cardiovascular Interventions (EAPCI), Heart Failure Association (HFA)
Councils: Council on Cardiovascular Nursing and Allied Professions, Council for Cardiology Practice, Council on Cardiovascular Primary Care, Council on Hypertension
Working Groups: Atherosclerosis & Vascular Biology, Cardiovascular Pharmacotherapy, Coronary Pathophysiology & Microcirculation, E-cardiology, Myocardial and Pericardial
Diseases, Peripheral Circulation, Thrombosis.
The content of these European Society of Cardiology (ESC) and European Atherosclerosis Society Guidelines has been published for personal and educational use only. No commercial
use is authorized. No part of the ESC Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of
a written request to Oxford University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC
(journals.permissions@oup.com).
Disclaimer. The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientiﬁc and medical knowledge and the evidence available at
the time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other ofﬁcial recommendations
or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encouraged
to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or
therapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and
accurate decisions in consideration of each patient’s health condition and in consultation with that patient and, where appropriate and/or necessary, the patient’s caregiver. Nor
do the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant ofﬁcial updated recommendations or guidelines issued by the competent
public health authorities in order to manage each patient’s case in light of the scientiﬁcally accepted data pursuant to their respective ethical and professional obligations. It is also the
health professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.
& 2016 European Society of Cardiology and European Atherosclerosis Association. All rights reserved. For permissions please email: journals.permissions@oup.com.
doi:10.1093/eurheartj/ehw272
European Heart Journal (2016) 37, 2999–3058
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
Franc¸ois Gueyfﬁer (France), Goran Krstacˇic´ (Croatia), Maddalena Lettino (Italy), Christos Lionis (Greece),
Gregory Y. H. Lip (UK), Pedro Marques-Vidal (Switzerland), Davor Milicic (Croatia), Juan Pedro-Botet (Spain),
Massimo F. Piepoli (Italy), Angelos G. Rigopoulos (Germany), Frank Ruschitzka (Switzerland), Jose´ Tun˜o´n (Spain),
Arnold von Eckardstein (Switzerland), Michal Vrablik (Czech Republic), Thomas W. Weiss (Austria), Bryan Williams
(UK), Stephan Windecker (Switzerland), and Reuven Zimlichman (Israel)
The disclosure forms of the authors and reviewers are available on the ESC website www.escardio.org/guidelines.
------------------------------------------------------------------------------------------------------------------------------------------------------
Keywords dyslipidaemias † cholesterol † triglycerides † low-density lipoproteins † high-density lipoproteins †
apolipoprotein B † lipoprotein remnants † total cardiovascular risk † treatment, lifestyle † treatment,
drugs † treatment, adherence
Table of Contents
List of abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
1. What is cardiovascular disease prevention? . . . . . . . . . . . . . 6
1.1 Deﬁnition and rationale . . . . . . . . . . . . . . . . . . . . . . 6
1.2 Development of the Joint Task Force guidelines . . . . . . 6
1.3 Cost-effectiveness of prevention . . . . . . . . . . . . . . . . 7
2. Total cardiovascular risk . . . . . . . . . . . . . . . . . . . . . . . . . 8
2.1 Total cardiovascular risk estimation . . . . . . . . . . . . . . 8
2.1.1 Rationale for assessing total cardiovascular disease
risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
2.1.2 How to use the risk estimation charts . . . . . . . . . . 12
2.2 Risk levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
2.2.1 Risk- based intervention strategies . . . . . . . . . . . . 13
3. Evaluation of laboratory lipid and apolipoprotein parameters . 14
3.1 Fasting or non-fasting? . . . . . . . . . . . . . . . . . . . . . . . 16
3.2 Intra-individual variation . . . . . . . . . . . . . . . . . . . . . . 16
3.3 Lipid and lipoprotein analyses . . . . . . . . . . . . . . . . . . 16
3.3.1 Total cholesterol . . . . . . . . . . . . . . . . . . . . . . . 16
3.3.2 Low-density lipoprotein cholesterol . . . . . . . . . . . 16
3.3.3 Non-high-density lipoprotein cholesterol . . . . . . . . 17
3.3.4 High-density lipoprotein cholesterol . . . . . . . . . . . 18
3.3.5 Triglycerides . . . . . . . . . . . . . . . . . . . . . . . . . . 18
3.3.6 Apolipoproteins . . . . . . . . . . . . . . . . . . . . . . . . 18
3.3.7 Lipoprotein(a) . . . . . . . . . . . . . . . . . . . . . . . . . 19
3.3.8 Lipoprotein particle size . . . . . . . . . . . . . . . . . . . 19
3.3.9 Genotyping . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
4. Treatment targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
5. Lifestyle modiﬁcations to improve the plasma lipid proﬁle . . . 21
5.1 The inﬂuence of lifestyle on total cholesterol and lowdensity
lipoprotein cholesterol levels . . . . . . . . . . . . . . . . 23
5.2 The inﬂuence of lifestyle on triglyceride levels . . . . . . . 24
5.3 The inﬂuence of lifestyle on high-density lipoprotein
cholesterol levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
5.4 Lifestyle recommendations to improve the plasma lipid
proﬁle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
5.4.1 Body weight and physical activity . . . . . . . . . . . . . 24
5.4.2 Dietary fat . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
5.4.3 Dietary carbohydrate and ﬁbre . . . . . . . . . . . . . . 25
5.4.4 Alcohol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
5.4.5 Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
5.5 Dietary supplements and functional foods for the
treatment of dyslipidaemias . . . . . . . . . . . . . . . . . . . . . . 25
5.5.1 Phytosterols . . . . . . . . . . . . . . . . . . . . . . . . . . 26
5.5.2 Monacolin and red yeast rice . . . . . . . . . . . . . . . . 26
5.5.3 Dietary ﬁbre . . . . . . . . . . . . . . . . . . . . . . . . . . 26
5.5.4 Soy protein . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
5.5.5 Policosanol and berberine . . . . . . . . . . . . . . . . . 26
5.5.6 n-3 unsaturated fatty acids . . . . . . . . . . . . . . . . . 26
5.6 Other features of a healthy diet contributing to
cardiovascular disease prevention . . . . . . . . . . . . . . . . . . 26
6. Drugs for treatment of hypercholesterolaemia . . . . . . . . . . 27
6.1 Statins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
6.1.1 Mechanism of action . . . . . . . . . . . . . . . . . . . . . 27
6.1.2 Efﬁcacy of cardiovascular disease prevention in clinical
studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
6.1.3 Adverse effects of statins . . . . . . . . . . . . . . . . . . 29
6.1.4 Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
6.2 Bile acid sequestrants . . . . . . . . . . . . . . . . . . . . . . . 30
6.2.1 Mechanism of action . . . . . . . . . . . . . . . . . . . . . 30
6.2.2 Efﬁcacy in clinical studies . . . . . . . . . . . . . . . . . . 30
6.2.3 Adverse effects and interactions . . . . . . . . . . . . . 30
6.3 Cholesterol absorption inhibitors . . . . . . . . . . . . . . . 30
6.3.1 Mechanism of action . . . . . . . . . . . . . . . . . . . . . 30
6.3.2 Efﬁcacy in clinical studies . . . . . . . . . . . . . . . . . . 31
6.3.3 Adverse effects and interactions . . . . . . . . . . . . . 31
6.4 PCSK9 inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . 31
6.4.1 Mechanism of action . . . . . . . . . . . . . . . . . . . . . 31
6.4.2 Efﬁcacy in clinical studies . . . . . . . . . . . . . . . . . . 31
6.4.3 Adverse effects and interactions . . . . . . . . . . . . . 31
6.5 Nicotinic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
6.6 Drug combinations . . . . . . . . . . . . . . . . . . . . . . . . . 32
6.6.1 Statins and cholesterol absorption inhibitors . . . . . 32
6.6.2 Statins and bile acid sequestrants . . . . . . . . . . . . . 32
6.6.3 Other combinations . . . . . . . . . . . . . . . . . . . . . 32
7. Drugs for treatment of hypertriglyceridaemia . . . . . . . . . . . 32
7.1 Triglycerides and cardiovascular disease risk . . . . . . . . . 32
7.2 Deﬁnition of hypertriglyceridaemia . . . . . . . . . . . . . . 33
7.3 Strategies to control plasma triglycerides . . . . . . . . . . . 33
ESC/EAS Guidelines
Online publish-ahead-of-print 28 August 2016
3000
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
7.4 Statins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
7.5 Fibrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
7.5.1 Mechanism of action . . . . . . . . . . . . . . . . . . . . . 33
7.5.2 Efﬁcacy in clinical trials . . . . . . . . . . . . . . . . . . . . 33
7.5.3 Adverse effects and interactions . . . . . . . . . . . . . 34
7.6 Nicotinic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
7.6.1 Mechanism of action . . . . . . . . . . . . . . . . . . . . . 34
7.6.2 Efﬁcacy in clinical trials . . . . . . . . . . . . . . . . . . . . 34
7.7 n-3 fatty acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
7.7.1 Mechanism of action . . . . . . . . . . . . . . . . . . . . . 34
7.7.2 Efﬁcacy in clinical trials . . . . . . . . . . . . . . . . . . . . 34
7.7.3 Safety and interactions . . . . . . . . . . . . . . . . . . . . 35
8. Drugs affecting high-density lipoprotein cholesterol (Table 20) 35
8.1 Statins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
8.2 Fibrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
8.3 Nicotinic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
8.4 Cholesteryl ester transfer protein inhibitors . . . . . . . . . 36
8.5 Future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . 36
9. Management of dyslipidaemia in different clinical settings . . . . 36
9.1 Familial dyslipidaemias . . . . . . . . . . . . . . . . . . . . . . . 36
9.1.1 Familial combined hyperlipidaemia . . . . . . . . . . . . 36
9.1.2 Familial hypercholesterolaemia . . . . . . . . . . . . . . 36
9.1.2.1 Heterozygous familial hypercholesterolaemia . . 36
9.1.2.2 Homozygous familial hypercholesterolaemia . . . 38
9.1.2.3 Familial hypercholesterolaemia in children . . . . 38
9.1.3 Familial dysbetalipoproteinaemia . . . . . . . . . . . . . 38
9.1.4 Genetic causes of hypertriglyceridaemia . . . . . . . . 38
9.1.4.1 Action to prevent acute pancreatitis in severe
hypertriglyceridaemia . . . . . . . . . . . . . . . . . . . . . . . 39
9.1.5 Other genetic disorders of lipoprotein metabolism
(Table 23) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
9.2 Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
9.3 Women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
9.3.1 Primary prevention . . . . . . . . . . . . . . . . . . . . . . 40
9.3.2 Secondary prevention . . . . . . . . . . . . . . . . . . . . 40
9.3.3 Non-statin lipid-lowering drugs . . . . . . . . . . . . . . 40
9.3.4 Hormone therapy . . . . . . . . . . . . . . . . . . . . . . . 40
9.4 Older persons . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
9.4.1 Primary prevention . . . . . . . . . . . . . . . . . . . . . . 41
9.4.2 Secondary prevention . . . . . . . . . . . . . . . . . . . . 41
9.4.3 Adverse effects, interactions and adherence . . . . . . 41
9.5 Diabetes and metabolic syndrome . . . . . . . . . . . . . . . 42
9.5.1 Speciﬁc features of dyslipidaemia in insulin resistance
and type 2 diabetes (Table 25) . . . . . . . . . . . . . . . . . . . 42
9.5.2 Evidence for lipid-lowering therapy . . . . . . . . . . . . 42
9.5.2.1 Low-density lipoprotein cholesterol . . . . . . . . 42
9.5.2.2 Triglycerides and high-density lipoprotein
cholesterol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
9.5.3 Treatment strategies for subjects with type 2 diabetes
and metabolic syndrome . . . . . . . . . . . . . . . . . . . . . . 43
9.5.4 Type 1 diabetes . . . . . . . . . . . . . . . . . . . . . . . . 43
9.6 Patients with acute coronary syndrome and patients
undergoing percutaneous coronary intervention . . . . . . . . . 43
9.6.1 Speciﬁc lipid management issues in acute coronary
syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
9.6.2 Lipid management issues in patients undergoing
percutaneous coronary intervention . . . . . . . . . . . . . . . 44
9.7 Heart failure and valvular diseases . . . . . . . . . . . . . . . 44
9.7.1 Prevention of incident heart failure in coronary artery
disease patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
9.7.2 Chronic heart failure . . . . . . . . . . . . . . . . . . . . . 44
9.7.3 Valvular disease . . . . . . . . . . . . . . . . . . . . . . . . 45
9.8 Autoimmune diseases . . . . . . . . . . . . . . . . . . . . . . . 45
9.9 Chronic kidney disease . . . . . . . . . . . . . . . . . . . . . . 45
9.9.1 Lipoprotein proﬁle in chronic kidney disease . . . . . 45
9.9.2 Evidence for lipid management in patients with
chronic kidney disease . . . . . . . . . . . . . . . . . . . . . . . . 46
9.9.3 Safety of lipid management in patients with chronic
kidney disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
9.9.4 Recommendations of lipid management for patients
with chronic kidney disease . . . . . . . . . . . . . . . . . . . . 46
9.10 Transplantation (Table 31) . . . . . . . . . . . . . . . . . . . 46
9.11 Peripheral arterial disease . . . . . . . . . . . . . . . . . . . . 47
9.11.1 Lower extremities arterial disease . . . . . . . . . . . 47
9.11.2 Carotid artery disease . . . . . . . . . . . . . . . . . . . 47
9.11.3 Retinal vascular disease . . . . . . . . . . . . . . . . . . 48
9.11.4 Secondary prevention in patients with aortic
abdominal aneurysm . . . . . . . . . . . . . . . . . . . . . . . . . 48
9.11.5 Renovascular atherosclerosis . . . . . . . . . . . . . . . 48
9.12 Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
9.12.1 Primary prevention of stroke . . . . . . . . . . . . . . . 48
9.12.2 Secondary prevention of stroke . . . . . . . . . . . . . 49
9.13 Human immunodeﬁciency virus patients . . . . . . . . . . 49
9.14 Mental disorders . . . . . . . . . . . . . . . . . . . . . . . . . . 49
10. Monitoring of lipids and enzymes in patients on lipid-lowering
therapy (Table 36) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
11. Strategies to encourage adoption of healthy lifestyle changes
and adherence to lipid-modifying therapies . . . . . . . . . . . . . . . 51
11.1 Achieving and adhering to healthy lifestyle changes . . . 51
11.2 Adhering to medications . . . . . . . . . . . . . . . . . . . . 54
12. To do and not to do messages from the Guidelines . . . . . . 57
13. Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
14. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
List of abbreviations
ABI ankle-brachial index
ACC American College of Cardiology
ACCELERATE Assessment of Clinical Effects of Cholesteryl Ester
Transfer Protein Inhibition with Evacetrapib
in Patients at a High-Risk for Vascular Outcomes
ACCORD Action to Control Cardiovascular Risk in
Diabetes
ACS acute coronary syndrome
AFCAPS/
TEXCAPS
Air Force/Texas Coronary Atherosclerosis Prevention
Study
AHA American Heart Association
AIM-HIGH Atherothrombosis Intervention in Metabolic
Syndrome with Low HDL/High Triglycerides:
Impact on Global Health Outcomes
ALT alanine aminotransferase
Apo apolipoprotein
ESC/EAS Guidelines 3001
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
ART antiretroviral treatment
ASSIGN CV risk estimation model from the Scottish
Intercollegiate Guidelines Network
ASTRONOMER Aortic Stenosis Progression Observation: Measuring
Effects of Rosuvastatin
AURORA A study to evaluate the Use of Rosuvastatin in
subjects On Regular haemodialysis: an Assessment
of survival and cardiovascular events
BIP Bezaﬁbrate Infarction Prevention study
BMI body mass index
CABG coronary artery bypass graft surgery
CAC coronary artery calcium
CAD coronary artery disease
CARE Cholesterol and Recurrent Events
CETP cholesteryl ester transfer protein
CHD coronary heart disease
CIMT carotid intima-media thickness
CK creatine kinase
CKD chronic kidney disease
CTT Cholesterol Treatment Trialists
CV cardiovascular
CVD cardiovascular disease
CYP cytochrome P450
4D Die Deutsche Diabetes Dialyse
DASH Dietary Approaches to Stop Hypertension
DGAT-2 diacylglycerol acyltransferase-2
DHA docosahexaenoic acid
DLCN Dutch Lipid Clinic Network
EAS European Atherosclerosis Society
EMA European Medicines Agency
EPA eicosapentaenoic acid
ER extended release
ESC European Society of Cardiology
ESRD end-stage renal disease
EU European Union
FACE-BD Fondamental Academic Centers of Expertise in
Bipolar Disorders
FATS Familial Atherosclerosis Treatment Study
FCH familial combined hyperlipidaemia
FDA US Food and Drug Administration
FDC ﬁxed-dose combination
FH familial hypercholesterolaemia
FIELD Fenoﬁbrate Intervention and Event Lowering in
Diabetes
FOCUS Fixed-Dose Combination Drug for Secondary
Cardiovascular Prevention
GFR glomerular ﬁltration rate
GISSI Gruppo Italiano per lo Studio della Sopravvivenza
nell’Infarto Miocardico
GP general practitioner
GWAS genome-wide association studies
HAART highly active antiretroviral treatment
HATS HDL-Atherosclerosis Treatment Study
HbA1C glycated haemoglobin
HeFH heterozygous familial hypercholesterolaemia
HDL-C high-density lipoprotein cholesterol
HF heart failure
HHS Helsinki Heart Study
HIV human immunodeﬁciency virus
HMG-CoA hydroxymethylglutaryl-coenzyme A
HPS Heart Protection Study
HPS2-THRIVE Heart Protection Study 2–Treatment of HDL
to Reduce the Incidence of Vascular Events
HoFH homozygous familial hypercholesterolaemia
HTG hypertriglyceridaemia
HR hazard ratio
hs-CRP high-sensitivity C-reactive protein
ICD International Classiﬁcation of Diseases
IDEAL Incremental Decrease In End-points Through
Aggressive Lipid-lowering Trial
IDL intermediate-density lipoproteins
ILLUMINATE Investigation of Lipid Level Management to
Understand its Impact in Atherosclerotic Events
IMPROVE-IT Improved Reduction of Outcomes: Vytorin Efﬁcacy
International Trial
JUPITER Justiﬁcation for the Use of Statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin
KDIGO Kidney Disease: Improving Global Outcomes
LAL lysosomal acid lipase
LCAT lecithin cholesterol acyltransferase
LDL-C low-density lipoprotein cholesterol
LDLR low-density lipoprotein receptor
LEAD lower extremities arterial disease
LIPID Long-Term Intervention with Pravastatin in Ischemic
Disease
LPL lipoprotein lipase
Lp lipoprotein
MetS metabolic syndrome
MI myocardial infarction
MTP microsomal triglyceride transfer protein
MUFA monounsaturated fatty acid
NICE National Institute for Health and Care
Excellence
NNRTI non-nucleoside reverse transcriptase inhibitor
NNT number needed to treat
NPC1L1 Niemann-Pick C1-like protein 1
NSTE-ACS non-ST elevation acute coronary syndrome
NYHA New York Heart Association
PAD peripheral arterial disease
PCI percutaneous coronary intervention
PCSK9 proprotein convertase subtilisin/kexin type 9
PPAR-a peroxisome proliferator-activated receptor-a
PROCAM Prospective Cardiovascular Munster Study
PROSPER Prospective Study of Pravastatin in the Elderly at
Risk
PUFA polyunsaturated fatty acid
RAAS renin–angiotensin–aldosterone system
RCT randomized controlled trial
REACH Reduction of Atherothrombosis for Continued
Health
REDUCE-IT Reduction of Cardiovascular Events with
EPA-Intervention Trial
ESC/EAS Guidelines3002
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
REVEAL Randomized Evaluation of the Effects of Anacetrapib
Through Lipid modiﬁcation
RR relative risk
RYR red yeast rice
4S Scandinavian Simvastatin Survival Study
SALTIRE Scottish Aortic Stenosis and Lipid Lowering
Trial, Impact on Regression
SAGE Studies Assessing Goals in the Elderly
SCORE Systemic Coronary Risk Estimation
SEAS Simvastatin and Ezetimibe in Aortic Stenosis
SFA saturated fatty acid
SHARP Study of Heart and Renal Protection
SLE systemic lupus erythematosus
SPARCL Stroke Prevention by Aggressive Reduction in
Cholesterol Levels
STEMI ST elevation myocardial infarction
STRENGTH Outcomes Study to Assess STatin Residual Risk
Reduction with EpaNova in HiGh CV Risk
PatienTs with Hypertriglyceridemia
TIA transient ischaemic attack
TC total cholesterol
T2DM type 2 diabetes mellitus
TG triglyceride
TNT Treatment to new targets
TRL triglyceride-rich lipoprotein
ULN upper limit of normal
UMPIRE Use of a Multidrug Pill In Reducing cardiovascular
Events
VA-HIT Veterans Affairs High-density lipoprotein Intervention
Trial
VLDL very low-density lipoprotein
WHO World Health Organization
Preamble
Guidelines summarize and evaluate all available evidence on a particular
issue at the time of the writing process, with the aim of assisting
health professionals in selecting the best management
strategies for an individual patient with a given condition, taking
into account the impact on outcome as well as the risk–beneﬁt ratio
of particular diagnostic or therapeutic means. Guidelines and
recommendations should help health professionals to make decisions
in their daily practice. However, the ﬁnal decisions concerning
an individual patient must be made by the responsible health
professional(s) in consultation with the patient and caregiver as
appropriate.
A great number of guidelines have been issued in recent years by
the European Society of Cardiology (ESC) and by the European Atherosclerosis
Society (EAS), as well as by other societies and organisations.
Because of the impact on clinical practice, quality criteria for the
development of guidelines have been established in order to make all
decisions transparent to the user. The recommendations for formulating
and issuing ESC Guidelines can be found on the ESC website
(http://www.escardio.org/Guidelines-&-Education/Clinical-PracticeGuidelines/Guidelines-development/Writing-ESC-Guidelines).
ESC
Guidelines represent the ofﬁcial position of the ESC on a given topic
and are regularly updated.
Members of this Task Force were selected by the ESC, including
representation from the European Association for Cardiovascular
Prevention & Rehabilitation (EACPR), and EAS to
represent professionals involved with the medical care of patients
with this pathology. Selected experts in the ﬁeld undertook
a comprehensive review of the published evidence for management
(including diagnosis, treatment, prevention and rehabilitation)
of a given condition according to ESC Committee for
Practice Guidelines (CPG) policy and approved by the EAS. A
critical evaluation of diagnostic and therapeutic procedures was
performed, including assessment of the risk–beneﬁt ratio. Estimates
of expected health outcomes for larger populations
were included, where data exist. The level of evidence and the
strength of the recommendation of particular management options
were weighed and graded according to predeﬁned scales,
as outlined in Tables 1 and 2
The experts of the writing and reviewing panels provided declaration
of interest forms for all relationships that might be perceived as
real or potential sources of conﬂicts of interest. These forms were
compiled into one ﬁle and can be found on the ESC website (http://
www.escardio.org/guidelines). Any changes in declarations of interest
that arise during the writing period must be notiﬁed to the ESC
and EAS and updated. The Task Force received its entire ﬁnancial
support from the ESC and EAS without any involvement from the
healthcare industry.
The ESC CPG supervises and coordinates the preparation of
new Guidelines produced by task forces, expert groups or consensus
panels. The Committee is also responsible for the endorsement
process of these Guidelines. The ESC Guidelines undergo
extensive review by the CPG and external experts, and in this
case by EAS-appointed experts. After appropriate revisions the
Guidelines are approved by all the experts involved in the Task
Force. The ﬁnalized document is approved by the CPG and EAS
for publication in the European Heart Journal and in Atherosclerosis.
The Guidelines were developed after careful consideration of
the scientiﬁc and medical knowledge and the evidence available at
the time of their dating.
The task of developing ESC and EAS Guidelines covers not
only integration of the most recent research, but also the creation
of educational tools and implementation programmes for
the recommendations. To implement the guidelines, condensed
pocket guideline versions, summary slides, booklets with essential
messages, summary cards for non-specialists and an electronic
version for digital applications (smartphones, etc.) are
produced. These versions are abridged and thus, if needed,
one should always refer to the full text version, which is freely
available on the ESC website. The National Societies of the
ESC are encouraged to endorse, translate and implement all
ESC Guidelines. Implementation programmes are needed because
it has been shown that the outcome of disease may be favourably
inﬂuenced by the thorough application of clinical
recommendations.
Surveys and registries are needed to verify that real-life daily practice
is in keeping with what is recommended in the guidelines, thus
ESC/EAS Guidelines 3003
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
completing the loop between clinical research, writing of guidelines,
disseminating them and implementing them into clinical practice.
Health professionals are encouraged to take the ESC and EAS
Guidelines fully into account when exercising their clinical judgment,
as well as in the determination and the implementation of preventive,
diagnostic or therapeutic medical strategies. However, the ESC
and EAS Guidelines do not override in any way whatsoever the individual
responsibility of health professionals to make appropriate
and accurate decisions in consideration of each patient’s health condition
and in consultation with that patient or the patient’s caregiver
where appropriate and/or necessary. It is also the health professional’s
responsibility to verify the rules and regulations applicable
to drugs and devices at the time of prescription.
1. What is cardiovascular disease
prevention?
1.1 Deﬁnition and rationale
Cardiovascular disease (CVD) kills .4 million people in Europe
each year. It kills more women [2.2 million (55%)] than men [1.8 million
(45%)], although cardiovascular (CV) deaths before the age of
65 years are more common in men (490 000 vs. 193 000).1
Prevention
is deﬁned as a coordinated set of actions, at the population level
or targeted at an individual, aimed at eradicating, eliminating or minimizing
the impact of CV diseases and their related disability. CVD
remains a leading cause of morbidity and mortality, despite improvements
in outcomes for CVD. More patients are surviving their ﬁrst
CVD event and are at high risk of recurrences. In addition, the
prevalence of some risk factors, notably diabetes and obesity, is increasing.
The importance of CVD prevention remains undisputed
and should be delivered at different levels: (i) in the general population
by promoting healthy lifestyle behaviour2
and (ii) at the
individual level, in those at moderate to high risk of CVD or patients
with established CVD, by tackling an unhealthy lifestyle (e.g. poorquality
diet, physical inactivity, smoking) and by reducing increased
levels of CV risk factors such as increased lipid or blood pressure
levels. Prevention is effective in reducing the impact of CVD; the
elimination of health risk behaviours would make it possible to prevent
at least 80% of CVD and even 40% of cancers, thus providing
added value for other chronic diseases.3,4
1.2 Development of the Joint Task Force
guidelines
The present guidelines represent an evidence-based consensus of
the European Task Force including the European Society of Cardiology
(ESC) and the European Atherosclerosis Society (EAS).
By appraising the current evidence and identifying remaining
knowledge gaps in managing the prevention of dyslipidaemias, the
Task Force formulated recommendations to guide actions to prevent
CVD in clinical practice by controlling elevated lipid plasma levels.
The Task Force followed the quality criteria for development of
Table 1 Classes of recommendations
Classes of
recommendations
Suggested wording to
use
Class I Evidence and/or general agreement
that a given treatment or
effective.
Is recommended/is
indicated
Class II
Class IIa Weight of evidence/opinion is in
favour of usefulness/efficacy.
Should be considered
Class IIb May be considered
Class III Evidence or general agreement that
the given treatment or procedure
is not useful/effective, and in some
cases may be harmful.
Is not recommended
Definition
procedure is beneficial, useful,
Conflicting evidence and/or a
divergence of opinion about the
usefulness/efficacy of the given
treatment or procedure.
Usefulness/efficacy is less well
established by evidence/opinion.
Table 2 Levels of evidence
Level of
evidence A
Data derived from multiple randomized
clinical trials or meta-analyses.
Level of
evidence B
Data derived from a single randomized
clinical trial or large non-randomized
studies.
Level of
evidence C
Consensus of opinion of the experts and/
or small studies, retrospective studies,
registries.
ESC/EAS Guidelines3004
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
guidelines, which can be found at http://www.escardio.org/
Guidelines-&-Education/Clinical-Practice-Guidelines/Guidelinesdevelopment/Writing-ESC-Guidelines.
Recommendations are
graded in classes (Table 1) and in levels of evidence (Table 2).
This document has been developed for healthcare professionals
to facilitate informed communication with individuals about their
CV risk and the beneﬁts of adopting and sustaining a healthy lifestyle
and of early modiﬁcation of their CV risk. In addition, the guidelines
provide tools for healthcare professionals to promote up-to-date
intervention strategies and integrate these strategies into national
or regional prevention frameworks and to translate them into locally
delivered healthcare services, in line with the recommendations
of the World Health Organization (WHO) Global Status Report on
Noncommunicable Diseases 2010.5
A lifetime approach to CV risk is considered.6
This implies that
apart from improving lifestyle habits and reducing risk factor levels
in patients with established CVD and in those at increased risk of
developing CVD, healthy people of all ages should be encouraged
to adopt or sustain a healthy lifestyle. Healthcare professionals
play an important role in achieving this in their clinical practice.
1.3 Cost-effectiveness of prevention
In 2009, healthcare costs related to CVD in Europe amounted to
E106 billion, representing 9% of the total healthcare expenditure
across the European Union (EU).8
In the USA, direct annual costs of
CVD are projected to triple between 2010 and 2030.9
Thus, CVD
represents a considerable economic burden to society, and this necessitates
an effective approach to CVD prevention. There is consensus
in favour of an approach combining strategies to improve
CV health across the population at large from childhood onwards,
with actions to improve CV health in individuals at increased risk of
CVD or with established CVD.
Most studies assessing the cost-effectiveness of prevention of
CVD combine evidence from clinical research with simulation approaches,
while data from randomized controlled trials (RCTs)
are relatively scarce.7,10,11
Cost-effectiveness results strongly depend
on parameters such as the target population’s age, the overall
population risk of CVD and the cost of interventions. Hence, results
obtained in one country might not be valid in another. Furthermore,
changes such as the introduction of generic drugs can considerably
change cost-effectiveness.12
In general, lifestyle changes may be
more cost effective at the population level than drug treatments
(Table 3).
More than half of the reduction in CV mortality in the last three
decades has been attributed to population-level changes in CV risk
factors, primarily reductions in cholesterol and blood pressure levels
and smoking.13 – 16
This favourable trend is partly offset by increases
in other major risk factors, such as obesity and type 2
diabetes.13 – 16
Ageing of the population also contributes to increasing
the absolute number of CVD events.17
Several population-level interventions have proven to efﬁciently
affect lifestyle in individuals, leading to this success: awareness and
knowledge of how lifestyle risk factors lead to CVD increased in recent
decades and undoubtedly contributed to the decline in smoking
and cholesterol levels. Moreover, legislation promoting a healthy
lifestyle, such as reduced salt intake and smoking bans, are cost
effective in preventing CVD.18 –22
Lowering blood cholesterol levels using statins10,11,23 – 25
and improving
blood pressure control are also cost effective.26,27
Importantly,
a sizable portion of patients on hypolipidaemic or
antihypertensive drug treatment fail to take their treatment adequately
or to reach their therapeutic goals,28,29
with clinical and
economic consequences.30
Reinforcing measures aimed at improving
adherence to treatment is cost effective.31,32
It has been suggested that the prescription to the whole population
older than 55 years of age of a single pill containing a combination
of CV drugs (the polypill) could prevent as much as 80% of
CVD events33
and be cost effective.34
Part of the cost-effectiveness
of the polypill is due to improvement in adherence to treatment, but
which combination of drugs is most cost effective in which target
population remains to be assessed.35
Considerable evidence has quantiﬁed the relative efforts and
costs in relation to health impact. The efforts may be depicted in
the health impact pyramid (Figure 1), where interventions with the
broadest impact on populations represent the base and interventions
with considerable individual effort are at the top.36
The cost-effectiveness of CVD prevention has been calculated in
various contexts. According to the WHO, policy and environmental
changes could reduce CVD in all countries for ,US$1 per person
per year, while interventions at the individual level are considerably
more expensive.37
. A report from the National Institute for Health
and Care Excellence (NICE) estimated that a UK national programme
reducing population CV risk by 1% would prevent 25 000
CVD cases and generate savings of E40 million per year.38
Coronary
artery disease (CAD) mortality rates could be halved by only
Box 1 Key messages
• Prevention of CVD, either by lifestyle changes or medication, is costeffective
in many scenarios, including population-based approaches
and actions directed at high-risk individuals.
• Cost-effectiveness depends on several factors, including baseline CV
risk,cost of drugs or other interventions,reimbursement procedures,
and uptake of preventive strategies.
CV ¼ cardiovascular; CVD ¼ cardiovascular disease.
Table 3 Suggestions for implementing healthy
lifestyles
Recommendation Classa
Level b
Ref c
Measures aimed at implementing
healthy lifestyles are more costeffective
than drug interventions at
the population level.
IIa B 7
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
ESC/EAS Guidelines 3005
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
modest risk factor reduction,39
and it has been suggested that eight
dietary priorities alone could halve CVD death.40
There is consensus that all the levels of the pyramid should be targeted
but that emphasis should be put on the second level. Targeting
lower levels in the health impact pyramid will also address the
socio-economic divide in CV health, which has not diminished despite
major improvements in the treatment of CVD in recent
decades.9,10
2. Total cardiovascular risk
2.1 Total cardiovascular risk estimation
CV risk in the context of these guidelines means the likelihood of a
person developing a fatal or non-fatal atherosclerotic CV event over
a deﬁned period of time.
2.1.1 Rationale for assessing total cardiovascular disease
risk
All current guidelines on the prevention of CVD in clinical practice
recommend the assessment of total CAD or CV risk, because atherosclerotic
CVD is usually the product of a number of risk factors,
and prevention of CVD in a given person should be adapted to
his/her total CV risk: the higher the risk, the more intense the action
should be.
Many risk assessment systems are available and have been comprehensively
reviewed, including different Framingham models,41
Systemic Coronary Risk Estimation (SCORE),42
ASSIGN (CV risk
estimation model from the Scottish Intercollegiate Guidelines Net-
work),43
Q-Risk,44
Prospective Cardiovascular Munster Study
(PROCAM),45
Reynolds,46,47
CUORE,48
the Pooled Cohort equa-
tions49
and Globorisk.50
Most guidelines use one of these risk estimation
systems.50 –52
One of the advantages of the SCORE system is that it can be recalibrated
for use in different populations by adjustment for secular
changes in CVD mortality and risk factor prevalences. Calibrated
country-speciﬁc versions exist for Belgium, Cyprus, Czech Republic,
Germany, Greece, Poland, Slovakia, Spain, Switzerland and Sweden,
and country-speciﬁc electronic versions for Bosnia and Herzegovina,
Croatia, Estonia, France, Romania, Russian Federation and Turkey
can be found at http://www.heartscore.org. Other risk
estimation systems can also be recalibrated, but the process is easier
for mortality than for total events. The European Guidelines on
CVD prevention in clinical practice (version 2012)6
recommend
use of the SCORE system because it is based on large, representative
European cohort datasets.
Risk charts such as SCORE are intended to facilitate risk estimation
in apparently healthy persons with no documented CVD. Patients
who have had a clinical event such as acute coronary
syndrome (ACS) or a stroke are at very high risk of a further event
and automatically qualify for risk factor evaluation and management
(Table 6).
Simple principles of risk assessment, developed in these guidelines,
can be deﬁned as follows:
(1) Persons with
† documented CVD
† type 1 or type 2 diabetes
† very high levels of individual risk factors
† chronic kidney disease (CKD) (refer to section 9.9)
are automatically at very high or high total CV risk. No risk estimation
models are needed for them; they all need active management
of all risk factors.
(2) For all other people, the use of a risk estimation system such as
SCORE is recommended to estimate total CV risk since many
people have several risk factors that, in combination, may result
in unexpectedly high levels of total CV risk.
The SCORE system estimates the 10-year cumulative risk of a ﬁrst
fatal atherosclerotic event, whether heart attack, stroke or other
occlusive arterial disease, including sudden cardiac death. Risk estimates
have been produced as charts for high- and low-risk regions in
Europe (Figures 2 and 3). All International Classiﬁcation of Diseases
(ICD) codes that are related to deaths from vascular origin caused
by atherosclerosis are included. Some other systems estimate CAD
risk only.
The reasons for retaining a system that estimates fatal as opposed
to total fatal + non-fatal events are that non-fatal events are dependent
on deﬁnition, developments in diagnostic tests and methods
of ascertainment, all of which can vary, resulting in very
Counseling
and education
Clinical
interventions
Long-lasting protective
interventions
Changing the context to make
individuals'default decisions healthy
Socioeconomic factors
Increasing
population
impact
Increasing
individual
effort needed
Figure 1 Health impact pyramid.
Box 2 Gaps in evidence
• Most cost-effectiveness studies rely on simulation. More data are
needed,particularly from randomized controlled trials.
• The effectiveness of the polypill in primary prevention awaits further
investigation.
ESC/EAS Guidelines3006
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
variable multipliers to convert fatal to total events. In addition, total
event charts, in contrast to those based on mortality, cannot easily
be recalibrated to suit different populations.
Naturally, the risk of total fatal and non-fatal events is higher, and
clinicians frequently ask for this to be quantiﬁed. The SCORE data
indicate that the total CVD event risk is about three times higher
Figure 2 SCORE chart: 10-year risk of fatal cardiovascular disease (CVD) in populations at high CVD risk based on the following risk factors:
age, gender, smoking, systolic blood pressure, and total cholesterol. To convert the risk of fatal CVD to risk of total (fatal + nonfatal) hard CVD,
multiply by 3 in men and 4 in women, and slightly less in old people. Note: the SCORE chart is for use in people without overt CVD, diabetes,
chronic kidney disease, familial hypercholesterolaemia or very high levels of individual risk factors because such people are already at high-risk and
need intensive risk factor advice.
ESC/EAS Guidelines 3007
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
than the risk of fatal CVD for men, so that a SCORE risk of 5% translates
into a CVD risk of 15% of total (fatal + non-fatal) hard CVD
endpoints; the multiplier is 4 in women and lower in older
persons.
Clinicians often ask for thresholds to trigger certain interventions.
This is problematic since risk is a continuum and there is no threshold
at which, for example, a drug is automatically indicated. This is
true for all continuous risk factors such as plasma cholesterol or
Figure 3 SCORE chart: 10-year risk of fatal cardiovascular disease (CVD) in populations at low CVD risk based on the following risk factors:
age, gender, smoking, systolic blood pressure, and total cholesterol. To convert the risk of fatal CVD to risk of total (fatal + non-fatal) hard CVD,
multiply by 3 in men and 4 in women, and slightly less in old people. Note: the SCORE chart is for use in people without overt CVD, diabetes,
chronic kidney disease, familial hypercholesterolaemia, or very high levels of individual risk factors because such people are already at high-risk and
need intensive risk factor advice.
ESC/EAS Guidelines3008
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
systolic blood pressure. Therefore, the goals that are proposed in
this document reﬂect this concept.
A particular problem relates to young people with high levels of
risk factors; a low absolute risk may conceal a very high relative risk
requiring intensive lifestyle advice. To motivate young people not to
delay changing their unhealthy lifestyle, an estimate of their relative
risk, illustrating that lifestyle changes can reduce relative risk substantially,
may be helpful (Figure 4).
Another approach to this problem in young people is to use CV
risk age. The risk age of a person with several CV risk factors is the
age of a person with the same level of risk but with ideal levels of
risk factors. Thus a high-risk 40-year-old may have a risk age ≥60
years. Risk age is an intuitive and easily understood way of illustrating
the likely reduction in life expectancy that a young person with
a low absolute but high relative risk of CVD will be exposed to if
preventive measures are not adopted. Risk age can be estimated
visually by looking at the SCORE chart (as illustrated in Figure 5).
In this chart, the risk age is calculated compared with someone
with ideal risk factor levels, which have been taken as nonsmoking,
total cholesterol of 4 mmol/L (155 mg/dL) and systolic
blood pressure of 120 mmHg. Risk age is also automatically calculated
as part of the latest revision of HeartScore (http://www
.HeartScore.org).
Risk age has been shown to be independent of the CV endpoint
used,51,52
which bypasses the dilemma of whether to use a risk estimation
system based on CVD mortality or on the more attractive
but less reliable endpoint of total CVD events. Risk age can be used
in any population regardless of baseline risk or secular changes in
mortality, and therefore avoids the need for recalibration. At present,
risk age is recommended for helping to communicate about
risk, especially to younger people with a low absolute risk but a
high relative risk. It is not currently recommended to base treatment
decisions on risk age.
Lifetime risk is another approach to illustrating the impact of risk
factors that may be useful in younger people.53
The greater the
burden of risk factors, the higher the lifetime risk. This approach
produces higher risk ﬁgures for younger people because of their
longer exposure times. It is therefore more useful as a way of illustrating
risk than as a guide to treatment because therapeutic trials
have been based on a ﬁxed follow-up period and not on lifetime
risk and such an approach would likely lead to excessive use of drugs
in young people.
Another problem relates to old people. In some age categories
the majority, especially of men, will have estimated CV death risks
exceeding the 5–10% level, based on age (and gender) only,
even when other CV risk factor levels are relatively low. This could
lead to excessive use of drugs in the elderly and should be evaluated
carefully by the clinician. Recent work has shown that
b-coefﬁcients are not constant with ageing and that SCORE overestimates
risk in older people.54
This article includes illustrative
charts in subjects older than 65 years of age. While such subjects
beneﬁt from smoking cessation and control of hypertension and
hyperlipidaemia, clinical judgement is required to avoid side effects
from overmedication.
SCORE charts are available for both total cholesterol (TC) and
the TC:high-density lipoprotein cholesterol (HDL-C) ratio. However,
subsequent work on the SCORE database has shown that
HDL-C can contribute more to risk estimation if entered as a separate
variable as opposed to the ratio. For example, HDL-C modiﬁes
risk at all levels of risk as estimated from the SCORE
cholesterol charts.55
Furthermore, this effect is seen in both genders
and in all age groups, including older women. This is particularly
important at levels of risk just below the 5% threshold for
intensive risk modiﬁcation; many of these subjects will qualify for
intensive advice if their HDL-C is low. Charts including HDL-C
are available on the ESC website (http://www.escardio.org/
guidelines). The additional impact of HDL-C on risk estimation
is illustrated in Figures 6 and 7. In these charts, HDL-C is used
categorically. The electronic version of SCORE, HeartScore
(http://www.heartscore.org), has been modiﬁed to take HDL-C
Figure 4 Relative risk chart for 10-year cardiovascular mortality. Please note that this chart shows RELATIVE not absolute risk. The
risks are RELATIVE to 1 in the bottom left. Thus, a person in the top right hand box has a relative risk that is 12 times higher than a person in the
bottom left.
ESC/EAS Guidelines 3009
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
into account on a continuous basis, which is even better; we recommend
its use in order to increase the accuracy of the risk evaluation.
Overall, HDL-C has a modest but useful effect in reﬁning risk
estimation,56
but this may not be universal, as its effect may not be
seen in some low-risk populations, particularly with a relatively
high mean HDL-C level.57
2.1.2 How to use the risk estimation charts
When it comes to European countries and to countries with cardiology
societies that belong to the ESC, the low-risk charts should
be considered for use in Austria, Belgium, Cyprus, Czech Republic,
Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Israel,
Italy, Luxembourg, Malta, The Netherlands, Norway, Portugal,
San Marino, Slovenia, Spain, Sweden, Switzerland and the
United Kingdom. While any cut-off point is arbitrary and open
to debate, in these guidelines the cut-off points for calling a country
‘low risk’ are based on age-adjusted 2012 CVD mortality rates
(,225/100 000 in men and ,175/100 000 in women) (http://
apps.who.int/gho/data/node.main.A865CARDIOVASCULAR?
lang=en).
The high-risk charts should be considered in all other countries.
Of these, some are at very high risk, and the high-risk chart may
underestimate risk in these countries. These are countries with a
CVD mortality rate more than double the cut-off of low-risk countries
according to 2012 WHO statistics (http://apps.who.int/
gho/data/node.main.A865CARDIOVASCULAR?lang=en): ≥450/
100 000 for men or ≥350/100 000 for women (Albania, Algeria,
Armenia, Azerbaijan, Belarus, Bulgaria, Egypt, Georgia, Kazakhstan,
Kyrgyzstan, Latvia, FYR Macedonia, Republic of Moldova, Russian
Federation, Syrian Arab Republic, Tajikistan, Turkmenistan, Ukraine
and Uzbekistan). The remaining high-risk countries are Bosnia and
Herzegovina, Croatia, Estonia, Hungary, Lithuania, Montenegro,
Morocco, Poland, Romania, Serbia, Slovakia, Tunisia and Turkey.
Note that several countries have undertaken national recalibrations
Figure 5 Illustration of the risk age concept.
ESC/EAS Guidelines3010
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
Figure 6 Risk function without high-density lipoprotein-cholesterol (HDL-C) for women in populations at high cardiovascular disease risk, with
examples of the corresponding estimated risk when different levels of HDL-C are included.
Box 3 How to use the risk estimation charts
to the person’s blood pressure and TC. Risk estimates will need to be
adjusted upwards as the person approaches the next age category.
Risk is initially assessed on the level of TC and systolic blood pressure
before treatment, if known. The longer the treatment and the more
effective it is, the greater the reduction in risk, but in general it will not
be more than about one-third of the baseline risk. For example, for a
person on antihypertensive drug treatment in whom the pre-treatment
blood pressure is not known,if the total CV SCORE risk is 6%,then the
pre-treatment total CV risk may have been 9%.
Low-risk persons should be offered advice to maintain their low-risk
status.While no threshold is universally applicable,the intensity of advice
should increase with increasing risk.
The charts may be used to give some indication of the effects of reducing
risk factors, given that there will be a time lag before the risk reduces
and that the results of randomized controlled trials in general give better
their cumulative risk.
To estimate a person’s 10-year risk of CVD death, find the table for his/
her gender, smoking status, and age. Within the table find the cell nearest
estimates of benefits. In general, those who stop smoking rapidly halve
Box 4 Qualiﬁers
The charts can assist in risk assessment and management but must be
interpreted in light of the clinician’s knowledge and experience and of
the patient’s pre-test likelihood of CVD.
Risk will be overestimated in countries with a decreasing CVD mortality,
and underestimated in countries in which mortality is increasing.This is
dealt with by recalibration (www.heartscore.org).
Risk estimates appear lower in women than in men.However,risk is only
deferred in women; the risk of a 60-year-old woman is similar to that of
a 50-year-old man.Ultimately more women die from CVD than men.
Relative risks may be unexpectedly high in young persons,even if absolute
risk levels are low.The relative risk chart (Figure 4 ) and the estimated
risk age (Figure 5 ) may be helpful in identifying and counselling such
persons.
ESC/EAS Guidelines 3011
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
to allow for time trends in mortality and risk factor distributions.
Such charts are likely to represent current risk levels better.
Social deprivation and psychosocial stress set the scene for increased
risk.57
For those at intermediate risk, other factors, including
metabolic factors such as increased apolipoprotein B (apoB),
lipoprotein(a) (Lp(a)), triglycerides (TGs) or high-sensitivity
C-reactive protein (hs-CRP) or the presence of albuminuria, may
improve risk classiﬁcation. Many other biomarkers are also associated
with increased CVD risk, although few of these have been
shown to be associated with appreciable reclassiﬁcation. Total CV
risk will also be higher than indicated in the SCORE charts in asymptomatic
persons with abnormal markers of subclinical atherosclerotic
vascular damage detected by coronary artery calcium (CAC),
ankle-brachial index (ABI), pulse wave velocity or carotid ultrasonography.
In studies comparing these markers, CAC had the best reclassiﬁcation
ability.58 – 60
Subjects in need of reclassiﬁcation are those belonging to the
intermediate CV risk group. Therefore the use of methods to detect
Figure 7 Risk function without high-density lipoprotein-cholesterol (HDL-C) for men in populations at high cardiovascular disease risk, with
examples of the corresponding estimated risk when different levels of HDL-C are included.
Box 5 Factors modifying SCORE risks
Social deprivation–the origin of many of the causes of CVD.
Obesity and central obesity as measured by the body mass index and
waist circumference,respectively.
Physical inactivity.
Psychosocial stress including vital exhaustion.
Family history of premature CVD (men:<55 years;women:<60 years).
Major psychiatric disorders.
Left ventricular hypertrophy.
Chronic kidney disease.
Obstructive sleep apnoea syndrome.
Autoimmune and other inflammatory disorders.
Treatment for human immunodeficiency virus (HIV) infection.
Atrial fibrillation.
ESC/EAS Guidelines3012
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
these markers should be of interest in that group (class IIa, level of
evidence B). Cut-off values that should be used in considering these
markers as modiﬁers of total CV risk are CAC score .400 Agatston
units, ABI ,0.9 or .1.40, aortic pulse wave velocity of 10 m/s and
the presence of plaques on carotid ultrasonography. Some factors
such as a high HDL-C or apoA1 and a family history of longevity
can also reduce risk.
2.2 Risk levels
A total CV risk estimate is part of a continuum. The cut-off points
that are used to deﬁne high risk are in part arbitrary and based on
the risk levels at which beneﬁt is evident in clinical trials. In clinical
practice, consideration should be given to practical issues in relation
to the local healthcare and health insurance systems. Not only
should those at high risk be identiﬁed and managed, but those at
moderate risk should also receive professional advice regarding lifestyle
changes; in some cases drug therapy will be needed to control
their plasma lipids.
In these subjects we realistically can
– prevent further increase in total CV risk,
– increase awareness of the danger of CV risk,
– improve risk communication and
– promote primary prevention efforts.
Low-risk people should be given advice to help them maintain this
status. Thus the intensity of preventive actions should be tailored to
the patient’s total CV risk. The strongest driver of total CV risk is
age, which can be considered as ‘exposure time’ to risk factors.
This raises the issue that most older people in high-risk countries
who smoke would be candidates for lipid-lowering drug treatment
even if they have satisfactory blood pressure levels. The clinician is
strongly recommended to use clinical judgment in making
therapeutic decisions in older people, with a ﬁrm commitment to
implementing lifestyle measures such as smoking cessation in the
ﬁrst instance.
With these considerations one can propose the following levels
of total CV risk (Table 4).
2.2.1 Risk-based intervention strategies
Table 5 presents suggested intervention strategies as a function of
total CV risk and low-density lipoprotein cholesterol (LDL-C) level.
This graded approach is based on evidence from multiple
meta-analyses and individual RCTs, which show a consistent and
graded reduction in CVD risk in response to reductions in TC
and LDL-C levels.61 – 71
These trials are consistent in showing that
the higher the initial LDL-C level, the greater the absolute reduction
in risk, while the relative risk reduction remains constant at any given
baseline LDL-C level. Advice on individual drug treatments is given
in section 6.
Table 4 Risk categories
Very high-risk Subjects with any of the following:
• Documented cardiovascular disease (CVD),
clinical or unequivocal on imaging.Documented
CVD includes previous myocardial infarction
(MI),acute coronary syndrome (ACS),
coronary revascularisation (percutaneous
coronary intervention (PCI),coronary artery
bypass graft surgery (CABG)) and other arterial
revascularization procedures,stroke and
transient ischaemic attack (TIA),and peripheral
arterial disease (PAD).Unequivocally
documented CVD on imaging is what has been
shown to be strongly predisposed to clinical
events, such as significant plaque on coronary
angiography or carotid ultrasound.
• DM with target organ damage such as
proteinuria or with a major risk factor such
as smoking,hypertension or dyslipidaemia.
• Severe CKD (GFR <30 mL/min/1.73 m2
).
• A calculated SCORE ≥10% for 10-year risk of
fatal CVD.
High-risk Subjects with:
• Markedly elevated single risk factors,in
particular cholesterol >8 mmol/L (>310 mg/dL)
(e.g.in familial hypercholesterolaemia) or
BP ≥180/110 mmHg.
• Most other people with DM (some young
people with type 1 diabetes may be at low or
moderate risk).
• Moderate CKD (GFR 30–59 mL/min/1.73 m2
).
• A calculated SCORE ≥5% and <10% for 10-year
risk of fatal CVD.
Moderate-risk SCORE is ≥1% and <5% for 10-year risk of fatal
CVD.
Low-risk SCORE <1% for 10-year risk of fatal CVD.
ACS ¼ acute coronary syndrome; AMI ¼ acute myocardial infarction; BP ¼ blood
pressure; CKD ¼ chronic kidney disease; DM ¼ diabetes mellitus; GFR ¼ glomerular
ﬁltration rate; PAD ¼ peripheral artery disease; SCORE ¼ systematic coronary risk
estimation; TIA ¼ transient ischaemic attack.
Box 6 Key messages
In apparently healthy persons, CVD risk is most frequently the result
of multiple, interacting risk factors. This is the basis for total CV risk
estimation and management.
men >40 years old and in women >50 years of age or post-menopausal.
A risk estimation system such as SCORE can assist in making logical
management decisions, and may help to avoid both under- or over-
treatment.
Certain individuals declare themselves to be at high or very high CVD
risk without needing risk scoring and require immediate attention to all
risk factors.
This is true for patients with documented CVD,diabetes or CKD.
All risk estimation systems are relatively crude and require attention to
qualifying statements.
Additional factors affecting risk can be accommodated in electronic risk
estimation systems such as HeartScore (www.heartscore.org).
with one risk factor, risk can still be reduced by trying harder with the
others.
Risk factor screening including the lipid profile should be considered in
The total risk approach allows flexibility–if perfection cannot be achieved
ESC/EAS Guidelines 3013
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
3. Evaluation of laboratory lipid
and apolipoprotein parameters
Screening for dyslipidaemia is always indicated in subjects with
clinical manifestations of CVD, in clinical conditions associated
with increased risk for CVD and whenever risk factor screening
is considered. In several clinical conditions, dyslipidaemia may
contribute to an increased risk of developing CVD. Autoimmune
chronic inﬂammatory conditions such as rheumatoid arthritis, systemic
lupus erythematosus (SLE) and psoriasis are associated with
increased CV risk and dyslipidaemia. Furthermore, in women, diabetes
or hypertension during pregnancy are risk indicators, and in
men, erectile dysfunction. Patients with CKD are also at increased
risk for CVD events and should be screened for dyslipidaemias.
Clinical manifestations of genetic dyslipidaemias, including xanthomas,
xanthelasmas and premature arcus cornealis (,45
years), should be sought because they may signal the presence
of a severe lipoprotein disorder, especially familial hypercholesterolaemia
(FH), which is the most frequent monogenic disorder
Table 5 Intervention strategies as a function of total cardiovascular risk and low-density lipoprotein cholesterol level
Total CV risk
(SCORE)
%
LDL-C levels
<70 mg/dL
<1.8 mmol/L
70 to <100 mg/dL
1.8 to <2.6 mmol/L
100 to <155 mg/dL
2.6 to <4.0 mmol/L
155 to <190 mg/dL
4.0 to <4.9 mmol/L
≥190 mg/dL
≥4.9 mmol/L
<1 No lipid intervention No lipid intervention No lipid intervention No lipid intervention
Lifestyle intervention,
consider drug if
uncontrolled
Classa
/Levelb
I/C I/C I/C I/C IIa/A
≥1 to <5 No lipid intervention No lipid intervention
Lifestyle intervention,
consider drug if
uncontrolled
Lifestyle intervention,
consider drug if
uncontrolled
Lifestyle intervention,
consider drug if
uncontrolled
Classa
/Levelb
I/C I/C IIa/A IIa/A I/A
≥5 to <10,
or high-risk
No lipid intervention
Lifestyle intervention,
consider drug if
uncontrolled
Lifestyle intervention
and concomitant drug
intervention
Lifestyle intervention
and concomitant drug
intervention
Lifestyle intervention
and concomitant drug
intervention
Classa
/Levelb
IIa/A IIa/A IIa/A I/A I/A
≥10 or
very high-risk
Lifestyle intervention,
consider drugc
Lifestyle intervention
and concomitant drug
intervention
Lifestyle intervention
and concomitant drug
intervention
Lifestyle intervention
and concomitant drug
intervention
Lifestyle intervention
and concomitant drug
intervention
Classa
/Levelb
IIa/A IIa/A I/A I/A I/A
CV ¼ cardiovascular; LDL-C ¼ low-density lipoprotein cholesterol; SCORE ¼ Systematic Coronary Risk Estimation.
a
Class of recommendation.
b
Level of evidence.
c
In patients with myocardial infarction, statin therapy should be considered irrespective of total cholesterol levels
Table 6 Recommendations for risk estimation
Recommendations Classa
Level b
Total risk estimation using a risk estimation
system such as SCORE is recommended for
asymptomatic adults >40 years of age without
evidence of CVD, diabetes, CKD or familial
hypercholesterolaemia.
I C
High and very high-risk individuals can be
detected on the basis of documented CVD,
diabetes mellitus, moderate to severe renal
disease, very high levels of individual risk
factors, familial hypercholesterolaemia or a high
SCORE risk and are a high priority for intensive
advice with regard to all risk factors.
I C
CVD ¼ cardiovascular disease; SCORE ¼ Systemic Coronary Risk Estimation.
a
Class of recommendation.
b
Level of evidence.
ESC/EAS Guidelines3014
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
associated with premature CVD. Antiretroviral therapies may
be associated with accelerated atherosclerosis. Screening for
dyslipidaemias is also indicated in patients with peripheral arterial
disease (PAD) or in the presence of increased carotid intimamedia
thickness (CIMT) or carotid plaques.
Screening for dyslipidaemias should be considered in all adult
men ≥40 years of age and in women ≥50 years of age or postmenopausal,
particularly in the presence of other risk factors (see
section 2.2). It is also indicated to screen offspring of patients with
severe dyslipidaemia and to follow them in specialized clinics if affected.
Similarly, screening for signiﬁcant lipoprotein disorders of
family members of patients with premature CVD is recommended
(see section 10) (Table 7).
The suggested analyses used for baseline lipid evaluation are TC,
TGs, HDL-C, LDL-C calculated with the Friedewald formula unless
TGs are elevated (.4.5 mmol/L or .400 mg/dL) or with a direct
method, and non-HDL-C. When available, apoB can be considered
as an equivalent to non-HDL-C. Additional plasma lipid analyses
that may be considered are Lp(a), apoB:apoA1 ratio and nonHDL-C:HDL-C
ratio (Tables 7 and 8).
The direct methods for HDL-C and LDL-C analysis are currently
widely used and are reliable in patients with normal lipid levels.72
However, in hypertriglyceridaemia (HTG) these methods have
been found to be unreliable, with variable results and variations between
the commercially available methods. Therefore, under these
conditions, the values obtained with direct methods may be over- or
underestimating the LDL-C and HDL-C levels. The use of
non-HDL-C may overcome some of these problems, but it is still
dependent on a correct analysis of HDL-C. An alternative to
non-HDL-C may be the analysis of apoB. The analysis of apoB is accurate,
with small variations, and is recommended as an alternative
when available. Near patient testing is also available using dry chemistry
methods. These methods may give a crude estimate, but should
be veriﬁed by analysis in an established certiﬁed laboratory.
3.1 Fasting or non-fasting?
Traditionally blood samples for lipid analysis have been drawn in the
fasting state. As recently shown, fasting and non-fasting sampling give
similar results for TC, LDL-C and HDL-C. TGs are affected by food,
resulting in, on average, an 0.3 mmol/L (27 mg/dL) higher plasma
level, depending on the composition and the time frame of the last
meal. For risk estimation, non-fasting has a prediction strength similar
to fasting, and non-fasting lipid levels can be used in screening and
in general risk estimation.73 – 76
It should be emphasized, however,
that the risk may be underestimated in patients with diabetes, because
in one study, patients with diabetes had up to 0.6 mmol/L lower
LDL-C in non-fasting samples.77
Furthermore, to characterize
Table 7 Recommendations for lipid analyses in
cardiovascular disease risk estimation
Recommendations Classa
Level b
TC is to be used for the estimation of total CV
risk by means of the SCORE system.
I C
LDL-C is recommended to be used as the
primary lipid analysis for screening, risk
estimation, diagnosis and management. HDL-C
is a strong independent risk factor and is
recommended to be used in the HeartScore
algorithm.
I C
TG adds information on risk and is indicated for
risk estimation.
I C
Non-HDL-C is a strong independent risk factor
and should be considered as a risk marker,
especially in subjects with high TG.
I C
ApoB should be considered as an alternative
risk marker whenever available, especially in
subjects with high TG.
IIa C
Lp(a) should be considered in selected cases
at high-risk, in patients with a family history
subjects with borderline risk.
IIa C
The ratio apoB/apoA1 may be considered as an
alternative analysis for risk estimation.
IIb C
The ratio non-HDL-C/HDL-C may be
considered as an alternative but HDL-C used in
HeartScore gives a better risk estimation.
IIb C
of premature CVD, and for reclassification in
Apo ¼ apolipoprotein; CKD ¼ chronic kidney disease; CVD ¼ cardiovascular
disease; HDL-C ¼ high-density lipoprotein-cholesterol; LDL-C ¼ low-density
lipoprotein-cholesterol; Lp ¼ lipoprotein; SCORE ¼ Systemic Coronary Risk
Estimation; TC ¼ total cholesterol; TG ¼ triglycerides.
a
Class of recommendation.
b
Level of evidence.
Table 8 Recommendations for lipid analyses for
characterization of dyslipidaemias before treatment
Recommendations Classa
Level b
LDL-C has to be used as the primary lipid
analysis.
I C
It is recommended to analyse HDL-C before
treatment.
I C
TG adds information about risk, and is indicated
for diagnosis and choice of treatment.
I C
Non-HDL-C is recommended to be calculated,
especially in subjects with high TG.
I C
When available, apoB should be an alternative
to non-HDL-C.
IIa C
Lp(a) should be recommended in selected cases
risk, and in subjects with a family history of
premature CVD (see Box 7).
IIa C
TC may be considered but is usually not enough
for the characterization of dyslipidaemia before
initiation of treatment.
IIb C
at high-risk, for reclassification at borderline
Apo ¼ apolipoprotein; CVD ¼ cardiovascular disease; HDL-C ¼ high-density
lipoprotein-cholesterol; LDL-C ¼ low-density lipoprotein-cholesterol; Lp ¼
lipoprotein; TC ¼ total cholesterol; TG ¼ triglycerides.
a
Class of recommendation.
b
Level of evidence.
ESC/EAS Guidelines 3015
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
severe dyslipidaemias further, and for follow-up of patients with
HTG, fasting samples are recommended.
3.2 Intra-individual variation
There is a considerable intra-individual variation in plasma lipids.
Variations of 5–10% for TC and .20% for TGs have been reported,
particularly in those patients with HTG. This is to some extent due
to analytical variation, but is also due to environmental factors
such as diet and physical activity, and a seasonal variation, with
higher levels of TC and HDL-C during the winter.78
3.3. Lipid and lipoprotein analyses
Throughout this section it should be noted that most risk estimation
systems and virtually all drug trials are based on TC and LDL-C, and
that clinical beneﬁt from using other measures, including apoB,
non-HDL-C and various ratios, while sometimes logical, has largely
been based on post hoc analyses. Non-HDL-C has recently been
proposed by locally developed guidelines such as NICE using the
QRISK2 risk calculator.79,80
While the role of the alternative analyses
is being established, traditional measures of risk such as TC,
LDL-C and HDL-C remain robust and supported by a major evidence
base. Furthermore, multiple clinical trials have established beyond
all reasonable doubt that, at least in high-risk subjects,
reduction of TC or LDL-C is associated with statistically and clinically
signiﬁcant reductions in CV events and mortality. Therefore, TC
and LDL-C remain the primary targets recommended in these
guidelines. However, for several reasons non-HDL-C and apoB
are recommended as secondary targets. In patients with elevated
TG levels, the extra risk carried with TG-rich lipoproteins is taken
into account. Furthermore, some of the methodological problems
with the direct methods for HDL-C and LDL-C may be reduced.
3.3.1 Total cholesterol
TC is recommended to be used to estimate total CV risk by means
of the SCORE system. In individual cases, however, TC may be misleading.
This is especially so in women, who often have higher
HDL-C levels, and in subjects with diabetes or with high TGs,
who often have low HDL-C levels. For an adequate risk analysis,
at least LDL-C and HDL-C should be analysed. Note that assessment
of total risk is not required in patients with familial hyperlipidaemia
(including FH) or those with TC .7.5 mmol/L (290 mg/dL).
These patients are always at high risk and should receive special
attention.
3.3.2 Low-density lipoprotein cholesterol
In most clinical studies LDL-C has been calculated using the Friedewald
formula.
Friedewald formula, in mmol/L: LDL-C ¼ TC 2 HDL-C 2 (TG/
2.2); in mg/dL: LDL-C ¼ TC 2 HDL-C 2 (TG/5).
The calculated value of LDL-C is based on a number of
assumptions:
† Methodological errors may accumulate since the formula necessitates
three separate analyses of TC, TGs and HDL-C.
† A constant cholesterol:TG ratio in very low-density lipoprotein
(VLDL) is assumed. With high TG values (.4.5 mmol/L or
.400 mg/dL), the formula cannot be used.
† The Friedewald formula may be unreliable when blood is obtained
under non-fasting conditions. Under these conditions,
non-HDL-C may be determined.
Despite its limitations, the calculated LDL-C value is still widely
used. With very low LDL-C or in patients with high TGs, the Friedewald
formula may underestimate LDL-C, even giving negative values.
Direct methods for the determination of LDL-C are available
and are now widely used. In general, comparisons between calculated
and direct LDL-C show good agreement.81
Several of the limitations
of the Friedewald formula may be overcome with the direct
methods. However, the direct methods have been found to be unreliable
in patients with HTG and should be used with caution in
these cases72
; also, they may underestimate very low values of
LDL-C. Non-HDL-C or apoB should, under these circumstances,
be considered as an alternative.
3.3.3 Non-high-density lipoprotein cholesterol
Non-HDL-C is used as an estimation of the total amount of
atherogenic lipoproteins in plasma (VLDL, VLDL remnants,
intermediate-density lipoprotein (IDL), LDL, Lp(a)) and relates
well to apoB levels. Non-HDL-C is easily calculated from TC minus
HDL-C. Some recent guidelines recommend non-HDL-C as a better
risk indicator than LDL-C.82
Several analyses have been published comparing these variables in
risk algorithms, but data are inconclusive. In some reports
non-HDL-C is superior, but in others, LDL-C and non-HDL-C
are reported to give similar information.83 – 85
Non-HDL-C has been shown to have a strong predictive power,
and although the scientiﬁc background from randomized trials is
weaker, there are practical aspects of using non-HDL-C instead of
LDL-C in certain situations. Non-HDL-C is simple to calculate and
does not require additional analyses. Both Friedewald’s formula
and direct LDL-C estimations have limitations in subjects with
HTG and in subjects with very low LDL-C. Non-HDL-C also includes
the atherogenic TG-rich lipoproteins (VLDL, IDL and
remnants), which is essential considering the recent information
from genome-wide association studies (GWASs) and Mendelian
randomization76,86 – 89
supporting TGs and remnant particles as
causative factors in atherogenesis.
Since all trials use LDL-C, we still recommend this as the primary
treatment target. However, non-HDL-C should be used as a secondary
target when the LDL-C goal is reached. Goals for
non-HDL-C are easily calculated as LDL-C goals plus 0.8 mmol/L
(30 mg/dL).
3.3.4 High-density lipoprotein cholesterol
Low HDL-C has been shown to be a strong and independent risk
factor in several studies and is included in most of the risk estimation
tools available, including HeartScore. Very high levels of HDL-C
have consistently not been found to be associated with atheropro-
tection.90
Based on epidemiological data, levels of HDL-C associated
with increased risk for men are ,1.0 mmol/L (40 mg/dL)
and for women are ,1.2 mmol/L (48 mg/dL). The causative role
of HDL-C for protection against CVD has been questioned in several
studies utilizing Mendelian randomization.87,89,91,92
Recent studies
suggest that HDL has a complex role in atherogenesis and that
the presence of dysfunctional HDL may be more relevant to the
ESC/EAS Guidelines3016
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
development of atherosclerosis than the HDL-C level.93 – 95
Most
available assays are of high quality, but the method used should be
evaluated against the available reference methods and controlled in
international quality programmes. It should also be considered that
HTG might interfere with the direct HDL-C assays.72
3.3.5 Triglycerides
TGs are determined by accurate enzymatic techniques. A rare error
occurs in patients with hyperglycerolaemia, where falsely very high
values for TGs are detected.
High TG levels are often associated with low HDL-C and high levels
of small dense LDL particles. In a number of meta-analyses, TGs
has been shown to be an independent risk factor.96,97
Furthermore,
recent genetic data support the contention that elevated TG levels
are a direct cause of CV disease.76,88
Recent studies suggest that non-fasting TGs may carry information
regarding remnant lipoproteins associated with increased
risk.76,86,98,99
For general screening and risk evaluation, non-fasting
TGs can be used.
3.3.6 Apolipoproteins
From a technical point of view, there are advantages in the determination
of apoB and apoA1. Good immunochemical methods
are available and easily run in conventional autoanalysers. The analytical
performance is good and the assays do not require fasting
conditions and are not sensitive to markedly elevated TG levels.
Apolipoprotein B. ApoB is the major apolipoprotein of the atherogenic
lipoprotein families (VLDL, IDL and LDL). ApoB is a good estimate
of the number of these particles in plasma. This might be of
special importance in the case of high concentrations of small dense
LDL. Several prospective studies have shown that apoB is equal to
LDL-C and non-HDL-C in risk prediction. ApoB has not been evaluated
as a primary treatment target in clinical trials, but several post
hoc analyses of clinical trials suggest that apoB may be not only a risk
marker, but also a treatment target.100
A major disadvantage of
apoB is that it is not included in algorithms for calculation of global
risk, and it has not been a predeﬁned treatment target in controlled
trials. Recent data from a meta-analysis83,90
indicate that apoB does
not provide any beneﬁt beyond non-HDL-C or traditional lipid ra-
tios.101
Likewise, apoB provided no beneﬁt beyond traditional lipid
markers in people with diabetes in the Fenoﬁbrate Intervention and
Event Lowering in Diabetes (FIELD) study.102
In contrast, in another
meta-analysis of LDL-C, non-HDL-C and apoB, the latter was superior
as a marker of CV risk.103
ApoB can be used as a secondary
target, as suggested for non-HDL-C, when analysis for apoB is
available.
Apolipoprotein A1. ApoA1 is the major protein of HDL-C and provides
a satisfactory estimate of HDL-C concentration. However,
each HDL particle may carry from one to ﬁve apoA1 molecules.
Plasma apoA1 levels ,120 mg/dL for men and ,140 mg/dL for
women correspond approximately to what is considered as low
for HDL-C.
Apolipoprotein B:apolipoprotein A1 ratio, total cholesterol:highdensity
lipoprotein cholesterol ratio and non-high-density lipoprotein
cholesterol:high-density lipoprotein cholesterol ratio. Ratios
between atherogenic lipoproteins and HDL-C or apoA1
(TC:HDL-C, non-HDL-C:HDL-C, apoB:apoA1) are useful for risk
estimation, but not for diagnosis or as treatment targets. The components
of the ratio have to be considered separately.
Apolipoprotein CIII. ApoCIII has been identiﬁed as a potentially important
new risk factor.104 –106
ApoCIII is a key regulator of TG metabolism,
and high apoCIII plasma levels are associated with high
plasma VLDL and plasma TGs. Furthermore, loss of function mutations
are associated with low TGs as well as with reduced risk
for CVD.106,107
ApoCIII has been identiﬁed as a new potential therapeutic
target that is currently being studied, but whether it has a role
in clinical practice is unknown and its measurements on a routine
basis are not encouraged.108
3.3.7 Lipoprotein(a)
Lp(a) has been found in several studies to be an additional independent
risk marker; indeed, genetic data show it to be causal in the pathophysiology
of atherosclerotic vascular disease and aortic stenosis.109–
111
Lp(a) has properties in common with LDL, but it contains a unique
protein, apolipoprotein(a) [apo(a)], that is structurally homologous
to plasminogen. The plasma level of Lp(a) is to a major extent genetically
determined. Several methods for determination of Lp(a) are
available, but standardization between assays is needed.112
The measurement
of Lp(a) is particularly stable over time. Plasma Lp(a) is not
recommended for risk screening in the general population; however,
Lp(a) measurement should be systematically considered in people
with high CVD risk or a strong family history of premature atherothrombotic
disease (Box 7).109
The risk is regarded as signiﬁcant
when Lp(a) is above the 80th percentile (50 mg/dL).109
Including
Lp(a) in risk evaluation has been shown to give a correct reclassiﬁca-
tion113,114
and should be considered in patients on the borderline between
high and moderate risk.
Reduction of Lp(a) has been shown with several of the
emerging lipid-lowering drugs. Proprotein convertase subtilisin/
kexin type 9 (PCSK9) inhibitors and nicotinic acid reduce Lp(a) by
30%.115 –117
An effect on CVD events targeting Lp(a) has not been
shown. Antisense drugs targeting the Lp(a) gene reduce the circulating
levels of this protein by up to 80%. A reasonable option for patients
at risk with high Lp(a) is an intensiﬁed treatment of the
modiﬁable risk factors, including LDL-C.
3.3.8 Lipoprotein particle size
Lipoproteins are heterogeneous, and evidence suggests that
subclasses of LDL and HDL may contribute differently to estimation
Box 7 Individuals who should be considered for
lipoprotein(a) screening
Individuals with:
• Premature CVD
• Familial hypercholesterolaemia
•A family history of premature CVD and/or elevated Lp(a)
• Recurrent CVD despite optimal lipid-lowering treatment
• ≥5% 10-year risk of fatal CVD according to SCORE
ESC/EAS Guidelines 3017
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
of the risk of CVD.118
However, the causal relation of subclasses to
atherosclerosis is unclear. Determination of small dense LDL may
be regarded as an emerging risk factor and may be used in the future,
but it is not currently recommended for risk estimation.119
3.3.9 Genotyping
Several genes have been associated with CVD. Large GWASs have
been published for coronary heart disease (CHD), as well as for associated
biomarkers and risk factors. At present, the use of genotyping
for risk estimation is not recommended since known risk loci
account for only a small proportion of risk.120
For the diagnosis of
speciﬁc genetic hyperlipidaemias, genotyping of apolipoprotein E
(apoE) and of genes associated with FH [low-density lipoprotein receptors
(LDLRs), apoB and PCSK9] should be considered. In FH, a
genetic diagnosis is important for family screening, to establish the
diagnosis in patients with borderline LDL-C and to improve patient
adherence to therapy.121
ApoE is present in three isoforms (apoE2, apoE3 and apoE4). ApoE
genotyping is used primarily for the diagnosis of dysbetalipoproteinaemia
(apoE2 homozygosity) and is indicated in cases with severe
combined hyperlipidaemia. With increasing knowledge about common
polymorphisms and lipoproteins, the importance of a polygenic
background to familial hyperlipidaemias is emphasized.67,122
Table 7 lists recommendations for lipid analyses in CVD risk
estimation, Table 8 lists recommendations for lipid analyses for characterization
of dyslipidaemias before treatment and Table 9 lists
recommendations for lipid analyses as treatment targets in the
prevention of CVD.
4. Treatment targets
In both the 2011 EAS/ESC guidelines for the management of
dyslipidaemias125
and the American Heart Association/American
College of Cardiology (AHA/ACC) guidelines on the treatment
of blood cholesterol to reduce atherosclerotic CV risk in
adults,71
the importance of LDL-C lowering to prevent CVD is
strongly emphasized. The approaches that are proposed to
reach that LDL-C reduction are different. The task force
charged with the development of the 2016 EAS/ESC updated
guidelines on dyslipidaemias examined this issue in depth. It
was recognized that the US expert panel conﬁned itself to a
simple, hard source of evidence coming from results in RCTs.
Despite this, there has not been an RCT to support the
AHA/ACC recommendation for the use of high-dose statins
in all high-risk people regardless of baseline LDL-C level. The
European Task Force felt that limiting the current knowledge
on CV prevention only to results from RCTs reduces the exploitation
of the potential that is available for prevention of
CVD. It is the concordance of the conclusions from many different
approaches (from basic science, clinical observations, genetics, epidemiology,
RCTs, etc.) that contributes to the understanding of the
causes of CVD and to the potential of prevention. The task force is
aware of the limitations of some of the sources of evidence and
accepts that RCTs have not examined different LDL-C goals systematically,
but felt that it was appropriate to look at the totality
of the evidence. Indeed, the task force accepts that the choice of
any given target goal for LDL-C may be open to debate given the
continuous nature of the relationship between LDL-C reduction
and reduction in risk. Particular consideration was given to results
from systematic reviews conﬁrming the dose-dependent reduction
in CVD with LDL-C lowering; the greater the LDL-C reduction,
the greater the CV risk reduction.65,66
The beneﬁts related to
LDL-C reduction are not speciﬁc for statin therapy.63
No level
of LDL-C below which beneﬁt ceases or harm occurs has been
deﬁned.
There is considerable individual variability in the LDL-C response
to dietary and drug treatments,61
which is traditionally
taken to support a tailored approach to management. Total
CV risk reduction should be individualized, and this can be
more speciﬁc if goals are deﬁned. The use of goals can also
aid patient–doctor communication. It is judged likely that a
goal approach may facilitate adherence to treatment, although
this consensus opinion has not been fully tested. For all these
reasons the European Task Force retains a goal approach to
lipid management and treatment goals are deﬁned, tailored
to the total CV risk level. There is also evidence suggesting
that lowering LDL-C beyond the goals that were set in
the previous EAS/ESC guidelines is associated with fewer
CVD events.126
Therefore, it seems appropriate to reduce
LDL-C as low as possible, at least in patients at very high
CV risk.
Table 9 Recommendations for lipid analyses as
treatment targets in the prevention of cardiovascular
disease
Recommendations Classa
Level b
Ref c
LDL-C is recommended as the
primary target for treatment.
I A 64, 68
TC should be considered as a
treatment target if other analyses
are not available.
IIa A 64, 123
Non-HDL-C should be considered
as a secondary treatment target.
IIa B 103
ApoB should be considered as a
secondary treatment target, when
available.
IIa B 103, 124
HDL-C is not recommended as a
target for treatment.
III A 92, 93
The ratios apoB/apoA1 and
non-HDL-C/HDL-C are not
recommended as targets for
treatment.
III B 103
Apo ¼ apolipoprotein; HDL-C ¼ high-density lipoprotein-cholesterol; LDL-C ¼
low-density lipoprotein-cholesterol; TC ¼ total cholesterol.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
ESC/EAS Guidelines3018
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
The lipid goals are part of a comprehensive CV risk reduction
strategy, summarized in Table 10. The rationale for the
non-lipid targets are given in the 2016 ESC Joint Prevention
guidelines.485
The targeted approach to lipid management is primarily aimed at
reducing LDL-C. For patients at a very high total CV risk, the goal is
an LDL-C ,1.8 mmol/L (70 mg/dL). At least a 50% reduction from
baseline (if .1.8 mmol/L) should also be achieved. For subjects at
high total CV risk, the goal is an LDL-C level ,2.6 mmol/L
(100 mg/dL). At least a 50% reduction from baseline [if
.2.6 mmol/L (100 mg/dL)] should also be achieved. In people at
moderate total CV risk, the LDL-C goal is ,3 mmol/L (115 mg/
dL) (Table 11).
When secondary targets are used the recommendations are
– non-HDL-C ,2.6 mmol/L (100 mg/dL) and ,3.4 mmol/L
(130 mg/dL) in subjects at very high and high total CV risk,
respectively (Class IIa, Level B).100,130
– apoB ,80 mg/dL and ,100 mg/dL in those at very high and high
total CV risk, respectively (Class IIa, Level B).100,131
Table 11 Recommendations for treatment goals for
low-density lipoprotein-cholesterol
Recommendations Classa
Level b
Ref c
In patients at VERY HIGH CV riskd
,
an LDL-C goal of <1.8 mmol/L
(70 mg/dL) or a reduction of at
least 50% if the baseline LDL-Ce
is
between 1.8 and 3.5 mmol/L
(70 and 135 mg/dL) is
recommended.
I B
61, 62,
65, 68,
69, 128
In patients at HIGH CV riskd
, an
LDL-C goal of <2.6 mmol/L
(100 mg/dL), or a reduction of at
least 50% if the baseline LDL-Ce
is
between 2.6 and 5.2 mmol/L
(100 and 200 mg/dL) is
recommended.
I B 65, 129
In subjects at LOW or MODERATE
riskd
an LDL-C goal of <3.0 mmol/L
(<115 mg/dL) should be considered.
IIa C CV
¼ cardiovascular; LDL-C ¼ low-density lipoprotein-cholesterol.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
d
For deﬁnitions see section 2.2.
e
The term “baseline LDL-C” refers to the level in a subject not taking any lipid
lowering medication.
Table 10 Treatment targets and goals for
cardiovascular disease prevention
Smoking No exposure to tobacco in any form.
Diet Healthy diet low in saturated fat with a focus on whole
Physical
activity
2.5–5 h moderately vigorous physical activity per week or
30–60 min most days.
Body
weight
BMI 20–25 kg/m2
, waist circumference <94 cm (men) and
<80 cm (women).
Blood
pressure
<140/90 mmHga
Lipids
LDL-C is
the
primary
targetb
Very high-risk: LDL-C <1.8 mmol/L
(70 mg/dL) or a reduction of at least 50% if the baselineb
is between 1.8 and 3.5 mmol/L (70 and 135 mg/dL).
High-risk: LDL-C <2.6 mmol/L (100 mg/dL) or
a reduction of at least 50% if the baselineb
is between 2.6
and 5.2 mmol/L (100 and 200 mg/dL).
Low to moderate risk: LDL-C <3.0 mmol/L
(115 mg/dL).
Non-HDL-C secondary targets are <2.6, 3.4 and
3.8 mmol/L (100, 130 and 145 mg/dL) for very high-,
high- and moderate-risk subjects, respectively.
HDL-C:no target,but >1.0 mmol/L (40 mg/dL) in men and
>1.2 mmol/L (48 mg/dL) in women indicates lower risk.
TG: no target but <1.7 mmol/L (150 mg/dL) indicates
lower risk and higher levels indicate a need to look for
other risk factors.
Diabetes HbA1c: <7% (<53 mmol/mol).
grain products, vegetables, fruit and fish.
BMI ¼ body mass index; HbA1C ¼ glycated haemoglobin; HDL-C ¼ high-density
lipoprotein-cholesterol; LDL-C ¼ low-density lipoprotein-cholesterol; TG ¼
triglycerides.
a
The BP target can be lower in some patients with type 2 diabetes127 and in some
high-risk patients without diabetes who can tolerate multiple antihypertensive
drugs.70
b
The term “baseline LDL-C“ refers to the level in a subject not taking any lipid
lowering medication.
Box 8 Recommendations for treatment goals for
lowdensity lipoprotein-cholesterol (LDL-C)–examples
Patient A Very high-risk, LDL-C >1.8 mmol/L (>70 mg/dL) on statin:
the goal is still <1.8 mmol/L (70 mg/dL).
Patient B High-risk, LDL-C >2.6 mmol/L (>100 mg/dL) on statin: the
goal is still <2.6 mmol/L (100 mg/dL).
Patient C Very high-risk, LDL-C 1.8–3.5 mmol/L (70–135 mg/dL)
not on pharmacological therapy: the goal is at least a
50% reduction.
Patient D High-risk, LDL-C 2.6–5.2 mmol/L (100–200 mg/dL)
not on pharmacological therapy: the goal is at least a
50% reduction.
Patient E Very high-risk, LDL-C >3.5 mmol/L (135 mg/dL) not in
pharmacological therapy:the goal is <1.8 mmol/L
(70 mg/dL).
Patient F High-risk LDL-C >5.2 mmol/L (200 mg/dL) not in
pharmacological therapy:the goal is <2.6 mmol/L
(100 mg/dL).
ESC/EAS Guidelines 3019
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
Secondary targets have also been deﬁned by inference for
non-HDL-C and for apoB; they receive a moderate grading, as they
have not been extensively studied in RCTs. Clinicians who are using
apoB in their practice can use targets levels of ,100 mg/dL and
,80 mg/dL for subjects at high or at very high total CV risk, respectively.
The speciﬁc goal for non-HDL-C should be 0.8 mmol/L (30 mg/
dL) higher than the corresponding LDL-C goal; adjusting
lipid-lowering therapy in accordance with these secondary targets
may be considered after having achieved an LDL-C goal in patients
at very high CV risk, although the clinical advantages of this approach
with respect to outcomes remain to be addressed. To date, no speciﬁc
goals for HDL-C or TG levels have been determined in clinical
trials, although increases in HDL-C predict atherosclerosis regression
and low HDL-C is associated with excess events and mortality in
CAD patients, even when LDL-C is ,1.8 mmol/L (70 mg/dL). However,
clinical trial evidence is lacking on the effectiveness of intervening
in these variables to reduce CV risk further.
Clinicians should use clinical judgment when considering further
treatment intensiﬁcation in patients at high or very high total CV risk.
5. Lifestyle modiﬁcations to
improve the plasma lipid proﬁle
The role of nutrition in the prevention of CVD has been extensively
reviewed.132 – 134
There is strong evidence showing that dietary factors
may inﬂuence atherogenesis directly or through effects on traditional
risk factors such as plasma lipids, blood pressure or glucose
levels.
Results from RCTs relating dietary patterns to CVD have been
reviewed.132
Some interventions resulted in signiﬁcant CVD prevention,
whereas others did not. In order to get an overall estimate
of the impact of dietary modiﬁcations on the CV risk, different
meta-analyses have been performed, sometimes with inconsistent
outcomes.135,136
This is due not only to methodological problems,
particularly inadequate sample size or the short duration of many
trials included in the systematic revision, but also to the difﬁculty
of evaluating the impact of a single dietary factor independently of
any other changes in the diet. Such studies rarely allow attribution
of reduction in CV risk to a single dietary component. These
Table 12 Impact of speciﬁc lifestyle changes on lipid levels
Magnitude of the effect Level of evidence References
Lifestyle interventions to reduce TC and LDL-C levels
Reduce dietary trans fat +++ A 136,139
Reduce dietary saturated fat +++ A 136, 137
++ A 140, 141
Use functional foods enriched with phytosterols ++ A 142, 143
Use red yeast rice supplements ++ A 144–146
Reduce excessive body weight ++ A 147, 148
Reduce dietary cholesterol + B 149
Increase habitual physical activity + B 150
Use soy protein products +/- B 151
Lifestyle interventions to reduce TG-rich lipoprotein levels
Reduce excessive body weight +++ A 147,148
Reduce alcohol intake +++ A 152, 153
Increase habitual physical activity ++ A 150, 154
Reduce total amount of dietary carbohydrate ++ A 148, 155
Use supplements of n-3 polyunsaturated fat ++ A 156, 157
Reduce intake of mono- and disaccharides ++ B 158, 159
Replace saturated fat with mono- or polyunsaturated fat + B 136, 137
Lifestyle interventions to increase HDL-C levels
Reduce dietary trans fat +++ A 136,160
Increase habitual physical activity +++ A 150, 161
Reduce excessive body weight ++ A 147, 148
Reduce dietary carbohydrates and replace them with unsaturated fat ++ A 148, 162
Modest consumption in those who take alcohol may be continued ++ B 152
Quit smoking + B 163
Among carbohydrate-rich foods prefer those with low glycaemic index and +/- C 164
Reduce intake of mono- and disaccharides +/- C 158, 159
Increase dietary fibre
high fibre content
HDL-C ¼ high-density lipoprotein-cholesterol; LDL-C ¼ low-density lipoprotein-cholesterol; TC ¼ total cholesterol; TG ¼ triglycerides.
The magnitude of the effect (+++ ¼ marked effects, ++ ¼ less pronounced effects, + ¼ small effects, – ¼ not effective) and the level of evidence refer to the impact of each
dietary modiﬁcation on plasma levels of a speciﬁc lipoprotein class.
ESC/EAS Guidelines3020
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
limitations suggest that caution is required in interpreting the results
of meta-analyses of RCTs in relation to the impact of a single dietary
change on CVD, particularly where they conﬂict with the existing
global research, including clinical studies on risk factors and epidemiological
observations. In this respect, it is relevant that a
meta-analysis of the relationship between improvement of the plasma
lipoprotein proﬁle and the rate of CV events has demonstrated
that non-HDL-C lowering translates into a reduction in risk independent
of the mechanisms (statins, resins, diet and ileal bypass)
involved.131
In summary, the available evidence from RCTs addressing the issue
of how to modify the habitual diet in order to contribute to
CVD prevention shows that the dietary patterns that have been
more extensively evaluated are the Dietary Approaches to Stop
Hypertension (DASH) diet, particularly in relation to blood pressure
control, and the Mediterranean diet; both have been proven
to be effective in reducing CV risk factors and, possibly, to contribute
to CVD prevention.133
They are characterized by high consumption
of fruits, vegetables and wholegrain cereal products;
frequent intake of legumes, nuts, ﬁsh, poultry and low fat dairy products
and limited intake of sweets, sugar-sweetened drinks and red
meat. The DASH diet and the Mediterranean diet derive a large proportion
of dietary fat from non-tropical vegetable oil rather than
from animal sources; the most relevant difference between them
is the emphasis on extra virgin olive oil given in the Mediterranean
diet. This latter dietary pattern has been proven in RCTs to be effective
in reducing CV diseases in primary and secondary preven-
tion.137,138
In particular, the PREDIMED trial, a multicentre
randomized intervention study conducted in Spain, evaluated the
impact of a Mediterranean type of diet, supplemented with either
extra-virgin olive oil or mixed nuts, on the rate of major CV events
[myocardial infarction (MI), stroke or death from CV causes) in individuals
at high CV risk but with no CVD at enrolment. The Mediterranean
diet supplemented with extra-virgin olive oil or nuts
signiﬁcantly reduced the incidence of major CV events by almost
30%.137
However, despite the strong support of lifestyle intervention
for CVD prevention coming from the PREDIMED and other
intervention studies with CVD endpoints, most evidence linking nutrition
to CVD is based on observational studies and investigations
of the effects of dietary changes on CV risk factors.
The inﬂuence of lifestyle changes and functional foods on lipoproteins
is evaluated and summarized in Table 12; in this table the magnitude
of the effects and the levels of evidence refer to the impact of
dietary modiﬁcations on the speciﬁc lipoprotein class and not to
CVD endpoints.
5.1 The inﬂuence of lifestyle on total
cholesterol and low-density lipoprotein
cholesterol levels
Saturated fatty acids (SFAs) are the dietary factor with the greatest
impact on LDL-C levels (0.02–0.04 mmol/L or 0.8–1.6 mg/dL of
LDL-C increase for every additional 1% energy coming from saturated
fat).165
Stearic acid, in contrast to other SFAs (lauric, myristic
and palmitic), does not increase TC levels. Trans unsaturated fatty
acids can be found in limited amounts (usually ,5% of total fat) in
dairy products and in meats from ruminants. ‘Partially hydrogenated
fatty acids’ of industrial origin represent the major source of trans
fatty acids in the diet; the average consumption of trans fatty acids
ranges from 0.2% to 6.5% of the total energy intake in different po-
pulations.166
Quantitatively, dietary trans fatty acids have a similar
elevating effect on LDL-C to that of SFAs; however, while SFAs increase
HDL-C levels, trans fats decrease them.137
If 1% of the dietary
energy derived from SFAs is replaced by n-6 polyunsaturated
fatty acids (PUFAs), LDL-C decreases by 0.051 mmol/L (2.0 mg/
dL); if replaced by monounsaturated fatty acids (MUFAs), the decrease
would be 0.041 mmol/L (1.6 mg/dL); and if replaced by
carbohydrate, it would be 0.032 mmol/L (1.2 mg/dL). PUFAs of
Table 13 Dietary recommendations to lower low-density lipoprotein-cholesterol and improve the overall lipoprotein
proﬁle
To be preferred To be used with moderation To be chosen occasionally in limited amounts
Cereals Whole grains
Vegetables Raw and cooked vegetables Potatoes Vegetables prepared in butter or cream
Legumes Lentils, beans, fava beans, peas,
chickpeas, soybean
Fruit Fresh or frozen fruit Dried fruit, jelly, jam, canned fruit,
sorbets, popsicles, fruit juice
Sweets and sweeteners Non-caloric sweeteners Sucrose, honey, chocolate, candies Cakes, ice creams, fructose, soft drinks
poultry without skin
Lean cuts of beef, lamb, pork or veal,
seafood, shellfish
Sausages, salami, bacon, spare ribs, hot dogs,
organ meats
Dairy food and eggs Skim milk and yogurt Low-fat milk, low-fat cheese and other
milk products, eggs
Regular cheese, cream, whole milk and yogurt
Cooking fat and dressings Vinegar,mustard,
fat-free dressings
Olive oil,non-tropical vegetable oils,
soft margarines,salad dressing,
mayonnaise,ketchup
Trans fats and hard margarines (better to avoid
them),palm and coconut oils,butter,lard,
bacon fat
Nuts/seeds All, unsalted (except coconut) Coconut
Cooking procedures Grilling, boiling, steaming Stir-frying, roasting Frying
Refined bread, rice and pasta, biscuits,
corn flakes
Pastries, muffins, pies, croissants
Meat and fish Lean and oily fish,
ESC/EAS Guidelines 3021
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
the n-3 series have no hypocholesterolaemic effect; conversely,
when they are used at high dosages (.3 g/day), the effect on
LDL-C levels is either neutral or a slight increase [particularly
with docosahexaenoic acid (DHA)] with a concomitant decrease
of TGs.165
A positive relationship exists between dietary cholesterol and
CAD mortality, which is partly independent of TC levels. Several experimental
studies in humans have evaluated the effects of dietary
cholesterol on cholesterol absorption and lipid metabolism and
have revealed marked variability among individuals.167,168
Dietary
carbohydrate is ‘neutral’ on LDL-C; therefore, carbohydrate-rich
foods represent one of the possible options to replace saturated
fat in the diet. However, the major drawback of their excessive consumption
is represented by untoward effects on plasma TGs and on
HDL-C levels.165
Dietary ﬁbre (particularly of the soluble type),
which is present in legumes, fruits, vegetables, and wholegrain cereals
(oats, barley), has a direct hypocholesterolaemic effect. Therefore,
carbohydrate foods rich in ﬁbre represent a good dietary
substitute for saturated fat in order to maximize the effects of the
diet on LDL-C levels and to minimize the untoward effects of a
high carbohydrate diet on other lipoproteins.140
Conversely, reﬁned
carbohydrate foods and beverages should not be recommended
to replace saturated fat since they may contribute to
elevated plasma TGs and lower HDL-C levels.
Body weight reduction also inﬂuences TC and LDL-C, but the
magnitude of the effect is rather small; in grossly obese subjects, a
decrease in LDL-C concentration of 0.2 mmol/L (8 mg/dL) is observed
for every 10 kg of weight loss; the reduction of LDL-C is
greater if weight loss is achieved with a low fat diet.147,148
Even smaller
is the reduction of LDL-C levels induced by regular physical ex-
ercise.150,169
However, the beneﬁcial effects of weight reduction
and physical exercise on the CV risk proﬁle go beyond LDL-C reduction
and involve not only other lipoprotein classes but also other
risk factors.
In Table 13, lifestyle interventions to lower TC and LDL-C are
summarized. Given the cultural diversity of the European populations,
they should be translated into practical behaviours, taking
into account local habits and socio-economic factors.
5.2 The inﬂuence of lifestyle on
triglyceride levels
A high monounsaturated fat diet signiﬁcantly improves insulin sensitivity
compared with a high saturated fat diet.170
This goes in parallel
with a reduction in TG levels, mostly in the post-prandial
period.171
A more relevant hypotriglyceridaemic effect is
observed when saturated fat is replaced by n-6 PUFA. A marked
reduction of TGs can be obtained with a high dosage of long chain
n-3 PUFAs; however, a dietary approach based exclusively on natural
foods will seldom reach an intake adequate to achieve a clinically
signiﬁcant effect. To this aim, either pharmacological
supplements or foods artiﬁcially enriched with n-3 PUFAs may
be utilized.172
In people with severe HTG, in whom chylomicrons
are equally present in the fasting state, it is appropriate to reduce
the total amount of dietary fat as much as possible (,30 g/day). In
these patients, the use of medium chain TGs (from C6 to C12) that
avoid the formation of chylomicrons may be considered since they
are directly transported and metabolized in the liver following
transport in the portal vein.
Glucose and lipid metabolism are strongly related, and any perturbation
of carbohydrate metabolism induced by a high carbohydrate
diet will also lead to an increase in TG concentrations.148,165
The greater and more rapid this perturbation, the more pronounced
are the metabolic consequences. Most detrimental effects
of a high carbohydrate diet could be minimized if
carbohydrate digestion and absorption were slowed down. The
glycaemic index permits identiﬁcation, among carbohydrate-rich
foods, of those with ‘fast’ and ‘slow’ absorption. In particular,
the detrimental effects of a high carbohydrate diet on TGs occur
mainly when reﬁned carbohydrate-rich foods are consumed,
while they are much less prominent if the diet is based largely
on ﬁbre-rich, low glycaemic index foods. This applies particularly
to people with diabetes or with metabolic syndrome
(MetS).173,174
Habitual consumption of signiﬁcant amounts (.10% energy) of
dietary fructose contributes to TG elevations, particularly in people
with HTG. These effects are dose dependent; with a habitual fructose
consumption between 15 and 20% of the total energy intake,
plasma TG increases as much as 30–40%. Sucrose, a disaccharidecontaining
glucose and fructose, represents an important source of
fructose in the diet.158,175
Weight reduction improves insulin sensitivity and decreases TG
levels. In many studies the reduction of TG levels due to weight reduction
is between 20–30%; this effect is usually preserved as long
as weight is not regained. Regular physical exercise reduces plasma
TG levels over and above the effect of weight reduction.150,169,176
Alcohol intake has a major impact on TG levels. While in individuals
with HTG even a small amount of alcohol can induce a further
elevation of TG concentrations, in the general population alcohol
exerts detrimental effects on TG levels only if the intake is
excessive.152,177
5.3 The inﬂuence of lifestyle on
high-density lipoprotein cholesterol levels
SFAs increase HDL-C levels in parallel with LDL-C; in contrast, trans
fats decrease them.137
MUFA consumption as a replacement for
SFAs has almost no effect on HDL-C, while n-6 PUFAs induce a
slight decrease. In general, n-3 fatty acids have limited (,5%) or
no effect on HDL-C levels.156,172
Increased carbohydrate consumption as an isocaloric substitution
for fat is associated with a signiﬁcant decrease in HDL-C
[0.01 mmol/L (0.4 mg/dL) for every 1% energy substitution]. In
this respect, both the glycaemic index and the ﬁbre content do
not seem to play a relevant role.178,179
The impact of fructose/sucrose
intake on HDL-C does not seem different from that of other
reﬁned carbohydrates.158,159
Moderate alcohol consumption is associated
with increased HDL-C levels as compared with abstainers,
with a dose-response relationship. Weight reduction has a beneﬁcial
inﬂuence on HDL-C levels: a 0.01 mmol/L (0.4 mg/dL) increase is
observed for every kilogram decrease in body weight when weight
reduction has stabilized. Aerobic physical activity corresponding to
a total energy expenditure of 1500–2200 kcal/week, such as 25–
30 km of brisk walking per week (or any equivalent activity), may
ESC/EAS Guidelines3022
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
increase HDL-C levels by 0.08–0.15 mmol/L (3.1–6 mg/dL).176
Smoking cessation may also contribute to HDL-C elevation, provided
that weight gain is prevented; this is often observed soon after
quitting smoking.163
5.4 Lifestyle recommendations to
improve the plasma lipid proﬁle
LDL-C represents the primary lipoprotein target for reducing CV
risk and therefore it deserves special emphasis in the evaluation of
lifestyle measures useful for CVD prevention. However, it may be
appropriate that the diet recommended to the general population,
and particularly to people at increased CV risk, should not only lower
LDL-C, but should also be able to improve plasma TG and
HDL-C levels (Table 12). This section focuses on dietary and other
lifestyle factors that have an effect on lipids. It has to be kept in mind
that dietary components, other lifestyle factors and weight loss also
contribute to reducing the overall CV risk through their inﬂuence
on other risk factors, e.g. hypertension, subclinical inﬂammation
or impaired insulin sensitivity.
5.4.1 Body weight and physical activity
Since overweight, obesity and abdominal adiposity often contribute
to dyslipidaemia, caloric intake should be reduced and energy expenditure
increased in those with excessive weight and/or abdominal
adiposity. Overweight is deﬁned as a body mass index (BMI)
≥25–30 kg/m2
and obesity as a BMI ≥30 kg/m2
.
Abdominal adiposity can be detected easily by measuring waist
circumference; this should be performed in all individuals who are
either overweight, have dyslipidaemia or are at increased CV risk.
Measurements of waist circumference .80 cm for women of any
ethnicity and .94 cm for men of European ancestry or .90 cm
for men of Asian origin indicate the presence of abdominal adiposity,
even in people of normal weight (Table 14).180
Body weight reduction,
even if modest (5–10% of basal body weight), improves
lipid abnormalities and favourably affects the other CV risk factors
often present in dyslipidaemic individuals.147
An even more
marked hypolipidaemic effect occurs when weight reduction is
more relevant, as observed in severely obese patients who undergo
bariatric surgery. This treatment seems to induce beneﬁcial effects
not only on the overall risk factor proﬁle, but also on CV
events.181
Weight reduction can be achieved by decreasing the consumption
of energy-dense foods, inducing a caloric deﬁcit of 300–500
kcal/day. To be effective in the long run, this advice should be incorporated
into structured, intensive lifestyle education programmes.
In order to facilitate the maintenance of body weight
close to the target, it is always appropriate to advise people
with dyslipidaemia to engage in regular physical exercise of moderate
intensity.150
Modest weight reduction and regular physical exercise of moderate
intensity are very effective in preventing type 2 diabetes and improving
all the metabolic abnormalities and CV risk factors clustering with insulin
resistance, which are often associated with abdominal adiposity.
Physical activity should be encouraged, with a goal of regular physical
exercise for at least 30 min/day every day.169
5.4.2 Dietary fat
Limiting as much as possible the intake of trans fat is a key measure
of the dietary prevention of CVD. Trying to avoid the consumption
of foods made with processed sources of trans fats provides the
most effective means of reducing the intake of trans fats to ,1%
of energy. Because the trans fatty acids produced in the partial hydrogenation
of vegetable oils account for 80% of total intake,
the food industry has an important role in decreasing the trans
fatty acid content of the food supply. As for saturated fat, its
consumption should be ,10% of the total caloric intake and
should be further reduced (,7% of energy) in the presence of
hypercholesterolaemia. For most individuals, a wide range of total
fat intakes is acceptable and will depend upon individual preferences
and characteristics. However, fat intakes that .35% of calories are
generally associated with increased intakes of both saturated fat and
calories. Conversely, a low intake of fats and oils increases the risk of
inadequate intakes of vitamin E and of essential fatty acids, and may
contribute to unfavourable changes in HDL-C.165
Fat intake should predominantly come from sources of MUFAs
and both n-6 and n-3 PUFAs. However, the intake of n-6 PUFAs
should be limited to ,10% of the energy intake, both to minimize
the risk of lipid peroxidation of plasma lipoproteins and to avoid any
clinically relevant HDL-C decrease.182
Not enough data are available
to make a recommendation regarding the optimal n-3:n-6 fatty
acid ratio.182,183
The cholesterol intake in the diet should be reduced
(,300 mg/day), particularly in people with high plasma cholesterol
levels.
5.4.3 Dietary carbohydrate and ﬁbre
Carbohydrate intake should range between 45 and 55% of total energy
intake. Consumption of vegetables, legumes, fruits, nuts and
wholegrain cereals should be particularly encouraged, together
with all the other foods rich in dietary ﬁbre and/or with a low glycaemic
index. A fat-modiﬁed diet that provides 25–40 g of total
dietary ﬁbre, including at least 7–13 g of soluble ﬁbre, is well tolerated,
effective and recommended for plasma lipid control; conversely,
there is no justiﬁcation for the recommendation of very low
carbohydrate diets.164
Intake of sugars should not exceed 10% of total energy (in addition
to the amount present in natural foods such as fruits and dairy
products); more restrictive advice concerning sugars may be useful
Table 14 Deﬁnition of central obesity
Waist circumference
Caucasians (Europids) Men ≥94 cm,women ≥80 cm
SouthAsians,Chinese,Japanese Men ≥90 cm,women ≥80 cm
South and CentralAmericans Use recommendations for South
available.
Sub-SaharanAfricans Use European data until more
Eastern Mediterranean and
Middle East (Arabic populations)
Use European data until more
Asians until more specific data are
specific data are available.
specific data are available.
ESC/EAS Guidelines 3023
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
for those needing to lose weight or with high plasma TG values,
MetS or diabetes. Soft drinks should be used with moderation by
the general population and should be drastically limited in those
individuals with elevated TG values.158,159
5.4.4 Alcohol
Moderate alcohol consumption [up to 20 g/day (2 units) for men
and 10 g/day (1 unit) for women] is acceptable for those who drink
alcoholic beverages, provided that TG levels are not elevated.
5.4.5 Smoking
Smoking cessation has clear beneﬁts on the overall CV risk, and speciﬁcally
on HDL-C, but special attention should be paid in order to
prevent weight gain in people who stop smoking.163
5.5 Dietary supplements and functional
foods for the treatment of dyslipidaemias
Innovative nutritional strategies to improve dyslipidaemias have
been developed. They are based on either changing some ‘risky’
dietary components or encouraging the consumption of speciﬁcally
targeted ‘healthy’ functional foods and/or dietary supplements;
these so-called nutraceuticals can be used either as alternatives or
in addition to lipid-lowering drugs.184
Nutritional evaluation of functional
foods includes not only the search for clinical evidence of
beneﬁcial effects relevant to improved health or reduction of disease
risk, but also the demonstration of good tolerability and the absence
of major undesirable effects. The substantiation of health
claims relevant for each food should be based on results from intervention
studies in humans that are consistent with the proposed
claims. Overall, the available evidence on functional foods so far
identiﬁed in this ﬁeld is incomplete; the major gap is the absence
of diet-based intervention trials of sufﬁcient duration to be relevant
for the natural history of dyslipidaemia and CVD.
5.5.1 Phytosterols
The principal phytosterols are sitosterol, campesterol and stigmasterol;
they occur naturally in vegetable oils and in smaller amounts in
vegetables, fresh fruits, chestnuts, grains and legumes. The dietary
intake of plant sterols ranges between an average of 250 mg/day
in Northern Europe to 500 mg/day in Mediterranean countries.
Phytosterols compete with cholesterol for intestinal absorption,
thereby modulating TC levels.
Phytosterols have been added to spreads and vegetable oils
(functional margarine, butter and cooking oils), as well as yoghurt
and other foods; however, food matrices do not signiﬁcantly inﬂuence
the cholesterol-lowering efﬁcacy of phytosterols at equivalent
doses.142
The daily consumption of 2 g of phytosterols can effectively
lower TC and LDL-C by 7–10% in humans (with a certain degree
of heterogeneity among individuals), while it has little or no effect on
HDL-C and TG levels.143
Although the effect of plant sterol consumption
on TC levels has been clearly shown, no studies have
been performed yet on the subsequent effect on CVD. However,
the meta-analysis of Robinson et al.131
indicates that LDL-C reduction
translates into CV beneﬁts, independent of the mechanism involved.
Long-term surveillance is also needed to guarantee the
safety of the regular use of phytosterol-enriched products. The
possible decrease in carotenoid and fat-soluble vitamin levels by
sterols/stanols can be prevented with a balanced diet rich in these
nutrients.185
Based on LDL-C lowering and the absence of adverse
signals, functional foods with plant sterols/stanols (at least
2 g/day with the main meal) may be considered: (i) in individuals
with high cholesterol levels at intermediate or low global CV
risk who do not qualify for pharmacotherapy; (ii) as an adjunct
to pharmacologic therapy in high- and very high-risk patients
who fail to achieve LDL-C goals on statins or are statin intolerant;
and (iii) in adults and children (.6 years) with FH, in line with current
guidance.142
5.5.2 Monacolin and red yeast rice
Red yeast rice (RYR) is a source of fermented pigment that has been
used in China as a food colorant and ﬂavour enhancer for centuries.
Hypocholesterolaemic effects of RYR are related to a statin-like
mechanism, inhibition of hydroxymethylglutaryl-coenzyme A
(HMG-CoA) reductase, of monacolins, which represent the bioactive
ingredient. Different commercial preparations of RYR have different
concentrations of monacolins, and lower TC and LDL-C to a variable
extent,145
but the long-term safety of the regular consumption of
these products is not fully documented. However, side effects similar
to those observed with statins have been reported in some people
using these nutraceuticals. Furthermore, their quality may vary widely.
In one RCT from China in patients with CAD, a partially puriﬁed
extract of RYR reduced recurrent events by 45%.144
No
other trial has been performed to conﬁrm this ﬁnding. A clinically
relevant hypocholesterolaemic effect (up to a 20% reduction) is
observed with RYR preparations providing a daily dose of
2.5–10 mg monacolin K.146
Nutraceuticals containing puriﬁed
RYR may be considered in people with elevated plasma cholesterol
concentrations who do not qualify for treatment with statins
in view of their global CV risk.
5.5.3 Dietary ﬁbre
Available evidence consistently demonstrates a TC- and LDL-C-lowering
effect of water-soluble ﬁbre from oat and barley beta-glucan. Foods
enriched with these ﬁbres are well tolerated, effective and recommended
for LDL-C lowering at a daily dose of at least 3 g/day.186,187
5.5.4 Soy protein
Soy protein has been indicated as being able to induce a modest
LDL-C-lowering effect when replacing animal protein foods.151
However, this was not conﬁrmed when changes in other dietary
components were taken into account.
5.5.5 Policosanol and berberine
Policosanol is a natural mixture of long chain aliphatic alcohols extracted
primarily from sugarcane wax.188
Studies show that policosanol
from sugarcane, rice or wheat germ has no signiﬁcant effect on
LDL-C, HDL-C, TGs, apoB, Lp(a), homocysteine, hs-CRP, ﬁbrinogen
or blood coagulation factors.189
As for berberine, a recent meta-analysis has evaluated its effects
on plasma lipids in humans; six trials were available for this purpose:
the berberine group contained 229 patients and the control group
contained 222 patients.190
The studies, showing a statistically
ESC/EAS Guidelines3024
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
signiﬁcant heterogeneity, were all performed in China in people of
Asian ethnicity. The comparative evaluation of berberine and lifestyle
intervention or placebo indicated that in the berberine group,
LDL-C and plasma TG levels were more effectively reduced than in
the control group. However, due to the lack of high-quality randomized
clinical trials, the efﬁcacy of berberine for treating dyslipidaemia
needs to be further validated.
5.5.6 n-3 unsaturated fatty acids
Observational evidence supports the recommendation that the
intake of ﬁsh (at least twice a week) and long chain n-3 fatty acids
supplements at low dosage may reduce the risk of CV death and
stroke in primary prevention, but have no major effects on plasma
lipoprotein metabolism.183
Pharmacological doses of n-3 fatty acids
(2–3 g/day) reduce TG levels up to 30%, but a higher dosage may
increase LDL-C. Alfa-linolenic acid (a medium chain n-3 fatty acid
present in chestnuts, some vegetables and some seed oils) is less effective
on TG levels. Long chain n-3 PUFAs also reduce the postprandial
lipaemic response.156,172
5.6 Other features of a healthy diet
contributing to cardiovascular disease
prevention
The results of the PREDIMED trial are clearly in support of a diet
inspired by the traditional Mediterranean diet as an effective approach
to the lifestyle prevention of CVDs. This type of diet is characterized
by the regular consumption of extra-virgin olive oil, fruits,
nuts, vegetables and cereals; a moderate intake of ﬁsh and poultry
and a low intake of dairy products, red meat, processed meats
and sweets; wine is consumed in moderation with meals.137
Dietary
choices inspired by this model should be recommended for both
primary and secondary prevention of CVD.
One of the important features of this type of diet is represented
by the consumption of large amounts of fruits and vegetables of different
types providing a sufﬁcient amount and variety of minerals,
vitamins and antioxidants, particularly polyphenols. New evidence
is accumulating on the possible beneﬁcial effects of these compounds,
which are also present in olive oil, red wine, coffee, tea
and cocoa, on subclinical inﬂammation and endothelial function, as
well as their beneﬁcial inﬂuence on plasma TGs at fasting and particularly
in the postprandial period.
As for the consumption of ﬁsh, at least two portions per week are
recommended to the general population for the prevention of
CVD, together with the regular consumption of other food sources
of n-3 PUFAs (nuts, soy and ﬂaxseed oil). For secondary prevention
of CVD, the use of n-3 PUFA supplements is no longer recommended
in view of the recent evidence showing no beneﬁt on
CVD of this supplementation in people who have already experienced
a CV event. Previous RCTs where omega-3 supplementation
was beneﬁcial were not blinded or had low use of standard CV medications
(such as statins).
Salt intake should be limited to ,5 g/day, not only by reducing
the amount of salt used for food seasoning, but especially by reducing
the consumption of foods preserved by the addition of salt; this
recommendation should be more stringent in people with hypertension
or MetS.132 – 134
Food choices to lower TC and LDL-C are summarized in
Table 13. Box 9 lists lifestyle measures and healthy food choices
for managing total CV risk. All individuals should be advised on lifestyles
associated with a lower CVD risk. High-risk subjects, in particular
those with dyslipidaemia, should receive specialist dietary
advice, if feasible.
6. Drugs for treatment of
hypercholesterolaemia
6.1 Statins
6.1.1 Mechanism of action
Statins reduce the synthesis of cholesterol in the liver by competitively
inhibiting HMG-CoA reductase activity. The reduction in
intracellular cholesterol concentration induces an increased expression
of LDLR on the surface of the hepatocytes, which results in increased
uptake of LDL-C from the blood and a decreased plasma
concentration of LDL-C and other apoB-containing lipoproteins,
including TG-rich particles.
The degree of LDL-C reduction is dose dependent and varies
between the different statins (supplementary Figure A and supplementary
Table A).191
There is also considerable interindividual
variation in LDL-C reduction with the same dose of drug.61
Poor response to statin treatment in clinical studies is to some
extent caused by poor compliance, but may also be explained
by a genetic background involving variations in genes of both
Box 9 Summary of lifestyle measures and healthy food
choices for managing total cardiovascular risk
Dietary recommendations should always take into account local food
habits; however, interest in healthy food choices from other cultures
should be promoted.
A wide variety of foods should be eaten. Energy intake should be
adjusted to prevent overweight and obesity.
sdooflaerecniargelohw,stun,semugel,selbategev,stiurffonoitpmusnoC
Foods rich in trans or saturated fat (hard margarines, tropical oils, fatty
or processed meat, sweets, cream, butter, regular cheese) should be
replaced with the above foods and with monounsaturated fat (extra
virgin olive oil) and polyunsaturated fat (non-tropical vegetable oils) in
order to keep trans fats <1.0% of total energy and saturated fat <10%
(<7% in the presence of high plasma cholesterol values).
Salt intake should be reduced to <5 g/day by avoiding table salt and
limiting salt in cooking, and by choosing fresh or frozen unsalted foods;
many processed and convenience foods,including bread,are high in salt.
For those who drink alcoholic beverages,moderation should be advised
(<10 g/day for women and <20 g/day for men) and patients with
hypertriglyceridaemia should abstain.
The intake of beverages and foods with added sugars, particularly soft
drinks,should be limited,especially for persons who are overweight,have
hypertriglyceridaemia,metabolic syndrome or diabetes.
Physical activity should be encouraged,aiming at regular physical exercise
for at least 30 min/day every day.
Use of and exposure to tobacco products should be avoided.
and fish (especially oily) should be encouraged.
ESC/EAS Guidelines 3025
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
cholesterol metabolism and of statin uptake and metabolism in
the liver.192,193
Furthermore, conditions causing high cholesterol
(e.g. hypothyroidism) should be considered. Indeed, interindividual
variations in statin response warrant monitoring of individual
response on initiation of therapy.
6.1.2 Efﬁcacy of cardiovascular disease prevention in
clinical studies
Statins are among the most studied drugs in CVD prevention, and
dealing with single studies is beyond the scope of the present guidelines.
A number of large-scale trials have demonstrated that statins
substantially reduce CV morbidity and mortality in both primary and
secondary prevention, in both genders and in all age groups. Statins
have also been shown to slow the progression or even promote
regression of coronary atherosclerosis.
Meta-analyses. A large number of meta-analyses have been performed
to analyse the effects of statins in larger populations and in
subgroups.64 – 66,68,129,194 – 200
In the large Cholesterol Treatment
Trialists (CTT) analysis data, .170 000 participants and 26 RCTs
with statins were included.64
A 10% proportional reduction in allcause
mortality and 20% proportional reduction in CAD death
per 1.0 mmol/L (40 mg/dL) LDL-C reduction was reported. The
risk of major coronary events was reduced by 23% and the risk
of stroke was reduced by 17% per 1 mmol/L (40 mg/dL) LDL-C
Supplementary Table A Percentage reduction of low-density lipoprotein cholesterol (LDL-C) requested to achieve
goals as a function of the starting value.
Starting LDL-C Reduction to reach LDL-C goal, %
mmol/L ~mg/dL <1.8 mmol/L
(~70 mg/dL)
<2.6 mmol/L
(~100 mg/dL)
<3 mmol/L
(~115 mg/dL)
>6.2 >240 >70 >60 >55
5.2–6.2 200–240 65–70 50–60 40–55
4.4–5.2 170–200 60–65 40–50 30–45
3.9–4.4 150–170 55–60 35–40 25–30
3.4–3.9 130–150 45–55 25–35 10–25
2.9–3.4 110–130 35–45 10–25 <10
2.3–2.9 90–110 22–35 <10 –
1.8–2.3 70–90 <22 – –
0
10
20
30
40
50
60
70
A20
ATOR
LDL%
FLUVA LOVA PRAVA SIMVA ROSU PITA
A10 A40 A80 F20 F40 F80 L10 L20 L40 L80 P10 P20 P40 S10 S20 S40 S80 R5 R10 R20 R40 P1 P2 P4
Weng TC, et al. J Clin Pharm Ther . 2010;35:139-151
Mukhtar RY, et Al. Int J Clin Pract . 2055;59(2):239-252
Supplementary Figure A A systematic review and meta-analysis of the therapeutic equivalence of statins. ATOR ¼ atorvastatin; FLUVA ¼
ﬂuvastatin; LOVA ¼ lovastatin; PRAVA ¼ pravastatin; SIMVA ¼ simvastatin; ROSU ¼ rosuvastatin; PITA ¼ pitavastatin.
ESC/EAS Guidelines3026
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
reduction. The beneﬁts were similar in all subgroups examined.
The beneﬁts were signiﬁcant within the ﬁrst year, but were greater
in subsequent years. There was no increased risk for any
non-CV cause of death, including cancer, in those receiving statins.
Other meta-analyses have conﬁrmed these results, coming to essentially
the same conclusions. Most of the meta-analyses include
studies in primary as well as secondary prevention. The absolute
beneﬁt from statin treatment may be less evident in patients in primary
prevention, who are typically at lower risk. Several
meta-analyses have speciﬁcally studied statins in primary preven-
tion.66,68,199
The largest of these was published as a Cochrane review
in 2013.200
The analysis included 19 studies with different
statins and with somewhat varying inclusion criteria. In this analysis,
all-cause mortality was reduced by 14%, CVD events by
27%, fatal and non-fatal coronary events by 27% and stroke by
22% per 1 mmol/L (40 mg/dL) LDL-C reduction. The relative
risk reduction in primary prevention is about the same as that observed
in secondary prevention. Similar results were also observed
in analyses of statin treatment in people with low risk of
vascular disease.66
However, it should be emphasized that in subjects
with lower risk, the absolute risk reduction is also lower.
Current available evidence from meta-analyses suggests that the
clinical beneﬁt is largely independent of the type of statin but depends
on the extent of LDL-C lowering, therefore the type of statin
used should reﬂect the LDL-C goal in a given patient.
The following scheme may be proposed.
† Evaluate the total CV risk of the subject.
† Involve the patient with decisions on CV risk management.
† Identify the LDL-C goal for that risk level.
† Calculate the percentage reduction of LDL-C required to achieve
that goal.
† Choose a statin and a dose that, on average, can provide this
reduction.
† Response to statin treatment is variable, therefore up-titration of
the dose may be required.
† If the highest tolerated statin dose does not reach the goal,
consider drug combinations.
† In addition, for subjects at very high and high risk, a ≥50% reduction
in LDL-C should be achieved.
Of course, these are general criteria for the choice of drug. Factors
such as the clinical condition of the subject, concomitant medications,
drug tolerability, local treatment tradition and drug cost will
play major roles in determining the ﬁnal choice of drug and dose.
Other effects of statins. Although the reduction of LDL-C is the major
effect of statins, a number of other, potentially important effects
have been suggested (pleiotropic effects of statins).201,202
Among
such effects that are potentially relevant for the prevention of
CVD are anti-inﬂammatory and anti-oxidant effects of statin treatment.
Effects have been shown in vitro and in experimental systems,
but their clinical relevance remains controversial.203
Furthermore, the effects of statins on a number of other clinical
conditions have been evaluated, including dementia,204
hepatic stea-
tosis,205
cancer,206,207
venous thromboembolism208
and polycystic
ovary syndrome.209
Available data are controversial and thus far
no clinically relevant effect on these conditions has been demonstrated.
Statins also reduce TGs by 30–50% and may increase
HDL-C by 5–10%. For indications for statins in HTG, see section
7.4.
The suggested effect on Alzheimer’s disease was recently reviewed
in a Cochrane analysis reporting no conclusive positive effect
from statins. Furthermore, case reports on neurocognitive
side effects of statins have not been conﬁrmed in analyses of larger
patient populations or in meta-analyses.210
6.1.3 Adverse effects of statins
Statins differ in their absorption, bioavailability, plasma protein binding,
excretion and solubility. Lovastatin and simvastatin are prodrugs,
whereas the other available statins are administered in their
active form. Their absorption rate varies between 20 and 98%. Many
statins undergo signiﬁcant hepatic metabolism via cytochrome P450
isoenzymes (CYPs), except pravastatin, rosuvastatin and pitavastatin.
These enzymes are expressed mainly in the liver and gut wall.
Although statins are generally well tolerated, there are adverse effects
to be considered when statins are prescribed.
Muscle. Muscle symptoms are the most commonly described clinically
relevant adverse effect of statin treatment.57
Rhabdomyolysis
is the most severe form of statin-induced myopathy, characterized
by severe muscular pain, muscle necrosis and myoglobinuria potentially
leading to renal failure and death. In rhabdomyolysis, creatine
kinase (CK) levels are elevated at least 10 times, often up to 40 times
the upper limit of normal.211
The frequency of rhabdomyolysis has
been estimated to represent 1–3 cases/100
p
000 patient-years.212
A more commonly described form of muscular adverse effect is
muscular pain and tenderness (myalgia) without CK elevation or
major functional loss. The actual frequency of this adverse effect,
however, is unclear, and varies between different reports. In
meta-analyses of RCTs, no increased frequency in statin-treated
groups has been shown.213,214
On the other hand, the reported frequency
varies between 10 and 15% in observational studies.215,216
One study, designed speciﬁcally to study the effects of statins on
muscle symptoms, suggests that the frequency of muscle-related
complaints is 5%.217
The diagnosis is based on the clinical observation
and whether symptoms disappear after discontinuation of
statins and recur with statin rechallenge. The symptoms are often
vague and the association with statin treatment is often difﬁcult to
conﬁrm. In patients with a high risk for CVD, it is essential to conﬁrm
the diagnosis before leaving the patient without the beneﬁts of
statin treatment. Risk factors for muscular adverse effects have been
identiﬁed. Among these, the interaction with concomitant drug
therapy should especially be considered (see below). Suggested
practical management of muscular symptoms is given in supplementary
material. In patients with high or very high risk for CVD, treatment
with the highest tolerable dose of statin should be considered,
in combination with a cholesterol absorption inhibitor, and if available
a PCSK9 inhibitor may also be considered.218,219
Several studies
have shown a considerable LDL-C lowering effect of alternative
dosing such as every other day or twice a week with atorvastatin
or rosuvastatin.57,220
Although no clinical endpoint trials are available,
this treatment should be considered in high-risk patients
who do not tolerate daily doses of statin treatment.
Liver. The activity of alanine aminotransferase (ALT) in plasma is
commonly used to assess hepatocellular damage. Mild elevation of
ALT occurs in 0.5–2.0% of patients on statin treatment, more
ESC/EAS Guidelines 3027
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
commonly with potent statins or high doses. The common deﬁnition
of clinically relevant ALT elevation has been an increase of
three times the upper limit of normal (ULN) on two occasions.
Mild elevation of ALT has not been shown to be associated with
true hepatotoxicity or changes in liver function. Progression to liver
failure is exceedingly rare, therefore routine monitoring of ALT during
statin treatment is no longer recommended.221
Patients with
mild ALT elevation due to steatosis have been studied during statin
treatment and there is no indication that statins cause any worsening
of liver disease.222– 224
Diabetes. Patients on statin treatment have been shown to exhibit an
increased risk of dysglycaemia and development of diabetes type 2. In a
meta-analysis including 91 140 subjects, the relative risk was increased
by 9% relative to placebo. The absolute risk was increased by 0.2%.
A minor, not clinically relevant elevation of glycated haemoglobin
(HbA1C) has also been observed. The number needed to cause one
case of diabetes was estimated at 255 over 4 years.225
However, the
risk is higher with the more potent statins in high doses,226
and the
risk for diabetes is higher in the elderly and in the presence of other
risk factors for diabetes such as overweight or insulin resistance.227
Overall, the absolute reduction in the risk of CVD in high-risk patients
outweighs the possible adverse effects of a small increase in
the incidence of diabetes.
Kidney. The effect of statin treatment on renal function is still being
debated. A recent Cochrane analysis could not ﬁnd support for beneﬁcial
effects on renal function based on studies where creatinine clearance
was available, and no deleterious effects were observed.228
An
increased frequency of proteinuria has been reported for all statins,
but has been analysed in more detail for rosuvastatin, probably due
to the high frequency of proteinuria observed with a higher dose
(80 mg). With a dose of 80 mg, a frequency of 12% was reported.
With the approved doses up to 40 mg, the frequency is much lower
and in line with the frequency for other statins. The proteinuria induced
by statins is of tubular origin and is supposed to be due to reduced
tubular reabsorption and not to glomerular dysfunction.229
In experimental
systems, reduced pinocytosis has been shown in renal cells. The
statin-induced reduced pinocytosis is directly related to the inhibition
of cholesterol synthesis.230
In clinical trials the frequency of proteinuria
is in general low and in most cases is not higher than for placebo.231
6.1.4 Interactions
A number of important drug interactions with statins have been described
that may increase the risk of adverse effects. Inhibitors and
inducers of enzymatic pathways involved in statin metabolism are
summarized in Table 15. All currently available statins, except pravastatin,
rosuvastatin and pitavastatin, undergo major hepatic metabolism
via the CYPs. These isoenzymes are mainly expressed in
the liver and intestine. Pravastatin does not undergo metabolism
through the CYP system, but is metabolized by sulfation and conjugation.
CYP3A isoenzymes are the most abundant, but other isoenzymes
such as CYP2C8, CYP2C9, CYP2C19 and CYP2D6 are
frequently involved in the metabolism of statins. Thus other
pharmacological substrates of these CYPs may interfere with statin
metabolism. Conversely, statin therapy may interfere with the catabolism
of other drugs that are metabolized by the same enzymatic
system.
Combinations of statins with ﬁbrates may enhance the risk for
myopathy. This risk is highest for gemﬁbrozil, and the association
of gemﬁbrozil with statins should be avoided. The increased risk
for myopathy when combining statins with other ﬁbrates such as fenoﬁbrate,
bezaﬁbrate or ciproﬁbrate seems to be small.234,235
The increased risk for myopathy with nicotinic acid has been debated,
but in recent reviews no increased risk of myopathy was
found with this agent.236,237
6.2 Bile acid sequestrants
6.2.1 Mechanism of action
Bile acids are synthesized in the liver from cholesterol and are released
into the intestinal lumen, but most of the bile acid is returned
to the liver from the terminal ileum via active absorption. The two
older bile acid sequestrants, cholestyramine and colestipol, are both
bile acid–binding exchange resins. Recently the synthetic drug colesevelam
was introduced. The bile acid sequestrants are not systemically
absorbed or altered by digestive enzymes, therefore the
beneﬁcial clinical effects are indirect. By binding the bile acids, the
drugs prevent the entry of bile acids into the blood and thereby remove
a large portion of the bile acids from the enterohepatic circulation.
The liver, depleted of bile, synthesizes more from hepatic
stores of cholesterol. The decrease in bile acid returned to the liver
leads to upregulation of key enzymes responsible for bile acid synthesis
from cholesterol, particularly CYP7A1. The increase in cholesterol
catabolism to bile acids results in a compensatory increase in
hepatic LDLR activity, clearing LDL-C from the circulation and thus
reducing LDL-C levels. These agents also reduce glucose levels in
hyperglycaemic patients. A recent Cochrane review found that colesevelam,
when added to other antidiabetic agents, showed signiﬁcant
effects on glycaemic control; however, more research on the
impact of CV risk is required.238
6.2.2 Efﬁcacy in clinical studies
At the top dose of 24 g of cholestyramine, 20 g of colestipol or 4.5 g
of colesevelam, a reduction in LDL-C of 18–25% has been observed.
No major effect on HDL-C has been reported, while TGs
may increase in some predisposed patients.
Table 15 Drugs potentially interacting with statins
metabolized by CYP3A4 leading to increased risk of
myopathy and rhabdomyolysis
Anti-infective agents Calcium
antagonists
Other
Itraconazole Verapamil Ciclosporin
Ketoconazole Diltiazem Danazol
Posaconazole Amlodipine Amiodarone
Erythromycin Ranolazine
Clarithromycin Grapefruit juice
Telithromycin Nefazodone
HIV protease inhibitors Gemfibrozil
Adapted from Egan and Colman232
and Wiklund et al.233
ESC/EAS Guidelines3028
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
In clinical trials, bile acid sequestrants have contributed greatly to
the demonstration of the efﬁcacy of LDL-C lowering in reducing CV
events in hypercholesterolaemic subjects, with a beneﬁt proportional
to the degree of LDL-C lowering. However, this study was
performed before many of the modern treatment options were
available.239 – 241
6.2.3 Adverse effects and interactions
Gastrointestinal adverse effects (most commonly ﬂatulence, constipation,
dyspepsia and nausea) are often present with these drugs,
even at low doses, which limits their practical use. These adverse effects
can be attenuated by beginning treatment at low doses and ingesting
ample ﬂuid with the drug. The dose should be increased
gradually. Reduced absorption of fat-soluble vitamins has been reported.
Furthermore, these drugs may increase circulating TG levels
in certain patients.
Bile acid sequestrants have major drug interactions with many
commonly prescribed drugs and should therefore be administered
either 4 h before or 1 h after other drugs. Colesevelam represents a
newer formulation of the bile acid sequestrant, which may be better
tolerated than cholestyramine. Colesevelam has fewer interactions
with other drugs and can be taken together with statins and several
other drugs.242
6.3 Cholesterol absorption inhibitors
6.3.1 Mechanism of action
Ezetimibe is the ﬁrst lipid-lowering drug that inhibits intestinal uptake
of dietary and biliary cholesterol without affecting the absorption
of fat-soluble nutrients. By inhibiting cholesterol absorption at
the level of the brush border of the intestine [by interaction with the
Niemann-Pick C1-like protein 1 (NPC1L1)], ezetimibe reduces the
amount of cholesterol delivered to the liver. In response to reduced
cholesterol delivery, the liver reacts by upregulating LDLR expression,
which in turn leads to increased clearance of LDL-C from the
blood.
6.3.2 Efﬁcacy in clinical studies
In clinical studies, ezetimibe in monotherapy reduces LDL-C in hypercholesterolaemic
patients by 15–22%. Combined therapy with
ezetimibe and a statin provides an incremental reduction in
LDL-C levels of 15–20%. The efﬁcacy of ezetimibe in association
with simvastatin has been addressed in subjects with aortic stenosis
in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study243
and in patients with CKD in the Study of Heart and Renal Protection
(SHARP) (see sections 9.7.3 and 9.9.2). In both the SEAS and
SHARP trials, a reduction in CV events was demonstrated in the
simvastatin–ezetimibe arm vs. placebo.243,244
In the Improved Reduction of Outcomes: Vytorin Efﬁcacy International
Trial (IMPROVE-IT) ezetimibe was added to simvastatin
(40 mg) in patients after ACS.63
A total of 18 144 patients were randomized
and 5314 patients over 7 years experienced a CVD event;
170 fewer events (32.7 vs. 34.7%) were recorded in the group taking
simvastatin plus ezetimibe (P ¼ 0.016). The average LDL-C during
the study was 1.8 mmol/L in the simvastatin group and 1.4 mmol/L
in patients taking ezetimibe plus simvastatin. Also, ischaemic stroke
was reduced by 21% in this trial (P ¼ 0.008). There was no evidence
of harm caused by the further LDL-C reduction. In this group of patients
already treated with statins to reach goals, the absolute beneﬁt
from added ezetimibe was small, although signiﬁcant. However,
the study supports the proposition that LDL-C lowering by means
other than statins is beneﬁcial and can be performed without adverse
effects. The beneﬁcial effect of ezetimibe is also supported
by genetic studies of mutations in NPC1L1. Naturally occurring mutations
that inactivate the protein were found to be associated with
reduced plasma LDL-C and reduced risk for CAD.245
Taken together with other studies such as the PRECISE-IVUS
study,246
IMPROVE-IT supports the proposal that ezetimibe should
be used as second-line therapy in association with statins when the
therapeutic goal is not achieved at the maximal tolerated statin dose
or in patients intolerant of statins or with contraindications to these
drugs.
6.3.3 Adverse effects and interactions
Ezetimibe is rapidly absorbed and extensively metabolized to
pharmacologically active ezetimibe glucuronide. The recommended
dose of ezetimibe of 10 mg/day can be administered in
the morning or evening without regard to food intake. There are
no clinically signiﬁcant effects of age, sex or race on ezetimibe
pharmacokinetics, and no dosage adjustment is necessary in patients
with mild hepatic impairment or mild to severe renal insufﬁciency.
Ezetimibe can be co-administered with any dose of any
statin. No major adverse effects have been reported; the most frequent
adverse effects are moderate elevations of liver enzymes
and muscle pain.
6.4 PCSK9 inhibitors
6.4.1 Mechanism of action
Recently a new class of drugs, PCSK9 inhibitors, has become available
that targets a protein (PCSK9) involved in the control of the
LDLR.247
Elevated levels/functions of this protein in plasma reduce
LDLR expression by promoting, upon binding, the LDLR lysosomal
catabolism and increase plasma LDL-C concentration, while lower
levels/functions of PCSK9 are related to lower plasma LDL-C le-
vels.248
Therapeutic strategies have been developed mainly using
monoclonal antibodies that reduce LDL-C levels by 60% independent
from the presence of a background lipid-lowering therapy.
The mechanism of action relates to the reduction of plasma levels of
PCSK9, which in turn is not available to bind the LDLR. Since this
interaction triggers the intracellular degradation of the LDLR, lower
levels of circulating PCSK9 will result in a higher expression of
LDLRs at the cell surface and therefore in a reduction of circulating
LDL-C levels.248
6.4.2 Efﬁcacy in clinical studies
The European Medicines Agency (EMA) and the US Food and Drug
Administration (FDA) have recently approved two monoclonal antibodies
(Mabs) for the control of elevated plasma LDL-C. The efﬁcacy
at reducing LDL-C is in the range of 50–70%, independent
of the presence of a background therapy (statins, ezetimibe, etc.);
preliminary data from phase 3 trials suggest a reduction of CV events
in line with the LDL-C reduction achieved.115,116
A recent
meta-analysis conﬁrmed these ﬁndings.249
No major effects are
ESC/EAS Guidelines 3029
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
reported on HDL-C or plasma TGs. However, the TG effect must
be reconﬁrmed in populations with higher starting plasma TG levels.
Given the mechanism of action, these drugs are effective at reducing
LDL-C in all patients with the capability of expressing LDLRs in
the liver. Therefore this pharmacological approach is effective in the
vast majority of patients, including those with heterozygous FH
(HeFH) and, albeit to a lower level, those with homozygous FH
(HoFH) with residual LDLR expression. Receptor-deﬁcient HoFH
responds poorly to the therapy.
People at very high total CV risk, people with HeFH (and some
with HoFH) on maximally tolerated doses of ﬁrst- and second-line
therapy and/or in apheresis and who are statin ‘intolerant’ with persistent
high levels of LDL-C are reasonable candidates for the use of
these drugs.
6.4.3 Adverse effects and interactions
Anti-PCSK9 Mabs are injected subcutaneously, usually every other
week, at doses up to 150 mg. The potential for interaction with orally
absorbed drugs is absent, as they will not interfere with pharmacokinetics
or pharmacodynamics. Anti-PCSK9 Mabs do not
modulate pathways involved in biotransformation or drug uptake/
extrusion from cells. Among the most frequently reported side effects
are itching at the site of injection and ﬂu-like symptoms. In
some studies an increase of patient-reported neurocognitive effects
was described. This ﬁnding requires further scrutiny.250
6.5 Nicotinic acid
Nicotinic acid has broad lipid-modulating action, raising HDL-C in a
dose-dependent manner by up to 25% and reducing LDL-C by 15–
18% and TGs by 20–40% at the 2 g/day dose. Nicotinic acid is unique
in lowering Lp(a) levels by up to 30% at this dose. After two
large studies with nicotinic acid, one with extended-release niacin251
and one with niacin plus laropiprant,252
showed no beneﬁcial effect,
but rather an increased frequency of serious adverse effects, no
medication containing nicotinic acid is currently approved in Europe.
For the role of niacin in hypertriglyceridaemia, see section 7.6.
6.6 Drug combinations
Although the LDL-C goals are attained with monotherapy in many
patients, a signiﬁcant proportion of high-risk subjects or patients
with very high LDL-C levels need additional treatment. There are
also patients who are statin intolerant or are not able to tolerate
higher statin doses. In these cases, combination therapy should be
considered (Table 19). More information on statin intolerance is
provided in Supplementary Figure C.
6.6.1 Statins and cholesterol absorption inhibitors
The combination of statins and ezetimibe is discussed above (see
section 6.3.2).
6.6.2 Statins and bile acid sequestrants
The combination of a statin and cholestyramine, colestipol or colesevelam
could be useful in achieving LDL-C goals. On average, the
addition of a bile acid sequestrant to a statin reduces LDL-C by an
additional 10–20%. However, there are no published clinical outcome
trials with either conventional bile acid sequestrants or colesevelam
in combination with other drugs. The combination has been
found to reduce atherosclerosis, as evaluated by coronary
angiography.253
6.6.3 Other combinations
In high-risk patients such as those with FH, or in cases of statin intolerance,
other combinations may be considered. Co-administration of
ezetimibe and bile acid sequestrants (colesevelam, colestipol or cholestyramine)
resulted in an additional reduction of LDL-C levels without
any additional adverse effects when compared with the stable bile
acid sequestrant regimen alone.254
Clinical outcome studies with these
combinations have not been performed.
Functional foods containing phytosterols as well as plant sterol–
containing tablets additionally reduce LDL-C levels by up to 5–10%
in patients taking a stable dose of a statin, and this combination is
also well tolerated and safe.142,255
Phytosterols and plant sterols
should be taken after a meal. However, it is still not known whether
this could reduce the risk of CVD since no trials with plant sterols or
stanols in combination with other lipid-lowering drugs are available
for CVD outcomes. The combination of red yeast with statins is not
recommended.
In patients at very high risk, with persistent high LDL-C despite
being treated with a maximal statin dose in combination with ezetimibe,
or in patients with statin intolerance, a PCSK9 inhibitor may
be considered.
Recommendations for the treatment of hypercholesterolaemia
are shown in Table 16.
Table 16 Recommendations for the pharmacological
treatment of hypercholesterolaemia
Recommendations Classa
Level b
Ref c
Prescribe statin up to the highest
recommended dose or highest
tolerable dose to reach the goal.
I A
62, 64,
68
In the case of statin intolerance,
ezetimibe or bile acid sequestrants,
or these combined, should be
considered.
IIa C
239,
256, 257
If the goal is not reached, statin
combination with a cholesterol
absorption inhibitor should be
considered.
IIa B 63
If the goal is not reached, statin
combination with a bile acid
sequestrant may be considered.
IIb C
In patients at very high-risk, with
persistent high LDL-C despite
treatment with maximal tolerated
statin dose, in combination with
ezetimibe or in patients with statin
intolerance, a PCSK9 inhibitor may
be considered.
IIb C 115, 116
LDL-C ¼ low-density lipoprotein-cholesterol; PCSK9 ¼ proprotein convertase
subtilisin/kexin type 9.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
ESC/EAS Guidelines3030
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
7. Drugs for treatment of
hypertriglyceridaemia
7.1 Triglycerides and cardiovascular
disease risk
Although the role of TGs as a risk factor for CVD has been strongly
debated, recent data favour the role of TG-rich lipoproteins as a
risk factor for CVD.87
Large prospective studies have reported
that non-fasting TGs predict CAD risk more strongly than fasting
TGs.98,99
Recent data from genetic studies utilizing a Mendelian
randomization design have consistently linked both non-fasting
TG levels as well as remnant cholesterol to increased risk of
CVD events and all-cause mortality.86,107
Remnant cholesterol
is a calculated parameter in these studies and equals TC 2
(HDL-C + LDL-C). These genetic data have strengthened the
position of remnant cholesterol as a causal factor driving atherosclerosis
and CVD events.75
Recently, remnant cholesterol has
turned out to be a good surrogate marker of TGs and remnants.90
The burden of HTG as a CVD risk factor is highlighted by the fact
that about one-third of adult individuals have TG levels
.1.7 mmol/L (150 mg/dL).258
HTG can have different causes
(Table 17), among which its polygenic nature is most important
in relation to CVD prevention.
7.2 Deﬁnition of hypertriglyceridaemia
The deﬁnition of different categories for elevated fasting TG levels
seems to be slightly variable in different guidelines and
recommendations.67,259
According to the EAS consensus document,
mild to moderate HTG is deﬁned as TGs .1.7 mmol/L
(150 mg/dL) and ,10 mmol/L (880 mg/dL); TGs .10 mmol/L is
deﬁned as severe HTG.260
Age/gender, race/ethnicity and lifestyle
are modulating factors at the population level for serum TGs. In
the Copenhagen general population 27% had TGs .1.7 mmol/
L.75
Severe HTG is rare and is typically associated with monogenic
mutations. Severe HTG is associated with an increased risk for
pancreatitis.
7.3 Strategies to control plasma
triglycerides
A level of fasting TGs ≤1.7 mmol/L (150 mg/dL) is desirable. The
ﬁrst step is to consider possible causes of HTG and to evaluate
the total CV risk. The primary goal is to achieve the LDL-C level recommended
based on the total CV risk level. As compared with the
overwhelming evidence for the beneﬁts of LDL-C reduction, the
evidence on the beneﬁts of lowering elevated TG levels is still modest,
and is primarily derived from subgroup or post hoc analyses.
However, recent evidence of TGs as a causal risk factor may encourage
TG lowering (Table 18).
Although the CVD risk is increased if fasting TGs are .1.7 mmol/
L (150 mg/dL),87
the use of drugs to lower TGs may only be considered
in high-risk subjects when TGs are .2.3 mmol/L (200 mg/dL)
and cannot be lowered by lifestyle measures. The available pharmacological
interventions include statins, ﬁbrates, PCSK9 inhibitors and
n-3 PUFAs.
For information on lifestyle management, please refer to
section 5.
7.4 Statins
Since statins have signiﬁcant effects on mortality as well as most
CVD outcome parameters, these drugs are the ﬁrst choice to
Table 17 Possible causes of hypertriglyceridaemia
Genetic predisposition
Obesity
Type 2 diabetes
Alcohol consumption
Diet high in simple carbohydrates
Renal disease
Hypothyroidism
Pregnancy (physiological triglyceride concentrations double during the
third trimester)
Paraproteinaemia and autoimmune disorders such as systemic lupus
erythematosus
Multiple medications including:
• Corticosteroids
• Oestrogens,especially those taken orally
•Tamoxifen
• Antihypertensives: adrenergic beta-blocking agents (to a different
degree),thiazides
• Isotretinoin
• Bile acid-binding resins
• Ciclosporin
•Antiretroviral regimens (protease inhibitors)
• Psychotropic medications:phenothiazines,second generation
antipsychotics
Table 18 Recommendations for drug treatments of
hypertriglyceridaemia
Recommendations Classa
Level b
Ref c
Drug treatment should be
considered in high-risk patients with
TG >2.3 mmol/L (200 mg/dL).
IIa B 261, 262
Statin treatment may be
choice for reducing CVD risk
in high-risk individuals with
hypertriglyceridaemia.
IIb B
263,
264
In high-risk patients with TG
>2.3 mmol/L (200 mg/dL) despite
be considered in combination with
statins.
IIb C 261–264
considered as the first drug of
statin treatment, fenofibrate may
CVD ¼ cardiovascular disease; TG ¼ triglycerides.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
ESC/EAS Guidelines 3031
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
reduce both total CVD risk and moderately elevated TG levels.
More potent statins (atorvastatin, rosuvastatin and pitavastatin)
demonstrate a robust lowering of TG levels, especially at high doses
and in patients with elevated TGs. In subgroup analyses from statin
trials, the risk reduction is the same in subjects with HTG as in
normotriglyceridaemic subjects.
7.5 Fibrates
7.5.1 Mechanism of action
Fibrates are agonists of peroxisome proliferator-activated
receptor-a (PPAR-a), acting via transcription factors regulating various
steps in lipid and lipoprotein metabolism. By interacting with
PPAR-a, ﬁbrates recruit different cofactors and regulate gene expression.
As a consequence, ﬁbrates have good efﬁcacy in lowering
fasting TG levels as well as post-prandial TGs and TG-rich lipoprotein
(TRL) remnant particles. The HDL-C raising effects of ﬁbrates
are modest.263
7.5.2 Efﬁcacy in clinical trials
The clinical effects of ﬁbrates are primarily illustrated by ﬁve prospective
RCTs: Helsinki Heart Study (HHS), Veterans Affairs Highdensity
lipoprotein Intervention Trial (VA-HIT), Bezaﬁbrate Infarction
Prevention (BIP) study, Fenoﬁbrate Intervention and Event
Lowering in Diabetes (FIELD) and Action to Control Cardiovascular
Risk in Diabetes (ACCORD) study, where fenoﬁbrate was added to
statin therapy.261,262,265 –267
Although the Helsinki Heart Study reported a signiﬁcant reduction
in CVD outcomes with gemﬁbrozil, neither the FIELD nor
the ACCORD study showed a reduction in total CVD outcomes.
Decreases in the rates of non-fatal MI were reported, although often
as a result of post hoc analyses. The effect was most evident in subjects
with elevated TG/low HDL-C levels. However, the data on
other outcome parameters have remained equivocal. Only one
study, ACCORD, has analysed the effect of a ﬁbrate as an add-on
treatment to a statin. No overall beneﬁt was reported in two recent
meta-analyses.268,269
Results from other meta-analyses suggest reduced
major CVD events in patients with high TGs and low
HDL-C in ﬁbrate-treated patients, but no decrease in CVD or total
mortality.270 –272
Thus the overall efﬁcacy of ﬁbrates on CVD outcomes
is much less robust than that of statins. Overall, the possible
beneﬁts of ﬁbrates require conﬁrmation.
7.5.3 Adverse effects and interactions
Fibrates are generally well tolerated with mild adverse effects,
gastrointestinal disturbances being reported in ,5% of patients
and skin rashes in 2%.273
In general, myopathy, liver enzyme elevations
and cholelithiasis represent the most well-known adverse effects
associated with ﬁbrate therapy.273
In the FIELD study, small
but signiﬁcant increases in the incidence of pancreatitis (0.8% vs.
0.5%) and pulmonary embolism (1.1% vs. 0.7%) and a nonsigniﬁcant
trend toward an increase in deep vein thrombosis
(1.4% vs. 1.0%) were seen in those taking fenoﬁbrate compared
with placebo; this is in line with data from other ﬁbrate studies.261
Elevations of both CK (.5 times above the ULN) and ALT (.3
times above the ULN) were reported more frequently for patients
on fenoﬁbrate than on placebo, but the incidence of these abnormalities
remained ,1% in both treatment groups. In the FIELD
study, one case of rhabdomyolysis was reported in the placebo
group and three cases in the fenoﬁbrate group.261
The risk of myopathy
has been reported to be 5.5-fold greater with ﬁbrate use as
a monotherapy compared with statin use. The risk of myopathy is
greater in patients with CKD, and it varies with different ﬁbrates
and statins used in combination. This is explained by the pharmacological
interaction between different ﬁbrates and glucuronidation
of statins. Gemﬁbrozil inhibits the metabolism of statins via
the glucuronidation pathway, which leads to highly increased plasma
concentrations of statins. As fenoﬁbrate does not share the
same pharmacokinetic pathways as gemﬁbrozil, the risk of myopathy
is much less with this combination therapy.273
As a class, ﬁbrates have been reported to raise both serum creatinine
and homocysteine in both short-term and long-term studies.
The increase of serum creatinine by ﬁbrate therapy seems to be fully
reversible when the drug is stopped. Data from meta-analyses suggest
that a reduction of calculated glomerular ﬁltration rate (GFR)
does not reﬂect any adverse effects on kidney function.274
The
increase in homocysteine by ﬁbrates has been considered to be
relatively innocent with respect to CVD risk. However, the
ﬁbrate-induced increase in homocysteine may blunt the increases
in both HDL-C and apoA1, and this may contribute to the smaller
than estimated beneﬁts of fenoﬁbrate in the outcome para-
meters.275
High homocysteine also promotes thrombosis, and the
increased trend to deep vein thrombosis seen in the FIELD study
was associated with the baseline homocysteine levels, but no interaction
was observed between the increase of homocysteine by
ﬁbrate and venous thromboembolic events.276
7.6 Nicotinic acid
7.6.1 Mechanism of action
Nicotinic acid has been reported to decrease fatty acid inﬂux to the
liver and the secretion of VLDL by the liver. This effect appears to be
mediated in part by the action on hormone-sensitive lipase in the
adipose tissue. Nicotinic acid has key action sites in both liver and
adipose tissue. In the liver, nicotinic acid inhibits diacylglycerol
acyltransferase-2 (DGAT-2), resulting in decreased secretion of
VLDL particles from the liver, which is also reﬂected in reductions
of both IDL and LDL particles.277
Nicotinic acid raises HDL-C and
apoA1 primarily by stimulating apoA1 production in the liver.277
The effects of nicotinic acid on lipolysis and fatty acid mobilization
in adipocytes are well established.
7.6.2 Efﬁcacy in clinical trials
Nicotinic acid has multiple effects on serum lipids and lipopro-
teins.277
Nicotinic acid effectively reduces not only TGs, but also
LDL-C, reﬂecting its effect on all apoB-containing proteins. Nicotinic
acid increases apoA1-containing lipoproteins, reﬂected in increases
of HDL-C and apoA1. At a daily dose of 2 g it reduces
TGs by 20–40% and LDL-C by 15–18% and increases HDL-C by
15–35%.257,277,278
The favourable effect on angiographic measures
has been reported in the Familial Atherosclerosis Treatment Study
(FATS) and in the HDL-Atherosclerosis Treatment Study
(HATS).279
Two large randomized clinical trials [the Atherothrombosis Intervention
in Metabolic Syndrome with Low HDL/High Triglycerides:
Impact on Global Health Outcomes (AIM-HIGH) and the Heart
ESC/EAS Guidelines3032
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
Protection Study 2-Treatment of HDL to Reduce the Incidence of
Vascular Events (HPS2-THRIVE)] using, respectively, extended release
(ER) nicotinic acid vs. placebo in addition to simvastatin, and
ER nicotinic acid/laropiprant vs. placebo in patients treated with simvastatin
(plus, if indicated, ezetimibe), failed to report positive beneﬁts
of the therapies on CV outcomes and have challenged the
position and beneﬁts of niacin in lipid management.251,252
Furthermore,
there was an increased frequency of severe adverse effects
in the niacin groups. Since the EMA suspended ER nicotinic acid/laropiprant,
this therapeutic option is unavailable in Europe.
7.7 n-3 fatty acids
7.7.1 Mechanism of action
n-3 fatty acids [eicosapentaenoic acid (EPA) and DHA] are used at
pharmacological doses to lower TGs. n-3 fatty acids (2–4 g/day) affect
serum lipids and lipoproteins, in particular VLDL concentration.
The underlying mechanism is poorly understood, although it may be
related, at least in part, to their ability to interact with PPARs and to
a decreased secretion of apoB.
7.7.2 Efﬁcacy in clinical trials
n-3 fatty acids reduce TGs, but their effects on other lipoproteins
are trivial. More detailed data on clinical outcomes are needed to
justify the use of prescription n-3 fatty acids.280
The recommended
doses of total EPA and DHA to lower TGs have varied between 2
and 4 g/day. Three recent studies in subjects with high TGs using
EPA reported a signiﬁcant reduction in serum TG levels of up to
45% in a dose-dependent manner.281 – 283
The efﬁcacy of omega-3
fatty acids to lower serum TGs has also been reported in
meta-analyses.284
One meta-analysis included 63 030 subjects
from 20 trials and reported no overall effect of omega-3 fatty acids
on composite CV events {relative risk [RR] 0.96 [95% conﬁdence
interval (CI) 0.90, 1.02]; P ¼ 0.24} or total mortality [RR 0.95
(95% Cl 0.86, 1.04); P ¼ 0.28]. A major side effect was gastrointestinal
disturbances.285
The FDA has approved the use of n-3 fatty
acids (prescription products) as an adjunct to diet if TGs are
.5.6 mmol/L (496 mg/dL). Although a recent Japanese study in patients
with hypercholesterolaemia reported a 19% reduction in
CVD outcome,286
the data remain inconclusive and their clinical efﬁcacy
appears to be related to non-lipid effects.287,288
Two randomized
placebo-controlled trials [Reduction of Cardiovascular
Events with EPA-Intervention Trial (REDUCE-IT) and Outcomes
Study to Assess STatin Residual Risk Reduction with EpaNova in
HiGh CV Risk PatienTs with Hypertriglyceridemia (STRENGTH)]
to study the potential beneﬁts of EPA on CVD outcomes in subjects
with elevated serum TGs are ongoing. REDUCE-IT aims to recruit
8000 subjects and STRENGTH 13 000 subjects.
7.7.3 Safety and interactions
The administration of n-3 fatty acids appears to be safe and devoid of
clinically signiﬁcant interactions. However, the antithrombotic effects
may increase the propensity to bleed, especially when given
in addition to aspirin/clopidogrel. Recently the data from one study
associated the risk of prostate cancer with high dietary intake of n-3
PUFAs.289
8. Drugs affecting high-density
lipoprotein cholesterol (Table 20)
Low levels of HDL-C constitute a strong, independent and inverse
predictor of the risk of premature development of atheroscler-
osis.83
Moreover, the increase in CV risk relative to low HDL-C levels
is especially dramatic over the range of HDL-C from 0.65 to
1.17 mmol/L (25 to 45 mg/dL).260
Results from a meta-analysis of
four intervention trials, which involved the use of intravascular ultrasound
to evaluate changes in coronary atheroma volume, indicated
that elevation ≥7.5% in HDL-C, together with a reduction in LDL-C
to a target of 2.0 mmol/L (,80 mg/dL), represented the minimum
requirement for plaque regression.290
Subjects with type 2 diabetes or those with mixed or combined
dyslipidaemia, renal and hepatic insufﬁciency states or autoimmune
diseases often present with low plasma concentrations of HDL-C. In
addition to low HDL-C, these disease states feature a moderate or
marked degree of HTG. The intravascular metabolism of TG-rich lipoproteins
(principally VLDL) is intimately linked to that of HDL.
Drug-induced elevation of HDL-C may lead to reductions in the
cholesterol content of both VLDL and LDL. The magnitude of reduction
in VLDL cholesterol (VLDL-C) and LDL-C under these circumstances
tends to differ markedly as a function of the speciﬁc
mechanism of action of the pharmacological agent concerned, as
Table 19 Summary of the efﬁcacy of drug
combinations for the management of mixed
dyslipidaemias
A combination of statins with fibrates can also be considered while
monitoring for myopathy, but the combination with gemfibrozil should
be avoided.
If TG are not controlled by statins or fibrates, prescription of n-3 fatty
acids may be considered to decrease TG further, and these combinations
are safe and well tolerated.
TG ¼ triglycerides.
Table 20 Recommendations if drug treatment of low
high-density lipoprotein cholesterol is considered
Recommendations Classa
Level b
Ref c
with a similar magnitude and these
drugs may be considered.
IIb B 262, 292
HDL-C may be attenuated in
people with type 2 diabetes.
IIb B 261, 262
Statins and fibrates raise HDL-C
The efficacy of fibrates to increase
HDL-C ¼ high-density lipoprotein cholesterol.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
ESC/EAS Guidelines 3033
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
well as the dose employed and the baseline lipid phenotype. Furthermore,
the percentage increase in HDL-C following treatment
tends to be greater in subjects with the lowest baseline levels.
The available options for elevating low HDL-C levels are relatively
few. While HDL-C levels may be increased by up to 10% by implementing
therapeutic lifestyle changes, including weight reduction,
exercise, smoking cessation and moderate alcohol consumption,
many patients will also require pharmacological intervention if an
HDL-C increase is sought. However, until now there has been no
clear direct evidence that raising HDL-C really results in CVD prevention.
Recent studies aimed at testing this hypothesis have failed
to show any beneﬁcial effect [ILLUMINATE (torcetrapib), Dalcetrapib
Outcomes (dal-OUTCOMES), ACCELERATE (evacetrapib),
HPS2-THRIVE (nicotinic acid plus statin), AIM-HIGH (nicotinic
acid on background statin)], although the population selection in
the last two studies may not have been optimal. The ongoing study
with a cholesteryl ester transfer protein (CETP) inhibitor, the Randomized
Evaluation of the Effects of Anacetrapib Through Lipid
modiﬁcation (REVEAL), will provide more information.
8.1 Statins
Statins produce modest elevations in HDL-C. In a meta-analysis291
of several intervention studies in dyslipidaemic patients, elevations in
HDL-C varied with dose among the respective statins; such elevations
were typically in the range of 5–10%. As a result of the marked
reductions in atherogenic apoB-containing lipoproteins by statins, it
is difﬁcult to assess the extent to which the effect on HDL-C levels
might contribute to the overall observed reductions in CV risk consistently
seen in statin intervention trials. Despite such an effect,
however, the elevated CV risk associated speciﬁcally with low
HDL-C levels was only partially corrected by statin treatment in
the Treatment to New Targets (TNT) trial.292
8.2 Fibrates
As a class, ﬁbrates differ in their potential to modulate the atherogenic
lipid proﬁle by concomitantly lowering TG levels (up to 50%)
and by raising those of HDL-C (up to 10–15% in short-term studies).
However, the HDL-raising effect has been markedly less ( 5%)
in the long-term intervention trials in people with type 2 dia-
betes261,262
; such differences appear to reﬂect distinctions in their
relative binding afﬁnities for PPARs, and notably for PPAR-a.293
8.3 Nicotinic acid
Nicotinic acid appears to increase HDL-C by partially reducing HDL
catabolism and by mainly increasing apoA1 synthesis by the liver.
The latter effect is regarded as the most relevant for the HDL func-
tions.263
Itsefﬁcacy in clinical trials and adverse effects and drug
interactions are described in section 7.6.
8.4 Cholesteryl ester transfer protein
inhibitors
To date, the most efﬁcacious pharmacological approach to elevation
of low HDL-C levels has involved direct inhibition of CETP by small
molecule inhibitors, which may induce an increase in HDL-C by
≥100% on a dose-dependent basis. Of the three CETP inhibitors developed
originally (torcetrapib, dalcetrapib and anacetrapib),
torcetrapib was withdrawn following an excess of mortality in the
torcetrapib arm of the Investigation of Lipid Level Management to
Understand its Impact in Atherosclerotic Events (ILLUMINATE)
trial.294
The Assessment of Clinical Effects of Cholesteryl Ester Transfer
Protein Inhibition with Evacetrapib in Patients at a High-Risk for
Vascular Outcomes (ACCELERATE) trial of evacetrapib in acute coronary
syndrome subjects on statins was terminated due to futility.
Retrospectively, it appears that the deleterious effects of torcetrapib
arose primarily from off-target toxicity related to activation
of the renin–angiotensin–aldosterone system (RAAS). The results
of the dalcetrapib trial (Dal-OUTCOMES) shows no effects in ACS
patients. Phase III trials with anacetrapib (REVEAL) are ongoing.
8.5 Future perspectives
Major developments in the search for efﬁcacious agents to raise
HDL-C and apoA1 with concomitant beneﬁt in atherosclerosis and
CV events are on the horizon. Among them, major interest is focused
on apoA1 mimetic peptides, which are not only active in cellular cholesterol
efﬂux, but may also exert a vast array of biological activities including
anti-inﬂammatory and immune-modulating effects. However,
the genetic studies suggesting that low HDL-C is not causative for
CVD may cast doubt on the possibilities of these treatment options.
9. Management of dyslipidaemia in
different clinical settings
9.1 Familial dyslipidaemias
Plasma lipid levels are to a very large extent determined by genetic
factors. In its more extreme forms this is manifested as familial
hyperlipidaemia. A number of monogenic lipid disorders have
been identiﬁed; among these, FH is most common and strongly related
to CVD. In general in patients with dyslipidaemia, most commonly
the pattern of inheritance does not suggest that there is a
major single gene disorder (monogenic) causing the abnormality,
but rather that it stems from inheriting more than one lipoprotein
gene variant that, on its own, might have relatively little effect, but
in combination with another or others has a greater inﬂuence on
TC, TGs or HDL-C. The pattern of inheritance is polygenic.295
It
is common to ﬁnd that high LDL-C, high TGs or low HDL-C affect
several family members.
9.1.1 Familial combined hyperlipidaemia
Familial combined hyperlipidaemia (FCH) is a highly prevalent dyslipidaemia
(1:100) and an important cause of premature CAD.
FCH is characterized by elevated levels of LDL-C, TGs or both.
The phenotype varies even among members of the same family.
FCH shares considerable phenotype overlap with type 2 diabetes
and MetS. FCH is a complex disease and the phenotype is determined
by interaction of multiple susceptibility genes and the environment.
The phenotype even within a family shows high inter- and
intraperson variability based on lipid values (TGs, LDL-C, HDL-C
and apoB). Therefore, the diagnosis is commonly missed in clinical
practice; the combination of apoB .120 mg/dL + TGs
.1.5 mmol/L (133 mg/dL) with a family history of premature
CVD can be used to identify subjects who most probably have
FCH.296
Currently, research is ongoing to deﬁne genetic markers;
ESC/EAS Guidelines3034
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
hopefully this approach will facilitate diagnosis of this frequent genetic
dyslipidaemia.
The concept of FCH is also valuable clinically in assessing CV risk.
It emphasizes both the importance of considering family history in
deciding how rigorously to treat dyslipidaemia and that elevated
LDL-C levels are riskier when HTG is also present. Statin treatment
decreases CV risk by the same relative amount in people with HTG
as in those without. Because the absolute risk is often greater in
those with HTG, they may therefore beneﬁt greatly from hypocholesterolaemic
therapy.
9.1.2 Familial hypercholesterolaemia
9.1.2.1 Heterozygous familial hypercholesterolaemia
FH is a common monogenic dyslipidaemia causing premature CVD
due to lifelong elevation of plasma levels of LDL-C. If left untreated,
men and women with heterozygous FH (HeFH) typically develop
CAD before the ages of 55 and 60 years, respectively. However, if
diagnosed early and properly treated, the risk for CAD may be dramatically
reduced, with some studies even suggesting a normal life
expectancy.
The frequency of HeFH in the population has earlier been estimated
at 1/500; however, recent studies from whole populations
suggest that the frequency is higher, in some populations as high
as 1/137.297
Based on extrapolations from available data, the frequency
of HeFH can be estimated to be between 1/200 and
1/250, putting the total number of cases at between 14 and 34 million
worldwide.121,298
Only a minor fraction of these are identiﬁed
and properly treated. The risk of CHD among individuals with definite
or probable HeFH is estimated to be increased at least 10-fold.
FH is a monogenic disease caused by loss of function mutations in
the LDLR or apoB genes or a gain of function mutation in the PCSK9
gene; 95% of FH is caused by mutations in LDLR. More than a thousand
different mutations have been identiﬁed in LDLR causing FH.
The different mutations cause reduced function or complete loss
of function. Complete loss of receptor function is associated with
more severe disease. A total of 4–5% of FH is caused by mutations
in apoB causing reduced binding to LDLR and 1% is caused by
mutations in PCSK9 causing increased catabolism of LDLR.
The diagnosis of FH is in most cases based on the clinical picture.
Different criteria for the diagnosis have been developed. The commonly
used criteria from the Dutch Lipid Clinic Network (DLCN)
are shown in Table 21. Other criteria are the Simon Broome register
or the WHO criteria.299,300
The clinical diagnosis of HeFH is based on family history of hypercholesterolaemia
or premature CHD, clinical history of the patient
regarding CVD and clinical signs. Finally, the diagnosis can be veriﬁed
by showing causative mutations in the three pathogenic genes. However,
in most studies the frequency of detectable mutations in patients
with a clinically deﬁnite or probable HeFH is only 60–70%.
This suggests that a considerable fraction of patients with FH have
either a polygenic cause of the disease or that other genes, not
yet identiﬁed, are involved.
Genetic testing and cascade screening. Probands (index
cases) should be identiﬁed according to the following criteria:
† plasma cholesterol ≥8 mmol/L (310 mg/dL) in an adult or adult
family member (or .95th percentile by age and gender for
country),
† premature CHD in the subject or a family member,
† tendon xanthomas in the subject or a family member or
† sudden premature cardiac death in a family member
The most effective way to identify new cases is to undertake cascade
screening of family members of a known index case. Cascade
screening is best performed by a lipid clinic with trained nurses
and physicians. In most families the cases may be identiﬁed with
TC or LDL-C analysis. However, when the causative mutation is
known, genetic testing is recommended since affected individuals
may present with TC below the clinical diagnostic criteria.
Cholesterol-lowering treatment should be initiated as soon as possible
after the diagnosis has been made. To improve risk assessment,
use of imaging techniques to detect asymptomatic atherosclerosis is
recommended. The concept of cumulative cholesterol burden illustrates
the importance of early treatment (for children, see below).
Treatment should be initiated with high-intensity statin treatment,
in most cases in combination with ezetimibe. LDL-C goals are
Table 21 Dutch Lipid Clinic Network diagnostic
criteria for familial hypercholesterolaemia
301
Criteria Points
1) Family history
First-degree relative with known premature (men:<55 years;
women:<60 years) coronary or vascular disease,or
First-degree relative with known LDL-C above the 95th
percentile
1
First-degree relative with tendinous xanthomata and/or arcus
cornealis,or
children <18 years of age with LDL-C above the 95th
percentile (see 9.1.2.3)
2
2) Clinical history
Patient with premature (men:<55 years;women:<60 years)
coronary artery disease
2
Patient with premature (men:<55 years;women:<60 years)
cerebral or peripheral vascular disease
1
3) Physical examinationa
Tendinous xanthomata 6
Arcus cornealis before age 45 years 4
4) LDL-C levels
LDL-C ≥ 8.5 mmol/L (325 mg/dL) 8
LDL-C 6.5–8.4 mmol/L (251–325 mg/dL) 5
LDL-C 5.0–6.4 mmol/L (191–250 mg/dL) 3
LDL-C 4.0–4.9 mmol/L (155–190 mg/dL) 1
5) DNA analysis
Functional mutation in the LDLR,apoB or PCSK9 gene 8
Choose only one score per group,the highest applicable
Diagnosis (diagnosis is based on the total number of points
obtained)
A‘probable’ FH diagnosis requires 6–8 points
A‘possible’ FH diagnosis requires 3–5 points
A ‘definite’ FH diagnosis requires >8 points
FH ¼ familial hypercholesterolaemia; LDL-C ¼ low-density
lipoproteincholesterol.
a
Exclusive of each other (i.e. maximum 6 points if both are present)
ESC/EAS Guidelines 3035
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
,2.6 mmol/L (100 mg/dL) or ,1.8 mmol/L (70 mg/dL) if CVD is
present.
PCSK9 antibodies have recently been registered for use in FH patients.
The drugs very efﬁciently lower LDL-C by up to 60% on top
of the statin. Randomized controlled studies have yet to report clinical
endpoints and therefore the use of these drugs should be limited.
PCSK9 inhibitors should be considered in patients with FH at very
high risk due to the presence of CVD, a family history of CAD at a
very young age or an LDL-C level far from goal even on maximal other
therapy. PCSK9 inhibitors should also be considered in HeFH patients
who cannot tolerate statins and in FH patients with high Lp(a).
Recommendations for the detection and treatment of patients
with HeFH are shown in Table 22.
9.1.2.2 Homozygous familial hypercholesterolaemia
Homozygous FH (HoFH) is a rare and life-threatening disease.
The clinical picture is characterized by extensive xanthomas, marked
premature and progressive CVD and total cholesterol .13 mmol/L
(500 mg/dL). Most patients develop CAD and aortic stenosis before
the age of 20 years and die before 30 years of age. The frequency of
HoFH is estimated to be 1/160 000–1/300 000. The early identiﬁcation
of these children and prompt referral to a specialized clinic is crucial.
The patients should be treated with available cholesterollowering
drugs and, when available, with lipoprotein apheresis. For
a more detailed discussion of HoFH, including the role of PCSK9
inhibitors and the microsomal triglyceride transfer protein (MTP) inhibitor
lomitapide, see the EAS consensus paper on HoFH.302
9.1.2.3 Familial hypercholesterolaemia in children
FH is diagnosed in children based on phenotypic criteria including elevated
LDL-C plus a family history of elevated LDL-C, premature CAD
and/or positive genetic testing.303
Testing during childhood is optimal
to discriminate between FH and non-FH using LDL-C. LDL-C
≥5 mmol/L (190 mg/dL) is most probably FH. In children with a family
history of high cholesterol or premature CHD, the cut-off point may
be put at ≥4.0 mmol/L (160 mg/dL). If a parent has a known genetic
defect, the diagnostic level for the child is ≥3.5 mmol/L (130 mg/dL).
Although placebo-controlled trials are missing in children, there
are observational studies suggesting that early treatment can reduce
LDL-C burden, improve endothelial function, substantially attenuate
development of atherosclerosis and improve coronary out-
comes.303
Treatment of children with FH includes a healthy lifestyle
and statin treatment. A heart-healthy diet should be adopted early in
life and statin treatment should be considered at 8–10 years of age.
Statin treatment should be started with low doses and the dose
should be increased to reach goals. The goal in children .10 years
of age is an LDL-C ,3.5 mmol/L (135 mg/dL) and at younger ages at
least a 50% reduction of LDL-C.
9.1.3 Familial dysbetalipoproteinaemia
Familial dysbetalipoproteinaemia (i.e. type III hyperlipoproteinaemia;
remnant removal disease) is rare and is generally inherited as
an autosomal recessive disorder with variable penetrance. It is
rare for it to be expressed in women before menopause. The majority
of cases are homozygous for the E2 isoform of apoE. ApoE is
important for hepatic clearance of chylomicron remnants and IDL.
ApoE2 binds less readily than isoforms E3 or E4 to hepatic receptors.
However, without some coincidental cause of dyslipidaemia,
apoE2 homozygosity does not generally cause familial dysbetalipoproteinaemia
syndrome. The syndrome often develops in the presence
of dyslipidaemia associated with HTG, diabetes mellitus,
obesity or hypothyroidism.
Familial dysbetalipoproteinaemia produces a characteristic clinical
syndrome in which both TC and TGs are elevated before treatment,
usually both in the range of 7–10 mmol/L. In severe cases,
patients develop tuberoeruptive xanthomata, particularly over the
elbows and knees, and palmar xanthomata in the skin creases of
the hands and wrists. The risk of CAD is very high, and accelerated
atherosclerosis of the femoral and tibial arteries is also prevalent.
The detection of apoE2 homozygosity in a dyslipidaemic patient is
diagnostic and analysis of apoE isoforms is now available in most clinical
laboratories. In older patients with xanthomata resembling
those of familial dysbetalipoproteinaemia, who prove not to be
Table 22 Recommendations for the detection and
treatment of patients with heterozygous familial
hypercholesterolaemia
Recommendations Classa
Level b
FH is recommended to be suspected in patients
with CHD before the age of 55 years for men
and 60 years for women, in subjects with
relatives with premature fatal or non-fatal
CVD, in subjects with relatives having tendon
xanthomas, and in subjects with severely
elevated LDL-C [in adults >5 mmol/L
(190 mg/dL), in children >4 mmol/L
(150 mg/dL)].
I C
with clinical criteria and, when available, with
DNA analysis.
I C
Family cascade screening is recommended to
be performed when an index case of FH is
diagnosed.
I C
FH patients are recommended to be treated
with intense-dose statin, often in combination
with ezetimibe.
I C
Treatment should be considered to aim at
reaching an LDL-C <2.6 mmol/L (100 mg/dL) or
in the presence of CVD <1.8 mmol/L
(70 mg/dL). If targets cannot be reached,
maximal reduction of LDL-C should be
considered using appropriate drug
combinations.
IIa C
Treatment with a PCSK9 antibody should be
considered in FH patients with CVD or with
other factors putting them at very high-risk
for CHD, such as other CV risk factors, family
history, high Lp(a) or statin intolerance.
IIa C
In children, testing is recommended from age
5 years, or earlier if homozygous FH is suspected.
I C
Children with FH should be educated to adopt
a proper diet and treated with statin from
8–10 years of age. Targets for treatment should
be LDL-C <3.5 mmol/L (135 mg/dL) at
>10 years of age.
IIa C
Diagnosis is recommended to be confirmed
CHD ¼ coronary heart disease; CVD ¼ cardiovascular disease; FH ¼ familial
hypercholesterolaemia; LDL-C ¼ low-density lipoprotein-cholesterol; Lp(a) ¼
lipoprotein(a).
a
Class of recommendation.
b
Level of evidence.
ESC/EAS Guidelines3036
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
homozygous for apoE2, a paraprotein should be sought. The treatment
of familial dysbetalipoproteinaemia should be undertaken in a
specialist clinic. Most cases respond well to treatment with a statin
or, if dominated by high TGs, a ﬁbrate; often a combination of a statin
and a ﬁbrate may be needed.
9.1.4 Genetic causes of hypertriglyceridaemia
The genetic aetiology for HTG seems to be very complex, with effects
of both common and rare genetic variants.67,304
Moderate elevation of
TG levels (between 2.0–10.0 mmol/L) is caused by the polygenic effect
of multiple genes inﬂuencing both VLDL production and removal. In
CVD prevention, polygenic moderate TG elevation is to be considered.
Monogenic severe HTG causes pancreatitis and lipid deposits.
Thus far, mutations in six genes (LPL, apoC2, apoA5, LMF1, GPIHBP1
and GPD1) with monogenic effect have been recognized to lead to severe
elevation of serum TGs due to disruption of the chylomicron removal
pathways. These mutations are inherited as an autosomal
recessive trait and are rare. A profound defect in the catabolism of chylomicrons
and VLDL results in chylomicronaemia and TG levels
.11.2 mmol/L (1000 mg/dL), with turbid and milky serum. Severe
HTG is seen in patients who are homozygous or compound heterozygous
for mutations of the enzyme lipoprotein lipase (LPL) and in the
other genes linked to catabolism of TG-rich lipoproteins. Recently,
gene therapy for LPL deﬁciency has been developed and tested in clinical
trials305
and the alipogene tiparvovec was approved by the EMA in
2013. A gain of function mutation in apoC3 leading to high apoC3 levels
can also cause severe HTG by the inhibition of LPL activity, whereas
loss of function mutations are associated with a favourable lipid proﬁle
with low TG levels.306
These ﬁndings have raised the possibility of
apoC3 as a novel lipid drug target. In summary, the development of
new therapeutic options for this rare disease raises the need for awareness
and screening of these patients.
9.1.4.1 Action to prevent acute pancreatitis in severe
hypertriglyceridaemia
The risk of pancreatitis is clinically signiﬁcant if TGs exceed
10 mmol/L (880 mg/dL), and actions to prevent acute pancreatitis
are mandatory. Notably, HTG is the cause of 10% of all cases with
pancreatitis, and patients can develop pancreatitis even when their TG
concentration is 5–10 mmol/L (440–880 mg/dL). Recent data from a
prospective cohort study (n ¼ 33 346) reported that the risk of acute
pancreatitis increased signiﬁcantly over the quartiles of serum TGs,
highlighting that serum TGs as a risk factor may have been underesti-
mated.307
Any factor that increases VLDL production can aggravate the
risk of pancreatitis, with alcohol consumption being the most common
contributing factor. The patient should be admitted to hospital if symptomatic,
or careful and close follow-up of the patient’s TG values
should be undertaken. Restriction of calories and fat content (10–
15% recommended) in the diet and alcohol abstinence are obligatory.
Fibrate therapy (fenoﬁbrate) should be initiated, with n-3 fatty acids
(2–4 g/day) as adjunct therapy or nicotinic acid. Lomitapide may also
be considered in severe cases.67
In patients with diabetes, insulin therapy
should be initiated to achieve good glycaemic control. In general, a
sharp decrease of TG values is seen within 2–5 days. In the acute setting,
plasmapheresis is able to rapidly lower TG levels.308
9.1.5 Other genetic disorders of lipoprotein metabolism
(Table 23)
Sometimes patients are encountered with extremely low levels of
LDL-C or HDL-C. The most common genetic hypolipidaemia is hypobetalipoproteinaemia,
which is dominantly inherited and often
due to truncation of apoB. Serum LDL-C is typically between 0.5
and 1.5 mmol/L (20–60 mg/dL). It is generally of no medical signiﬁcance.
A more profound deﬁciency of apoB occurs in abetalipoproteinaemia
when steatorrhoea and neurological or other
complications require specialist treatment. Almost absent levels of
HDL-C occur in Tangier disease (analphalipoproteinaemia) and
very low levels of HDL-C occur in lecithin cholesterol acyltransferase
(LCAT) deﬁciency. Both these conditions are associated with
distinct clinical syndromes and require specialist investigation.
Very high levels of HDL-C are detected in patients with CETP deﬁciency.
In the heterozygous form, typically levels of 2.0–2.4 mmol/L
(80–90 mg/dL) are observed, and levels ≥5 mmol/L (200 mg/dL)
are observed in homozygotes. This is not associated with atherosclerotic
disease and may be associated with reduced risk.
Lysosomal acid lipase (LAL) deﬁciency or cholesterol ester storage
disease (in children with Wolman disease) is a rare cause
Table 23 Genetic disorders of lipoprotein metabolism
Disorder Prevalence Gene(s) Effect on lipoproteins
HeFH 1 in 200–250 LDLR
APO B
PCSK9
↑LDL-C
HoFH 1 in 160 000–320 000 LDLR
APO B
PCSK9
↑↑LDL-C
FCH 1 in 100/200 USF1 + modifying genes ↑LDL-C ↑VLDL-C ↑apoB
Familial dysbetalipoproteinaemia 1 in 5000 APO E ↑↑ IDL and chylomicron
remnants (βVLDL)
1 in 106
LPL
APO C2
↑↑ chylomicrons andVLDL-C
Tangier disease (analphalipoproteinaemia) 1 in 106
ABCA1 ↓↓HDL-C
1 in 106
LCAT ↓HDL-C
Familial lipoprotein lipase deficiency
Familial LCAT deficiency
apo ¼ apolipoprotein; FCH ¼ familial combined hyperlipidaemia; HeFH ¼ heterozygous familial hypercholesterolaemia; HoFH ¼ homozygous familial hypercholesterolaemia;
HDL-C ¼ high-density lipoprotein-cholesterol; IDL ¼ intermediate-density lipoprotein; LCAT ¼ lecithin cholesterol acyltransferase; LDL-C ¼ low-density
lipoproteincholesterol; VLDL ¼ very low-density lipoprotein-cholesterol.
ESC/EAS Guidelines 3037
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
(recessive transmission) of elevated LDL-C and low HDL-C accompanied
by hepatomegaly and microvesicular hepatosteatosis. Statin
treatment does decrease LDL-C, and therefore could prevent CVD
in these patients, but it cannot stop the progression of liver damage.
Enzyme replacement therapy with sebelipase alfa might offer a treatment
solution in the near future.309
9.2 Children
Only children with FH should be considered for lipid-lowering drug
treatment. In other cases of dyslipidaemia in children, focus should
be on diet and treatment of underlying metabolic disorders. HoFH
patients should be treated with lipid-lowering drugs as early as possible,
and the same is true for HeFH patents with extremely high
LDL-C, i.e. ≥400 mg/dL ( 10.3 mmol/L).310
In the case of other
HeFH children, statin treatment is generally withheld until sometime
between the ages of 8 and 10 years. There is evidence from carotid
ultrasound measurements that increased CIMT in children with
HeFH compared with siblings who have not inherited HeFH can
be detected from the age of 6 years onwards, and that the progression
of increasing CIMT can be ameliorated with statin therapy and/
or apheresis.311
However, the exact age at which to start statin
treatment is a matter of clinical judgement.
9.3 Women
Among several studies that have evaluated the impact of
lipid-lowering therapy on primary and secondary prevention of
CAD, only a few have included women, usually in small numbers,
and the results have often not been separately reported by gen-
der.312
The most recent CTT meta-analysis, however, indicates a
similar relative beneﬁt in men and women.65
9.3.1 Primary prevention
The beneﬁt of statins in primary prevention is less well-established
in women than in men. This may be because of their lower baseline
risk and their underrepresentation in trials, and points to the need
to include gender balance and sufﬁcient numbers to detect modest
absolute treatment effects in future trials.
The 2013 Cochrane analysis showed reductions of all-cause mortality,
vascular events and revascularisations with statins in primary
prevention. Effects in women were similar to those in men.200
In
postmenopausal women, plaque rupture was found to be a more
common cause of ACS than plaque erosion and is correlated with
TC levels.313
A recent meta-analysis of statin trials in the CTT database compared
the effects of statin therapy between men and women.65
The
proportional (relative risk) reductions in major coronary events,
coronary revascularisations and stroke did not differ signiﬁcantly
by gender. All-cause mortality reductions were seen in both women
and men, showing that statin therapy is of similar effectiveness. Signiﬁcant
decreases in vascular events in primary prevention were
seen in both women and men. Thus statin use should be considered
for primary prevention in women at high CV risk with the same
indications as for men.
9.3.2 Secondary prevention
More data coming from large RCTs of secondary prevention are available
for women. The results of these trials concordantly show that
lipid-lowering therapy substantially reduces CV events in these patients,
although no reduction in total mortality risk could be
demonstrated. The meta-analysis of Walsh and Pignone314
reported
a 26% reduction of CV mortality, a 29% reduction of MI and a 20% reduction
of total CAD events in a cohort of 8272 females with previous
CVD mainly treated with statins. The CTT meta-analysis also indicates
that the beneﬁt overall is similar in men and women.65
Therefore, secondary
prevention of CV events in women should routinely include a
statin-based lipid-lowering regimen, with the same recommendations
and therapeutic goals that are applied to men.
9.3.3 Non-statin lipid-lowering drugs
No deﬁnitive evidence of cardioprotective effects was available until
recently. The IMPROVE-IT study63
included patients at least 50 years
of age who had been hospitalized within the preceding 10 days for an
ACS (24% women). The combination of simvastatin–ezetimibe was
compared with simvastatin monotherapy. The rate of the composite
endpoint of death from CV causes, MI or stroke was signiﬁcantly lower,
by 1.8 percentage points, in the combination group and the beneﬁt
of simvastatin–ezetimibe was consistent for women.63
The ACCORD lipid study showed less primary event reduction
with combination therapy in women, but the recent FIELD study
analysis showed consistent CV event reduction in women and
men.315
Ezetimibe, or ﬁbrates, alone or in combination with statins,
can be used, depending on the type of dyslipidaemia and adverse
effect proﬁles. Recent data with PCSK9 inhibitors indicate a similar
efﬁcacy in reducing LDL-C in women vs. men.115,116
9.3.4 Hormone therapy
Currently used third-generation low-dose oestrogen–progestin oral
contraceptives do not appear to increase adverse coronary events316
and can be used, after baseline lipid proﬁle assessment, in women
with acceptable TC levels. In contrast, alternative contraceptive measures
should be recommended in women with hypercholesterolaemia
[LDL-C .4 mmol/L (160 mg/dL)] or with multiple risk
factors and in those at high risk of thrombotic events.317
Oestrogen
replacement therapy, despite some favourable effects on the lipid
proﬁle, has not been demonstrated to reduce CV risk and cannot
be recommended for CVD prevention in women.318
No
lipid-lowering drugs should be administered during pregnancy and
the period of breastfeeding since data on possible adverse effects
are lacking. However, bile acid sequestrants may be considered.
Box 10 lists the main measures in the management of dyslipidaemia
in women.
9.4 Older persons
The proportion of older people in society is increasing and, as a consequence,
.80% of individuals who die from CVD are .65 years of
age. The proportion of patients with MI .85 years of age has increased
several fold.319
Coronary care has also been improved for
Box 10 Management of dyslipidaemia in women
Statin treatment is recommended for primary prevention of CAD in
high-risk women.64,65
Statins are recommended for secondary prevention in women with the
same indications and targets as in men.64,65
Lipid-lowering drugs should not be given when pregnancy is planned,
during pregnancy or during the breastfeeding period. However, bile acid
sequestrants (which are not absorbed) may be considered.
ESC/EAS Guidelines3038
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
older adults, with improving prognosis after the ﬁrst MI.320
To target
the older population with risk reduction is important since CVD or
subclinical atherosclerosis is common and dyslipidaemia is frequent.
Results from a meta-analysis on blood cholesterol and vascular
mortality indicates that high TC is a signiﬁcant risk factor for CAD
mortality at all ages, but this association is attenuated in older adults;
1 mmol/L (38.7 mg/dL) lower TC was associated with about onehalf
[hazard ratio (HR) 0.44] lower CAD mortality in the age group
40–49 years compared with an HR of 0.85 in those 80–89 years
old.321,322
However, although a relative risk reduction is seen in
the oldest subjects, the increased frequency of CAD means that
the absolute number of cases associated with cholesterol is highest
in this group. Evidence for treatment in this group, particularly for
those .80–85 years of age, is limited, and clinical judgement should
guide decisions in the very old.
9.4.1 Primary prevention
The most important way to prevent CVD in older adults is to promote
a healthy lifestyle and reduction of risk factors early in life. Several
studies have shown that a healthy lifestyle early in life prevents
CVD in older age and reduces lifetime risk for CVD.53,323 – 325
Lifetime
prevention includes no smoking, control of blood pressure,
healthy eating habits, regular exercise and controlling body weight.
No primary prevention study has speciﬁcally targeted the older
population.326
Available data are based on subgroup analyses from
controlled studies. In a recent meta-analysis, subjects .65 years of
age (n ¼ 24 674) from eight studies were included.327
Statin treatment
reduced MI (RR 0.61) and stroke (RR 0.76). The reduction
in all-cause mortality was not signiﬁcant (RR 0.94). In the Air
Force/Texas Coronary Atherosclerosis Prevention (AFCAPS-TEXCAP)
study, risk reduction was similar above and below the median
age (57 years for men and 62 years for women).328
In the Justiﬁcation
for the Use of Statins in Prevention: an Intervention Trial Evaluating
Rosuvastatin (JUPITER) trial a post hoc analysis of subjects
older and younger than 70 years showed that the relative risk reduction
for a composite CVD endpoint was similar in the two groups.
The number needed to treat for 4 years to prevent one major event
was 24 in the older group and 36 in the younger age group.329
9.4.2 Secondary prevention
Also in secondary prevention, very few studies have targeted the older
population. The Prospective Study of Pravastatin in the Elderly at Risk
(PROSPER) study included patients 70–82 years of age with CVD or
at high risk for CVD.330
Patients were treated with pravastatin 40 mg
daily or placebo. The relative risk reduction for a combined CAD endpoint
was reduced by 15%, whereas no reduction was shown for
stroke. In the Studies Assessing Goals in the Elderly (SAGE) trial,
893 patients 65–83 years of age with stable CAD were recruited to
treatment with atorvastatin 80 mg or pravastatin 40 mg.331
The atorvastatin
group had a lower all-cause mortality (HR 0.33) and a nonsigniﬁcant
trend towards reduction in major CAD events.
Subgroup analyses in randomized trials have been performed for
several studies. In the Scandinavian Simvastatin Survival Study (4S)
trial, patients .65 years of age had a similar relative risk reduction
as younger patients.332
In the Heart Protection Study (HPS), 20 536
individuals were allocated to simvastatin or placebo. After 5 years
the relative risk reduction was 18% for coronary death and 25%
for coronary events. The reduction was similar in age groups
,65, 65–70 and .70 years.333
Similar results were found in subgroup
analyses of the Long-Term Intervention with Pravastatin in Ischemic
Disease (LIPID),334
Cholesterol and Recurrent Events
(CARE)335
and TNT trials.336
From data in the LIPID trial the
authors calculated that per 1000 persons treated, 45 deaths and
47 major coronary events would be prevented in the older group
over 6 years compared with 22 deaths and 32 major coronary
events in younger patients over the same time period.
In a CTT meta-analysis, rate ratios for the effects of statins on major
vascular events were 0.78, 0.78 and 0.84 in age groups ,65, 65–
75 and .75 years, respectively.64
Results from an MI registry study
in Sweden demonstrate that statin treatment is associated with lower
CV mortality in very old post-MI patients without (which is
important to stress) increasing the risk of cancer.337
9.4.3 Adverse effects, interactions and adherence
The safety and adverse effects of statins are a matter of special concern
in older adults because they often have co-morbidities, take multiple
medications and have altered pharmacokinetics and pharmacodynamics.
Statin–drug interactions are a concern primarily because of their
potential to increase muscle-related statin-associated adverse effects
such as myalgia without CK elevation, myopathy with CK elevation
and the rare but serious rhabdomyolysis. Statin treatment should be
started at a low dose to avoid adverse events and then titrated to
achieve optimal LDL-C levels with an appropriate dose.
Older adults are less likely to be prescribed lipid-lowering medications,
or adhere to statin therapy, than younger or middle-age
subjects. Cost, adverse effects, coronary events occurring despite
being on lipid-lowering agents and the wrong perception that the
drug is not beneﬁcial are among the reasons for non-adherence. Improving
patient understanding of CV risk, the medication regimen
and potential beneﬁts of persistence with statin therapy may enhance
adherence.
Table 24 Recommendations for the treatment of
dyslipidaemia in older adults
Recommendations Classa
Level b
Ref c
Treatment with statins is
recommended for older adults with
established CVD in the same way as
for younger patients.
I A 334, 337
Since older people often have
co-morbidities and have altered
pharmacokinetics, lipid-lowering
medication should be started at a
lower dose and then titrated with
caution to achieve target lipid levels
that are the same as in younger
subjects.
IIa C
Statin therapy should be considered
in older adults free from CVD,
particularly in the presence of
hypertension, smoking, diabetes
and dyslipidaemia.
IIa B
62, 64,
65
CVD ¼ cardiovascular disease.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
ESC/EAS Guidelines 3039
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
Table 24 lists the recommendations for treatment of dyslipidaemia
in older adults.
9.5 Diabetes and metabolic syndrome
Diabetes seems to be the fastest increasing disease in the world and
it is estimated that the number of people with diabetes will increase
from 350 million today up to 550 million by 2030.338
Despite signiﬁcant
advantages in the management strategies that lessen CVD
risk factors, CVD has remained the leading cause of morbidity and
mortality in patients with type 2 diabetes mellitus (T2DM). It has
been estimated that the years of life lost for a 50-year-old person
with diabetes averages at 6 years and 58% of this difference is
due to excess vascular disease.339
Diabetes itself is an independent
risk factor for CVD and is associated with a higher risk of CVD, even
more so in women. Although the difference in CVD risk between
individuals with and without diabetes has narrowed substantially
over the last decades, there are strong associations between diabetes
and vascular outcomes.340,341
Recent data indicate that diabetes per se
increases CVD risk about two-fold on average, but the risk is subject
to wide variation depending on the population.342
Importantly, those
with diabetes and CAD are at substantially higher CVD risk for future
events. Hypertension, dyslipidaemia and abdominal obesity commonly
co-exist with T2DM and further aggravate the risk, which is highest in
people with T2DM and features of MetS.343,344
Importantly, diabetes
confers excess mortality risk following ACS despite modern therapies,
highlighting the poor prognosis of coronary patients with T2DM and
the need for intensive therapy.345
Even more frequent are conditions predisposing to diabetes, such
as the so-called metabolic syndrome. The term MetS refers to the
clustering of different cardiometabolic risk factors: central obesity,
raised serum TGs, reduced HDL-C, glucose intolerance and high
blood pressure.346,347
Scoring systems that dichotomize these variables
may miss some of the associated risk; a practical approach is
that if one component is identiﬁed, a systematic search should be
made for others.
MetS identiﬁes people at a higher risk of CVD than the general
population. Data from recent meta-analyses indicate that people
with MetS have a two-fold increase in CV outcomes and a
1.5-fold increase in all-cause mortality.348
How to capture the extra
risk beyond the traditional risk factors in clinical practice is a debated
issue. A combination of large waist circumference and elevation
of TGs is a simple and inexpensive screening tool to discriminate
people with MetS at high CVD risk for global risk evaluation.180
9.5.1 Speciﬁc features of dyslipidaemia in insulin resistance
and type 2 diabetes (Table 25)
Diabetic dyslipidaemia is a cluster of plasma lipid and lipoprotein abnormalities
that are metabolically interrelated. The increase in large
VLDL particles in T2DM initiates a sequence of events that generates
atherogenic remnants, small dense LDL and small TG-rich
dense HDL particles.349
These components are not isolated abnormalities
but are closely linked to each other. Both LDL and HDL
particles show variable compositional changes that are reﬂected
in their functions. Notably apoCIII levels are increased in subjects
with T2DM.350
Together, TRL remnants, small dense LDL and small
dense HDL comprise the atherogenic lipid proﬁle, which is also
characterized by an increase in apoB concentration due to an increased
number of apoB-containing particles. Importantly, TRLs,
including chylomicrons, VLDL and their remnants, carry a single
apoB molecule, also like LDL particles. Therefore the malignant nature
of diabetic dyslipidaemia is not always revealed by the lipid measures
used in clinical practice, as LDL-C may remain within the
normal range. It may be better revealed by non-HDL-C. Elevation
of TGs or low HDL-C is seen in about half of subjects with
T2DM.351
The abnormal features of the lipid proﬁle precede the onset
of T2DM by several years and are common in subjects with central
obesity, MetS and T2DM.
9.5.2 Evidence for lipid-lowering therapy
9.5.2.1 Low-density lipoprotein cholesterol
LDL-C is stipulated to be the primary target of lipid-lowering therapy
in diabetes. Trials speciﬁcally performed in subjects with T2DM
as well as subsets of individuals with diabetes in major statin trials
have consistently demonstrated signiﬁcant beneﬁts of statin therapy
on CVD events in people with T2DM.64
Statin therapy reduces the
5-year incidence of major CVD events by 23% per 1 mmol/L reduction
in LDL-C, regardless of the initial LDL-C or other baseline characteristics
based on meta-analysis.64
The CTT meta-analysis further
indicates that subjects with T2DM will have a relative risk reduction
that is comparable to that seen in non-diabetic patients, but being at
higher absolute risk, the absolute beneﬁt will be greater, resulting in
a lower number needed to treat (NNT). Recent studies have suggested
an increased incidence of diabetes in patients treated with
statins.225
This effect must not lessen our attention to the treatment
of patients, as the overall beneﬁt in CV events reduction remains.
9.5.2.2 Triglycerides and high-density lipoprotein cholesterol
Clinical beneﬁts achieved by the treatment of atherogenic dyslipidaemia
(high TGs and low HDL-C) are still a matter of discussion. Although
the Helsinki Heart Study reported a signiﬁcant reduction in
CVD outcomes with gemﬁbrozil, neither the FIELD nor the ACCORD
study showed a reduction in total CVD outcomes.261,262,265
The
FIELD trial failed to reduce signiﬁcantly the primary endpoint of
CAD events (CAD death or non-fatal MI). CVD events were reduced
signiﬁcantly by 11%. In a post hoc analysis of the FIELD study,
fenoﬁbrate reduced CVD events by 27% in those with elevated TGs
Table 25 Summary of dyslipidaemia in metabolic
syndrome and in type 2 diabetes
Dyslipidaemia in MetS represents a cluster of lipid and lipoprotein
abnormalities including elevation of both fasting and postprandial TG,
apoB,and small dense LDL and low HDL-C and apoA1.
Non-HDL-C or apoB are good surrogate markers ofTRLs and remnants
and are a secondary objective of therapy. Non-HDL-C <3.4 mmol/L
(<130 mg/dL) or apoB <100 mg/dL is desirable in those at high-risk,
and <2.6 mmol/L (<100 mg/dL) and <80 mg/dL, respectively, in those at
very high-risk.
Increased waist circumference and elevation ofTG seems to be a simple
tool to capture the high-risk subjects with MetS.
Atherogenic dyslipidaemia is one of the major risk factors for CVD in
people with type 2 diabetes.
apoB ¼ apolipoprotein B; CVD ¼ cardiovascular disease; HDL-C ¼ high-density
lipoprotein-cholesterol; LDL-C ¼ low-density lipoprotein-cholesterol; MetS ¼
metabolic syndrome; TG ¼ triglycerides; TRLs ¼ triglyceride-rich lipoproteins.
ESC/EAS Guidelines3040
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
[.2.3 mmol/L ( 204 mg/dL)] and reduced HDL-C (NNT ¼
23).351
The ACCORD trial conﬁrmed this: patients who had both
TG levels in the higher third [≥2.3 mmol/L (204 mg/dL)] and an
HDL-C level in the lower third [≤0.88 mmol/L (34 mg/dL)], representing
17% of all participants, appeared to beneﬁt from adding fenoﬁbrate
to simvastatin.262
A post hoc analysis of patients with low HDL-C [,1 mmol/L
( 40 mg/dL)] and elevated TGs [.1.80 mmol/L ( 160 mg/dL)] in
the 4S trial demonstrated a relative risk for major coronary events of
0.48 with simvastatin. The respective relative risk for overall mortality
was 0.44.352
Consistent with these ﬁndings, a meta-analysis of ﬁbrates
in the prevention of CVD in 11 590 people with T2DM showed that
ﬁbrates signiﬁcantly reduced the risk of non-fatal MI by 21%, but had
no effect on the risk of overall mortality or coronary mortality.353
The concept of raising HDL-C seems attractive based on the
strength of the relationship between low HDL-C and increased
CVD risk in observational studies. Evidence for a beneﬁcial clinical
effect of raising HDL-C is lacking, with lifestyle modiﬁcation providing
the ﬁrst option due to its multifaceted effects.
9.5.3 Treatment strategies for subjects with type 2
diabetes and metabolic syndrome
Lifestyle therapy to improve the atherogenic lipid proﬁle should be recommended
to all subjects with T2DM and MetS (see section 5). Dietary
advice should be tailored according to the individual’s needs. If
LDL-C goals are not achieved on maximally tolerated doses of statins,
drug combinations may offer additional lowering of LDL-C, but the
evidence from outcome studies is limited.354
Patients with T2DM
,40 years of age, with a short duration of therapy, without other
risk factors, without complications and with an LDL-C level
,2.6 mmol/L (100 mg/ dL) may not need lipid-lowering drugs.
9.5.4 Type 1 diabetes
Type 1 diabetes is associated with high CVD risk, in particular in patients
with microalbuminuria and renal disease.355
Conclusive evidence
supports the proposition that hyperglycaemia accelerates
atherosclerosis. Emerging evidence highlights the frequent coexistence
of MetS with type 1 diabetes, resulting in this so-called double
diabetes increasing CVD risk.356
The lipid proﬁle in type 1 diabetic subjects with good glycaemic
control is ‘supernormal’ and characterized by subnormal TGs and
LDL-C, whereas HDL-C is usually within the upper normal range
or slightly elevated. This is explained by subcutaneous administration
of insulin that increases LPL activity in adipose tissue and skeletal
muscle and consequently the turnover rate of VLDL particles.
However, there are potentially atherogenic changes in the composition
of both HDL and LDL particles. In all patients with type 1 diabetes
and in the presence of microalbuminuria and renal disease,
LDL-C lowering (at least 30%) with statins as the ﬁrst choice
(drug combination may be considered if needed) is recommended
irrespective of the basal LDL-C concentration.
Recommendations for the treatment of dyslipidaemia in diabetes
are shown in Table 26.
9.6 Patients with acute coronary
syndrome and patients undergoing
percutaneous coronary intervention
Patients who have presented recently with ACS are at high risk of
experiencing further CV events. In these patients, lipid management
should be undertaken in the context of a comprehensive global
risk management strategy that includes lifestyle adaptations,
management of risk factors and the use of cardioprotective drugs
in certain subgroups. Ideally, this can be well coordinated through
participation in a multidisciplinary cardiac rehabilitation
programme.
9.6.1 Speciﬁc lipid management issues in acute coronary
syndrome
Data from speciﬁc trials358 – 360
and meta-analysis support routine
early use of prompt, intensive and prolonged statin therapy. Thus
we recommend that high-intensity statin therapy be initiated during
the ﬁrst 1–4 days of hospitalization for the index ACS; the dose should
aim at reaching the LDL-C goal of ,1.8 mmol/L ( 70 mg/dL) or a
50% reduction of LDL-C as indicated in Table 11 on treatment goals.
The use of lower-intensity statin therapy should be considered in patients
at increased risk of adverse effects with high-intensity statins (e.g.
the elderly, hepatic impairment, renal impairment or potential for
interaction with essential concomitant therapy). Ezetimibe further
Table 26 Recommendations for the treatment of dyslipidaemia in diabetes
Recommendations Classa
Level b
Ref c
In all patients with type I diabetes and in the presence of microalbuminuria and/or renal disease, LDL-C lowering (at least
I C 64, 357
In patients with type 2 diabetes and CVD or CKD, and in those without CVD who are >40 years of age with one or more
other CVD risk factors or markers of target organ damage, the recommended goal for LDL-C is <1.8 mmol/L (<70 mg/dL)
and the secondary goal for non-HDL-C is <2.6 mmol/L (<100 mg/dL) and for apoB is <80 mg/dL.
I B 62, 64
In all patients with type 2 diabetes and no additional risk factors and/or evidence of target organ damage, LDL-C <2.6 mmol/L
(<100 mg/dL) is the primary goal. Non-HDL-C <3.4 mmol/L (<130 mg/dL) and apoB <100 mg/dL are the secondary goals.
I B 62, 64
50%) with statins as the first choice is recommended irrespective of the baseline LDL-C concentration.
apoB ¼ apolipoprotein B; CKD ¼ chronic kidney disease; CVD ¼ cardiovascular disease; HDL-C ¼ high-density lipoprotein-cholesterol; LDL-C ¼ low-density
lipoproteincholesterol; MetS ¼ metabolic syndrome; TG ¼ triglycerides.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
ESC/EAS Guidelines 3041
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
reduced LDL-C and offered additional beneﬁt (6.4% relative risk reduction
in composite clinical endpoint) in association with simvastatin
in post-ACS patients.63
Results in studies with PCSK9 inhibitors that
included post-ACS/very high-risk patients were promising115,116
and
deﬁnitive outcome studies are awaited.
Lipids should be re-evaluated 4–6 weeks after ACS to determine
whether lipid goals have been reached and whether there are any
safety issues; the therapeutic regimen can then be adapted accordingly.
Supplementation with highly puriﬁed n-3 PUFAs reduced mortality
in survivors of MI in one study (Gruppo Italiano per lo Studio della
Sopravvivenza nell’Infarto Miocardico (GISSI)], but failed to affect clinical
outcomes in two more recent trials using modern evidence-based
prevention therapies (most patients were on statins), and therefore
cannot be recommended in routine practice.361
Furthermore, in patients
who had experienced a recent ACS, the CETP inhibitor dalcetrapib
did not reduce the risk of recurrent CV events.362
9.6.2 Lipid management issues in patients undergoing
percutaneous coronary intervention
In an individual patient meta-analysis of 13 randomized studies that
included 3341 patients, it was shown that either pretreatment
with high-dose statin (ranging from .2 weeks to a single dose)
in statin-naı¨ve patients (11 studies) or loading of a high-dose statin
in patients receiving chronic statin therapy decreased periprocedural
MI and 30-day adverse events in patients undergoing percutaneous
coronary intervention (PCI).363 – 365
In all but one study,
PCI was performed in the setting of stable angina, or in a
non-emergent fashion in non-ST elevation ACS (NSTE-ACS). In
one study in the setting of primary PCI that was included in the
meta-analysis, coronary ﬂow was improved.366
Thus a strategy
of routine short pretreatment or loading (on the background of
chronic therapy) with high-dose statin before PCI should be considered
in elective PCI or in NSTE-ACS (class IIa, level of evidence
A).363 – 365
High-dose statin pretreatment or loading before primary
or delayed PCI for ST elevation MI (STEMI) requires further
study. Statin pretreatment is also effective in reducing the risk of
contrast-induced acute kidney injury after coronary angiography
or intervention.367
Recommendations for lipid-lowering therapy in patients
with ACS and patients undergoing PCI are shown in
Table 27.
9.7 Heart failure and valvular diseases
9.7.1 Prevention of incident heart failure in coronary
artery disease patients
The onset of heart failure (HF) increases the risk of mortality and
morbidity three to four times compared with patients without HF.
Pooling of results from RCTs suggested that cholesterol lowering
with statin treatment reduced incident HF by 9–45% in patients
with CAD.368,369
Four key prospective RCTs compared more intensive
vs. less intensive drug regimens. The more intense approach reduced
the incidence of hospitalization due to HF by an average of
27% in patients with acute and stable CAD without previous
HF.358,370 – 372
However, there is no evidence that statins can prevent
HF of non-ischaemic origin.
9.7.2 Chronic heart failure
HF patients have lower TC and LDL-C than patients without HF. In
contrast to patients without HF, low TC portends a poor prognosis
in HF. Routine administration of statins in patients with HF is not advised.
In two large RCTs373,374
there was no beneﬁt on hard endpoints,
such as CV mortality and non-fatal MI and stroke, in spite
of a decrease in hospitalizations373,375
and a marked reduction of
LDL-C and hs-CRP in patients with mainly systolic heart failure. In
any case, there is no evidence for harm in patients on statin treatment
after the occurrence of HF, and therefore there is no need
for discontinuation if patients are already on this medication. n-3
PUFAs may have a small beneﬁt. In the GISSI-HF RCT, a signiﬁcant
effect on primary endpoints (all-cause death and hospitalization for
Table 27 Recommendations for lipid-lowering therapy in patients with acute coronary syndrome and patients
undergoing percutaneous coronary intervention
Recommendations Classa
Level b
Ref c
It is recommended to initiate or continue high dose statins early after admission in all ACS patients without contraindication
or history of intolerance, regardless of initial LDL-C values.
I A
64,
358–360
If the LDL-C target is not reached with the highest tolerable statin dose, ezetimibe should be considered in combination
with statins in post-ACS patients.
IIa B 63
If the LDL-C target is not reached with the highest tolerable statin dose and/or ezetimibe, PCSK9 inhibitors may be
considered on top of lipid-lowering therapy; or alone or in combination with ezetimibe in statin intolerant patients or in
whom a statin is contra-indicated.
IIb C 115, 116
Lipids should be re-evaluated 4–6 weeks after ACS to determine whether target levels of LDL-C <1.8 mmol/L
(<70 mg/dL) or a reduction of at least 50% if the baseline is between 1.8 and 3.5 mmol/L (70 and 135 mg/dL) have been
reached and whether there are any safety issues. The therapy dose should then be adapted accordingly.
IIa C
Routine short pretreatment or loading (on the background of chronic therapy) with high-dose statins before PCI should be
considered in elective PCI or in NSTE-ACS.
IIa A 363–365
ACS ¼ acute coronary syndrome; LDL-C ¼ low-density lipoprotein-cholesterol; NSTE-ACS ¼ non-ST elevation acute coronary syndrome; PCI ¼ percutaneous coronary
intervention; PCSK9 ¼ proprotein convertase subtilisin/kexin type 9.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
ESC/EAS Guidelines3042
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
HF) was found in HF patients with New York Heart Association
(NYHA) classiﬁcations II–IV.376
9.7.3 Valvular disease
Aortic stenosis increases the risk of CV events and mortality. Suggestions
for an association between aortic stenosis, LDL-C and Lp(a), as
well as between cholesterol and increased risk for calciﬁcation of
bioprosthetic valves, were matched with early observational noncontrolled
trials that showed beneﬁcial effects of aggressive lipid lowering
in slowing the progression of aortic stenosis. However, this was
not conﬁrmed in RCTs.243,377,378
The Scottish Aortic Stenosis and
Lipid Lowering Trial, Impact on Regression (SALTIRE; 155 patients,
80 mg atorvastatin or placebo), the SEAS (1873 patients, simvastatin
40 mg plus ezetimibe 10 mg or placebo) and the Aortic Stenosis Progression
Observation: Measuring Effects of Rosuvastatin (ASTRONOMER;
269 patients, rosuvastatin 40 mg or placebo) trials failed to
show a reduction in the progression of aortic stenosis or related
events in patients with mild to moderate aortic stenosis. Notably, ischaemic
events were reduced by 21% in the SEAS trial. Furthermore,
in a post hoc analysis of the RCTs Incremental Decrease In Endpoints
Through Aggressive Lipid-lowering Trial (IDEAL) and Stroke
Prevention by Aggressive Reduction in Cholesterol Levels
(SPARCL), high-dose versus usual-dose statin therapy or placebo
did not impact the incidence of aortic valve stenosis among patients
without known aortic valve stenosis.379
Aortic valve sclerosis (calciﬁcation
of the aortic leaﬂets without impairment in leaﬂet excursion
or a signiﬁcant transvalvular pressure gradient) is associated with an
increased risk of CAD even in the absence of increased risk proﬁles.
In such patients, statins, acting at an earlier disease stage, may be useful
both for aortic valve disease and CAD progression; however, this
warrants further investigation.380
Regarding rheumatic mitral stenosis
and bioprosthetic valves, small observational studies suggest a
beneﬁt of statin treatment.381,382
Recommendations for lipid-lowering therapy in patients with HF
and valvular diseases are shown in Table 28.
9.8 Autoimmune diseases
Autoimmune diseases, including rheumatoid arthritis, SLE, psoriasis
and anti-phospholipid syndrome, are characterized by enhanced
atherosclerosis and consequently higher CV morbidity and mortality
rates compared with the general population.383 –385
The immune
system is believed to be involved in the pathogenesis of atherosclerosis.
Inﬂammatory components of the immune response as well as
autoimmune elements (e.g. autoantibodies, autoantigens and autoreactive
lymphocytes) are involved in these processes. These diseases
are characterized by inﬂammatory vasculitis and endothelial
dysfunction. Therefore particular attention should be paid to conventional
CVD risk factor treatment, including dyslipidaemia, in
these patients. Statins are effective in reducing disease activity, CV
events and mortality (particularly in primary prevention) in this setting,
while their discontinuation increases MI and mortality.386
However,
there is no ﬁrm indication to use lipid-lowering therapy only on
the basis of the presence of the disease (Table 29). Furthermore, no
speciﬁc LDL-C goal beyond that indicated by individual total risk has
been set for such patients.
9.9 Chronic kidney disease
CKD is deﬁned as abnormalities of kidney structure or function,
present for .3 months, with implications for health. CKD can be
classiﬁed on the basis of the GFR into ﬁve categories.387
In the adult
population, a decreasing GFR is associated with an increased CVD
risk, independent of other CV risk factors.388 –391
The CV mortality
in patients with stage 3 and stage 4 CKD is two-fold and three-fold
higher, respectively, when compared with patients with normal renal
function.391
Patients with CKD and established CVD have a much
higher mortality rate compared with patients with CVD and normal
renal function.392
Therefore patients with CKD are considered high
risk (stage 3 CKD) or very high risk (stage 4–5 CKD or on dialysis)
and there is no need to use risk estimation models in these patients.
9.9.1 Lipoprotein proﬁle in chronic kidney disease
The lipid proﬁle shows both quantitative and qualitative abnormalities
that worsen with declining GFR, being most pronounced in subjects
with end-stage renal disease (ESRD). In the initial stages of CKD,
TGs are speciﬁcally elevated and HDL-C lowered; the elevation of
TGs is caused by both increased production and impaired removal
of TRLs due to changes in regulatory enzymes and proteins. Consequently,
non-HDL-C and apoB levels are clearly increased. LDL subclasses
display a shift to an excess of small dense LDL particles. In
patients with ESRD, the catabolic rate of LDL is markedly prolonged,
resulting in clear elevation of both TC and LDL-C levels. Plasma Lp(a)
levels also start to increase early due to the prolonged residence times
Table 28 Recommendations for the treatment of
dyslipidaemia in heart failure or valvular disease
Recommendations Classa
Level b
Ref c
Cholesterol-lowering therapy with
statins is not recommended (but is
not harmful either) in patients with
heart failure in the absence of other
indications for their use.
III A 373, 374
n-3 PUFAs 1 g/day may be
considered for addition to optimal
treatment in patients with heart
failure.
IIb B 376
Cholesterol-lowering treatment is
not recommended in patients with
aortic valvular stenosis without
CAD in the absence of other
indications for their use.
III A
243,
377, 378
CAD ¼ coronary artery disease; PUFAs ¼ polyunsaturated fatty acids.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
Table 29 Recommendation for the treatment of
dyslipidaemia in autoimmune diseases
Recommendation Classa
Level b
The universal use of lipid-lowering drugs is
not recommended
III C
a
Class of recommendation.
b
Level of evidence.
ESC/EAS Guidelines 3043
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
of these particles in the circulation. Altogether, most patients with
stage 3–5 CKD have mixed dyslipidaemia and the lipid proﬁle is highly
atherogenic, with adverse changes in all lipoproteins.
9.9.2 Evidence for lipid management in patients with
chronic kidney disease
In a systematic review of 50 studies including 45 285 participants, the
beneﬁts and harms of statins were evaluated in comparison with placebo
or no treatment (47 studies) or another statin (3 studies) in
adults with CKD and no CVD at baseline.393
Statins consistently
lowered the death rate and major coronary events by 20%; statinrelated
effects on stroke and kidney function were found to be uncertain.
These results are in line with those from a meta-analysis of
11 RCTs including 21 293 patients with CKD, of whom 6857 were
receiving dialysis.394
In patients with CKD not on dialysis, treatment
with statins reduced all-cause mortality by 34%, CV mortality by
31%, CV events by 45% and stroke by 34%. In patients receiving dialysis,
treatment with statins had no effect on all-cause mortality and
stroke, but reduced CV mortality by 21% and CV events by 19%.
Stage 5 CKD (or on dialysis) is indeed a very high-risk condition
in which different factors inﬂuence outcome; results from RCTs
of lipid-altering therapies have not provided convincing evidence
of reduced CVD events in such patients.
In the 4D trial (Die Deutsche Diabetes Dialyse studie) involving a
cohort of 1200 patients with diabetes on haemodialysis, atorvastatin
had no positive effect on the primary composite endpoint of
CVD.395
The results from AURORA (A study to evaluate the Use
of Rosuvastatin in subjects On Regular haemodialysis: an Assessment
of survival and cardiovascular events), involving 2776 patients
on haemodialysis, show that rosuvastatin lowered LDL-C as expected
but had no signiﬁcant effect on the composite CVD end-
point.396
The neutral results question the beneﬁts of statins in
these very high-risk patients with poor outcomes.
In the SHARP study397
simvastatin and ezetimibe combination
therapy was associated with lower risk for major atherosclerotic
events (coronary death, MI, non-haemorrhagic stroke or any revascularization)
compared with placebo in persons with CKD stage
3A–5. The trial did not have sufﬁcient power to assess the effects
in the primary outcome separately in dialysis and non-dialysis patients,
but there was no good statistical evidence that the proportional
effects in dialysis patients differed from those seen in
patients not on dialysis; in general, CV risk was much lower in the
patients in the SHARP trial compared with those of the AURORA
and 4D trials, reﬂected in the lower event and mortality rates.
A cost-effectiveness analysis of statins for primary CVD prevention
in CKD398
showed that statins reduced absolute CVD risk in
patients with CKD but that the increased risk for rhabdomyolysis,
and competing risks associated with progressive CKD, partly offset
these gains. A systematic review of the beneﬁts and harms of statins
in patients with a functioning kidney transplant included 3465 patients,
free of CHD, from 22 studies. The authors concluded that
statins may reduce CV events, although treatment effects were imprecise;
due to heterogeneity, different statin regimens could not be
compared and additional studies are recommended.228
9.9.3 Safety of lipid management in patients with chronic
kidney disease
Safety issues and dose adjustment are important in advanced stages
of CKD (stages 3–5), as adverse events are commonly dose related
and due to increased blood concentration of the compound. Preference
should be given to regimens and doses that have been shown
to be beneﬁcial in RCTs conducted speciﬁcally in such patients.399
Prevention of coronary events has been documented with ﬂuvastatin
80 mg, atorvastatin 20 mg, rosuvastatin 10 mg, simvastatin/ezetimibe
20/10 mg, pravastatin 40 mg and simvastatin 40 mg. Lower
doses than those used in the trials may be appropriate in Asian
countries and in patients on polypharmacy and with co-morbidities.
Furthermore, statins that are eliminated mainly by the hepatic route
may be preferred (ﬂuvastatin, atorvastatin, pitavastatin). Statins metabolized
via CYP3A4 may result in adverse effects due to drug–
drug interactions, and special caution is required.
9.9.4 Recommendations of lipid management for patients
with chronic kidney disease
Based on the evidence for lipid management in patients with CKD,
the Kidney Disease: Improving Global Outcomes (KDIGO) organization
developed an updated clinical practice guideline for lipid
management in CKD.399
In line with this, but with a focus on those
patients at high or very high risk for developing CVD, recommendations
are summarized in Table 30.
9.10 Transplantation (Table 31)
Lipid abnormalities are common in patients who have undergone
solid organ transplantation and predispose patients to the development
of both atherosclerotic disease and transplant arterial vasculopathy,
resulting in major vascular events. Common general causes of
dyslipidaemia in these patients are diabetes, obesity, MetS and CKD.
Table 30 Recommendations for lipid management in
patients with moderate to severe chronic kidney disease
Recommendations Classa
Level b
Ref c
Patients with stage 3–5 CKD have
to be considered at high or very
high CV risk.
I A 388–392
The use of statins or statin/
ezetimibe combination is indicated
in patients with non-dialysisdependent
CKD.
I A
393,
394, 397
In patients with dialysis-dependent
CKD and free of atherosclerotic
CVD, statins should not be
initiated.
III A 395, 396
In patients already on statins,
ezetimibe or a statin/ezetimibe
combination at the time of dialysis
initiation, these drugs should be
continued, particularly in patients
with CVD.
IIa C
In adult kidney transplant recipients
treatment with statins may be
considered.
IIb C
CKD ¼ chronic kidney disease; CV ¼ cardiovascular.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
ESC/EAS Guidelines3044
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
Immunosuppressive drug regimens also have important adverse
effects on lipid metabolism. Glucocorticoid therapy causes weight
gain and exacerbates insulin resistance, leading to increases in TC,
VLDL and TGs and in the size and density of LDL particles. Calcineurin
inhibitors increase the activity of hepatic lipase, decrease
LPL and bind LDLR, resulting in reduced clearance of atherogenic
lipoproteins. A greater adverse impact on lipid proﬁles is seen
with ciclosporin than with tacrolimus. Sirolimus, a structural analogue
of tacrolimus, causes dyslipidaemia in almost half of the patients
receiving it. Patients should receive healthy lifestyle advice
as recommended for patients at increased risk of CVD.
Statins have a similar effect on lipids in transplant recipients as in the
general population. Although randomized trial data have shown that
statins have the potential to improve outcomes in heart transplant patients400
– 402
and renal transplant patients,403
the amounts of outcome
data are not extensive. A recent systematic review
demonstrated a strong trend towards reduced CVD events and mortality
with statins in renal transplant patients.403
Several potential drug
interactions must also be considered, especially with ciclosporin
which is metabolized through CYP3A4 and may increase systemic statin
exposure and the risk of myopathy. Fluvastatin, pravastatin, pitavastatin
and rosuvastatin have less potential for interaction.402
Tacrolimus
is also metabolized by CYP3A4, but appears to have less potential for
harmful interaction with statins than ciclosporin. Other drugs that inﬂuence
CYP3A4 activity should be avoided if possible and used with
extreme caution in patients receiving both calcineurin inhibitors and
statins. Statins are recommended as the ﬁrst-line agents for lipid lowering
in transplant patients. Initiation should be at low doses with
careful up-titration and caution regarding potential drug–drug interactions.
Initiation of therapy with low-dose pravastatin or ﬂuvastatin is
recommended for those on ciclosporin. For patients with dyslipidaemia
who are unable to take statins, ezetimibe could be considered as
an alternative in those with high LDL-C.404
No outcome data are available
for this drug, which should generally be reserved for second-line
use. Care is required with the use of ﬁbrates, as they can decrease ciclosporin
levels and have the potential to cause myopathy. Extreme
caution is required if ﬁbrate therapy is planned in combination with
a statin. Cholestyramine is not effective as monotherapy in heart
transplant patients and has the potential to reduce absorption of immunosuppressants,
minimized by separate administration.
9.11 Peripheral arterial disease
The term PAD encompasses all vascular sites, including carotid, vertebral,
upper extremity, mesenteric, renal and lower extremity arteries.
The aorta is often included in the term.405
PAD is a common
manifestation of atherosclerosis, and such patients are at elevated
risk of coronary events, with PAD representing an independent risk
factor for MI and CV death.405,406
Elevated CV risk has led to inclusion
of PAD among the list of ‘risk equivalent’ conditions, and therapeutic
strategies of secondary prevention should be implemented. Yet, despite
the high CV morbidity and mortality risk, PAD patients are usually
inadequately managed compared with CAD patients.406
9.11.1 Lower extremities arterial disease
A low ABI (,0.90) is diagnostic for lower extremities arterial disease
(LEAD). Either a low (,0.90) or a high (.1.40, related to stiffened
arteries) ABI is predictive of CV morbidity and mortality. Cholesterollowering
therapy reduces the risk of ischaemic CV events and worsening
of claudication, while it also improves walking performance. As for
cardiac events, a systematic review of 18 trials including .10 000
patients, with cholesterol levels ranging from normal to elevated,
reportedthatlipid-loweringtherapyinsubjectsaffectedbyatherosclerosis
of the lower limbs is associated with a 20% reduction in total CV
events, together with a non-signiﬁcant 14% reduction of all-cause
mortality.407
Regarding limb prognosis, in the Reduction of Atherothrombosis
for Continued Health (REACH) registry, statin use was associatedwithan
18%lowerrateofadverselimboutcomes.408
Evenin
the most advanced stages of the disease (critical limb ischaemia), statin
therapy improved rates of 1-year mortality and major adverse CV
events and increased amputation-free survival.409
9.11.2 Carotid artery disease
While there are currently no randomized studies that have assessed
whether lipid-lowering treatments reduce the incidence of CV
events in patients enrolled on the basis of carotid atherosclerotic
disease and without previous CV events, lipid-lowering therapy reduced
stroke in numerous studies. In a meta-analysis of RCTs enrolling
.90 000 patients, Amarenco et al.410
reported that statin
therapy leads to a 21% reduction in the incidence of all strokes in
different populations and that this effect is mainly driven by the extent
of LDL-C reduction. CIMT is reduced with statins in
RCTs,410,411
yet the predictive role of this biomarker (but not of carotid
plaque) is somewhat compromised in light of recent data.60
Modest regression of carotid atherosclerosis with niacin in most
(but not all) imaging studies was not supported by clinical beneﬁt
in the AIM-HIGH and HPS2-THRIVE trials.251,252
Table 31 Recommendations for the treatment of
dyslipidaemia in transplant patients
Recommendations Classa
Level b
Ref c
Global CV risk management
strategies have to be developed in
transplant patients.
I C
Statins should be considered as
patients. Initiation should be at low
doses with careful up-titration and
with caution regarding potential
drug–drug interactions, particularly
for those on ciclosporin.
IIa B 402
In patients who are intolerant of
dyslipidaemia and high residual
risk despite a maximally tolerated
statin dose, alternative or additional
therapy may be considered:
ezetimibe for whose where high
LDL-C is the principal abnormality;
hypertriglyceridaemia and/or low
HDL-C is the principal abnormality.
IIb C
the first-line agents in transplant
statins or those with significant
or; fibrates for those where
CV ¼ cardiovascular; HDL ¼ high-density lipoprotein-cholesterol;
LDL ¼ low-density lipoprotein-cholesterol.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
ESC/EAS Guidelines 3045
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
9.11.3 Retinal vascular disease
Atherosclerotic changes of retinal arteries correlate with TC,
LDL-C, TG and apoB levels and also with CAD.412
Fenoﬁbrate reduces
the progression of diabetic retinopathy.413,414
9.11.4 Secondary prevention in patients with aortic
abdominal aneurysm
The presence of an abdominal aortic aneurysm represents a
risk-equivalent condition and is associated with age, male gender, personal
history of atherosclerotic CVD, smoking, hypertension and dys-
lipidaemia,415
while, in contrast, diabetic patients are at decreased risk.
There are currently no available clinical trials on the reduction of CV
risk with lipid-lowering therapy in patients affected by this condition.
Systematic reviews,416
mostly based onretrospective non-randomized
studies,havereportedthatthereisstillinconclusiveevidencethatstatin
therapy reduces perioperative CV morbidity and mortality. In an RCT
comparing atorvastatin 20 mg with placebo, the composite endpoint
of cardiac death, MI, stroke and unstable angina was signiﬁcantly reduced
in 100 patients undergoing vascular non-cardiac surgery, including
abdominal aortic aneurysm repair.417
In another double-blind
placebo-controlled trial in 497 patients undergoing vascular surgery,
perioperative ﬂuvastatin therapy (80 mg/day) was associated with an
improvement in postoperative cardiac outcome.418
Based on a recent meta-analysis, statin therapy is likely effective in
the prevention of growth of small (,55 mm in diameter) abdominal
aortic aneurysms.419
9.11.5 Renovascular atherosclerosis
Although lipid-lowering therapy has never been tested in an RCT
in patients affected by renovascular atherosclerosis, a recent
population-based study showed that in patients .65 years of age
with atherosclerotic renovascular disease, the risk of a major cardiorenal
composite endpoint (MI, stroke, HF, acute renal failure, dialysis
and death) was signiﬁcantly lower in statin users than in non-users.420
The recommendations for lipid-lowering drugs in patients with
PAD are shown in Table 32.
9.12 Stroke
Stroke has a heterogeneous aetiology, including cardiac thromboembolism
(often associated with atrial ﬁbrillation), carotid artery
and proximal aortic atherosclerosis and thromboembolism, small
vessel cerebrovascular disease and intracranial haemorrhage (including
intracerebral and subarachnoid haemorrhage). Dyslipidaemia
may play a variable role in the pathogenesis of stroke
according to the particular aetiology. The relationship between dyslipidaemia
and atherothrombotic events, including ischaemic stroke
and TIA, is well recognized, while the association of dyslipidaemia
with other types of stroke is uncertain. Notwithstanding, concomitant
control of other aetiologic factors, such as hypertension, is of
paramount importance.
9.12.1 Primary prevention of stroke
The use of statin therapy in adults at high risk of CVD due to LDL-C or
other CV risk factors, including arterial hypertension, as well as in the
setting of established CVD, reduces the risk of ischaemic stroke or
TIA.64,69,128,330,422 –426
. Risk reduction for a ﬁrst ischaemic stroke is
21% per 1.0 mmol/L LDL-C reduction,64
and it is similar between
men and women.65
Beneﬁcial effects are retained over long-term
follow-up.427
A recent meta-analysis of RCTs in subjects .65 years
of age at high CV risk without established CV disease showed that statins
signiﬁcantly reduce the incidence of MI and stroke, but do not signiﬁcantly
prolong survival in the short-term.327
More intensive lipid
lowering with statins is associated with a lower riskof stroke compared
with less intensive regimens.64,65,128,422
Concerns for increased risk of
haemorrhagic stroke with statin treatment do not appear to be justi-
ﬁed.423
The addition of ezetimibe to simvastatin in post-ACS patients
had an incremental beneﬁcial effect for ischaemic stroke or all strokes
(marginal statistical signiﬁcance for the latter).63
Niacin did not reduce
strokeoverlong-termfollow-upinpatientswithCVDintheAIM-HIGH
and HPS2-THRIVE trials.251,252
In fact, the increased rate of ischaemic
stroke in the AIM-HIGH trial and the trend (P ¼ 0.08) for increased
haemorrhagic stroke in the HPS2-THRIVE trial raised concerns and
contributed to haltingofthe AIM-HIGHtrial before itsplanned conclusion.
Primary prevention of stroke contributes to the overall indication
forstartingtreatmentwithstatinsinallpatientswithestablishedatherosclerotic
disease and in patients at high risk for developing CVD, in accordance
with the recommendations given in Table 33.
Table 32 Recommendations for lipid-lowering drugs
in patients with peripheral arterial disease (including
carotid artery disease)
Recommendations Classa
Level b
Ref c
PAD is a very-high-risk condition
and lipid-lowering therapy (mostly
statins) is recommended in these
patients.
I A 407, 421
Statin therapy should be considered
to prevent the progression of
abdominal aortic aneurysm.
IIa B 419
PAD ¼ peripheral arterial disease.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
Table 33 Recommendations for lipid-lowering drugs
for primary and secondary prevention of stroke
Recommendations Classa
Level b
Ref c
Statin therapy to reach established
treatment goals is recommended in
patients at high or very high CV risk
for primary prevention of stroke.
I A
64, 65,
422, 426
Lipid-lowering therapy is
recommended in patients with
other manifestations of CVD for
primary prevention of stroke.
I A
63–65,
422, 426
Intensive statin therapy is
recommended in patients with
a history of non-cardioembolic
ischaemic stroke or TIA for
secondary prevention of stroke
I A 422, 428
CVD ¼ cardiovascular disease; TIA ¼ transient ischaemic attack.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
ESC/EAS Guidelines3046
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
9.12.2 Secondary prevention of stroke
Following stroke or TIA, patients are at risk not only of recurrent
cerebrovascular events, but also of other major CV events, including
MI. Secondary prevention therapy with statins reduces the risk of recurrent
stroke (by 12%), MI and vascular death.422,428
Statin pretreatment
at TIA onset was associated with reduced recurrent
early stroke risk in patients with carotid stenosis in a pooled data
analysis, supporting an as-early-as-possible initiation of statins after
stroke.429
However, the aetiology of stroke may inﬂuence the response
to statins, and those patients with evidence of atherothrombosis
underlying their cerebrovascular events appear to beneﬁt
most, while those with haemorrhagic stroke may not beneﬁt.422
9.13 Human immunodeﬁciency virus
patients
HIV-infected patients typically have low TC and LDL-C, as well as
low HDL-C and increased TGs.430,431
Antiretroviral treatment
(ART) or highly active antiretroviral treatment (HAART; when
drugs are used in combination) causes marked increases in TC,
LDL-C and TGs and a predominance of small dense LDL particles,
while HDL-C remains low. The extent of lipid changes differs between
and within antiretroviral drug classes. Newer protease inhibitors,
non-nucleoside reverse transcriptase inhibitors (NNRTIs) or
integrase inhibitors affect lipoprotein metabolism to a lesser extent.
ART also reduces insulin sensitivity and promotes hypertension and
body fat redistribution (lipodystrophy that involves lipoatrophy,
which refers to a loss of fat in the face, buttocks and limbs, and/or
lipohypertrophy, in which there is an accumulation of fat in
the breasts, neck, back or stomach region) that additionally contribute
to CVD risk. HIV-infected patients have a higher risk for CVD
when compared with HIV-uninfected individuals [RR 1.61 (95% CI
1.43, 1.83)], while ART (and especially older protease inhibitors)
further increases this risk, up to two-fold [RR 2.00 (95% CI 1.70,
2.37)].431 – 433
CVD risk remains high even after adjusting for traditional
risk factors.434
ART may particularly accelerate the onset
of CAD-related events in young male heavy smokers with dyslipidaemia.
Nevertheless, absolute CVD risk increase with ART is moderate
and should be put into perspective with the beneﬁts of HIV
treatment.
Dietary changes and regular physical activity, as well as switching
to another ART regimen, may act favourably on dyslipidaemia, but
most patients still need pharmacological therapy to reach lipid goals.
Statins are effective, but drug interactions with ART need to be considered.
Statins metabolized in the liver via the CYP3A4 or CYP2C9
are susceptible to drug interactions with protease inhibitors and
the NNRTI efavirenz. Pravastatin is not signiﬁcantly metabolized via
the CYP isoenzyme system and is therefore a preferred statin in
HIV-infected individuals. Preferred statins include atorvastatin,
ﬂuvastatin, pitavastatin and rosuvastatin, although caution should be
exercised. Combination of simvastatin or lovastatin with any protease
inhibitor or efavirenz is not recommended. The HIV drug interaction
database of the University of Liverpool (http://www.
hiv-druginteractions.org) is a very helpful tool for checking drug interactions
(Supplementary Figure B). For patients who cannot tolerate
statin treatment, ezetimibe could be an option.435
Fibrates and ﬁsh
oil may be prescribed when HTG is predominant.436
Use of bile
acid sequestrants is not recommended because they increase TGs
and their effects on the absorption of antiretroviral drugs have not
been studied.
There are no data on the effects of statins, ezetimibe or ﬁbrates
on CV events in dyslipidaemic HIV-infected patients.
The recommendations for lipid-lowering drugs in HIV patients
are shown in Table 34.
9.14 Mental disorders
The presence of a major mental illness such as schizophrenia or bipolar
disorder has deleterious effects on the risk of developing
CVD. This is related to an unhealthy lifestyle in the majority of
these patients (sedentary behaviour, unbalanced diet, smoking),
but also to drug treatment. Some antipsychotics, antidepressants,
anxiolytics and mood stabilizers are associated with weight gain
and cardiometabolic disturbances, including dyslipidaemia and
dysglycaemia.
In patients with ﬁrst-episode schizophrenia spectrum disorders,
cardiometabolic risk factors were present early in the illness;
this was related to the underlying disorder, unhealthy
lifestyle and antipsychotic medications, which interact with
each other.437
All this explains the higher prevalence of obesity,
MetS, diabetes and dyslipidaemia in patients with these psychiatric
diseases.438
It also results in a greater incidence of CVD
and in more CV deaths in psychiatric patients suffering from
these disorders.
In a Finnish cohort of patients with schizophrenia, life expectancy
was about 2 decades less than in persons of similar age from the general
population.439
In patients with bipolar disorder there was a reduction
in life expectancy of 12–14 years.440
Among 654 patients
with bipolar disorder in the Fondamental Advanced Centers of Expertise
in Bipolar Disorders (FACE-BD) cohort, 18.5% met the criteria
for MetS; only 11% and 28% of the patients with
hypercholesterolaemia and high fasting glycaemia, respectively,
were treated for these conditions.441
Patients with the aforementioned
psychiatric diseases are in general less compliant with chronic
drug treatments and therefore have their CV risk factors less well
controlled.
CVD accounts for much of the excess mortality in psychiatric pa-
tients.442
CVD develops more than a decade earlier in patients with
bipolar disorders than in controls.443
Therefore it could be recommended
to start primary prevention earlier rather than later in these
patients. This is well summarized in a position paper of the European
Table 34 Recommendation for lipid-lowering drugs in
human immunodeﬁciency virus patients
Recommendation Classa
Level b
Lipid lowering therapy (mostly statins)
should be considered in HIV patients with
dyslipidaemia to achieve the LDL-C goal as
IIa C
defined for high-risk subjects
HIV ¼ human immunodeﬁciency virus; LDL-C ¼ low-density lipoproteincholesterol.
a
Class of recommendation.
b
Level of evidence.
ESC/EAS Guidelines 3047
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
Psychiatric Association supported by the European Association for
the Study of Diabetes and by the ESC.444
Statins are equally effective in lowering LDL-C in psychiatric patients
treated with second-generation antipsychotics445
; however,
in only a limited number of these patients are preventive actions taken
both in regard to lifestyle and to the use of cardioprotective
drugs. The odds of the use of statins was approximately halved in
patients with schizophrenia compared with controls.446
Unfortunately, no RCTs with ‘hard’ CV outcome measures have
so far been conducted in patients with these major mental diseases.
It is reasonable to expect that the favourable metabolic effects
of treatment that have been demonstrated result in the
prevention of CV events in the long term. However, several questions
remain that need to be addressed in further studies in patients
with these major mental disorders, regarding long-term
safety of statins in association with antipsychotics that also predispose
to diabetes and prevention of premature CV mortality and
incidence.
Table 35 lists the recommendations for the lipid-lowering drug
treatment of patients with mental disorders.
a
Unboosted atazanavir
Numbers refer to increased or decreased AUC of the lipid-lowering drug as observed in drug-drug interaction studies.
↑ Potential increased exposure of the lipid-lowering drug
↓ Potential decreased exposure of the lipid-lowering drug
↔
⇑ Potential increased exposure of HIV drug
⇓ Potential decreased exposure of HIV drug
These drugs should not be coadministered.
Potential interaction which may require a dosage adjustment or close monitoring.
Potential interaction predicted to be of weak intensity (<2 fold ↑AUC or <50% ↓AUC). No a priori dosage adjustment is recommended.
Colour Legend
Text Legend
Lipid-Lowering Treatment Selector
Charts revised August 2013. Full information available at www.hiv-druginteractions.org and www.hiv-druginteractionslite.org
ATV/r DRV/r FPV/r IDV/r LPV/r SQV/r EFV ETV NVP RPV MVC EVG/c RAL ABC FTC 3TC TDF ZDV
Statins
Atorvastatin ↑ ↑ ↑153% ↑ ↑490% ↑ ↓43% ↓37% ↓ ↔ ↔ ↑ ↔ ↔ ↔ ↔ ↔ ↔
Fluvastatin ↔ ↔ ↔ ↑ ↔ ↑ ↑ ↑ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔
Lovastatin ↑ ↑ ↑ ↑ ↑ ↑ ↓ ↓ ↓ ↔ ↔ ↑ ↔ ↔ ↔ ↔ ↔ ↔
Pravastatin ↔ ↑81% ↔ ↑ ↔ ↓50% ↓44% ↓ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔
Rosuvastatin ↑213% ↑48% ↑8% ↑ ↑107% ↑ ↔ ↑ ↔ ↔ ↔ ↑48% ↔ ↔ ↔ ↔ ↔ ↔
Simvastatin ↑ ↑ ↑ ↑ ↑ ↑ ↓68% ↓ ↓ ↔ ↔ ↑ ↔ ↔ ↔ ↔ ↔ ↔
Fibrates
↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔
↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↑⇑ ↔
↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔
↓ ↓ ↓ ↓ ↓41% ↓ ↔ ↔ ↔ ↔ ↔ ↔ ↑ ↔ ↔ ↔ ↔ ↔
Ezetimibe ↑a ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔
Bezafibrate
Clofibrate
Fenofibrate
Gemfibrozil
No clinically significant interaction expected.
No signficant effect
Supplementary ﬁgure B HIV-drug interaction database of the University of Liverpool.
Table 35 Recommendations for lipid-lowering
pharmacological treatment in patients with mental
disorders
Recommendations Classa
Level b
estimating total CV risk.
I C
The management of total CV risk in patients
with a psychiatric disorder is not different
from what is recommended in patients at
high/very high CV risk.
I C
In patients with psychiatric disorders
particular attention has to be paid to
adherence to lifestyle changes and compliance
with drug treatment.
I C
Major psychiatric disorders are modifiers for
CV ¼ cardiovascular.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
ESC/EAS Guidelines3048
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
10. Monitoring of lipids and
enzymes in patients on
lipid-lowering therapy (Table 36)
Evidence from trials for what tests should be carried out to monitor
lipids in patients on treatment is limited. Similar limited evidence
applies to tests of possible toxicity, such as ALT and CK.
Recommendations stem from consensus rather than evidencebased
medicine.
Response to therapy can be assessed at 6–8 weeks from initiation
of therapy, but response to lifestyle may take longer.
Standard practice for subsequent follow-up monitoring is 6–
12 months, but such monitoring intervals are arbitrary. As a
minimum, LDL-C should be assessed whenever available, but
better management decisions will probably occur if a full lipid
proﬁle is performed, including HDL-C and TGs. Non-HDL-C
or apoB should also be analysed, and used as a secondary treatment
target. A separate issue is the impact of regular lipid monitoring
in promoting patient adherence to lifestyle changes or
drug regimens that impact positively on their health, as found
in a range of studies. It is unclear whether only the process of
monitoring is critical in achieving this or whether a combination
of education, regular contact and adherence assessment is
required.
Where lipid-lowering therapy is implemented, safety blood
tests are advised, including ALT and CK at baseline, to identify
the limited number of patients where treatment is contraindicated.
CK should be checked in patients with high risk for myopathy,
such as the very elderly with co-morbidities, patients with
earlier muscle symptoms or patients on interacting drugs. A systematic
review found that the incidence of drug-induced hepatotoxicity
in patients taking statins is unknown, with very few cases
occurring in large-scale RCTs.212,214
Recent reviews are encouraging
about the safety of long-term statin therapy.221,222
ALT is
recommended 8–12 weeks after the start of lipid-lowering therapy
or dose change, but routine control of ALT during treatment
is not recommended and should be performed, if indicated,
based on clinical observations. In patients whose liver function
tests rise above three times the ULN, explanations such as alcohol
ingestion or non-alcoholic fatty liver disease should be
sought and the levels monitored. If levels remain elevated then
lipid-lowering therapy should be stopped, but may be cautiously
reintroduced under monitoring after levels have returned to
normal.
There is no predictive value of routine repeat CK testing
for rhabdomyolysis since the level can increase for many
reasons, including muscle injury or excess muscular exercise.
However, CK must be assessed immediately in patients, especially
the elderly, presenting with muscle pain and weakness,
and treatment stopped if .10 times the ULN. Strategies to
handle CK elevations are given in Table 35 and in the supplementary
material. Due to the increased frequency of diabetes
during statin treatment, regular checks of HbA1C should be
considered in patients at high risk of developing diabetes,
such as the elderly or those with MetS, obesity or signs of insulin
resistance.
11. Strategies to encourage
adoption of healthy lifestyle
changes and adherence to
lipid-modifying therapies
Terminology to describe the way patients follow their medication
regimens and sustain behavioural changes has evolved
over the years to include terms such as compliance, adherence
and concordance. Compliance (http://medical-dictionary.
thefreedictionary.com/Compliance) is deﬁned as a ‘willingness
to follow a prescribed course of treatment’, but also has connotations
of obeying orders in a subservient way. Adherence (http://
apps.who.int/medicinedocs/en/d/Js4883e/6.html) is deﬁned as
‘the extent to which a person’s behaviour—taking medication,
following a diet, and/or executing lifestyle changes—corresponds
with agreed recommendations from a healthcare provider’
and is literally deﬁned as sticking to something. Finally,
concordance (http://www.drugs.com/dict/concordance.html) is
deﬁned as ‘a negotiated, shared agreement between clinician
and patient concerning treatment regimen(s), outcomes, and
behaviours; a more cooperative relationship than those based
on issues of compliance and noncompliance’.
While the terms adherence and concordance are today considered
more acceptable than compliance, for the purposes of this
guideline, the term adherence will be used, as it is most commonly
used in practice and research today.
11.1 Achieving and adhering to healthy
lifestyle changes
Behavioural strategies to promote the adoption of healthy lifestyle
habits are covered in brief in this section; however, more detail is
available in the ESC Guidelines on cardiovascular disease prevention
in clinical practice.6
No smoking, healthy eating and being physically active are the
foundations of preventive cardiology because of their favourable impact
on CV risk, including modiﬁcation of the lipid proﬁle. Healthy
lifestyle habits will also enhance effectiveness and reduce the need
for drug therapy.
Helping patients to change to healthier lifestyle habits is most effectively
achieved through formal programmes of preventive care,
possibly because of the intensive follow-up and multidisciplinary expertise
they provide.447
However, in everyday care, adherence to
both healthy lifestyle changes and medication regimens is a challenge
to both professionals and patients.
A comprehensive patient- and family-centred approach located
in one healthcare setting is recommended rather than addressing
single risk factors with more than one intervention in
different locations. Drawing on expertise from different disciplines
in smoking cessation, dietetics, physical activity, exercise
and health psychology is also essential, regardless of whether
these experts have direct involvement with patients as dedicated
members of a team or whether this expertise is achieved
by the provision of training to doctors and nurses delivering
care.447
ESC/EAS Guidelines 3049
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
The adoption of effective strategies to help patients to change behaviours
is now made easier with the development of a hierarchical taxonomy
of behaviour change strategies.448
The taxonomy has
developed a system of standardized labelling of behavioural strategies,
whichallowsacleardescriptionofcomplexinterventions449
inresearch
reports and their subsequent translationinto clinicalpractice initiatives.
Table 36 Summary of recommendations for monitoring lipids and enzymes in patients on lipid-lowering therapy
Testing lipids
How often should lipids be tested?
• Before starting lipid-lowering drug treatment,at least two measurements should be made,with an interval of 1–12 weeks,with the exception of conditions
where concomitant drug treatment is suggested such asACS and very high-risk patients.
How often should a patient’s lipids be tested after starting lipid-lowering treatment?
• 8 (±4) weeks after starting treatment.
• 8 (±4) weeks after adjustment of treatment until within the target range.
How often should lipids be tested once a patient has reached the target or optimal lipid level?
• Annually (unless there is adherence problems or other specific reasons for more frequent reviews).
Monitoring liver and muscle enzymes
How often should liver enzymes (ALT) be routinely measured in patients on lipid-lowering drugs?
• Before treatment.
• Once 8–12 weeks after starting a drug treatment or after dose increase.
• Routine control ofALT thereafter is not recommended during lipid-lowering treatment.
What if liver enzymes become elevated in a person taking lipid-lowering drugs?
IfALT <3x ULN:
• Continue therapy.
• Recheck liver enzymes in 4–6 weeks.
If value rises to ≥3x ULN
• Stop lipid-lowering therapy or reduce dose and recheck liver enzymes within 4–6 weeks.
• Cautious reintroduction of therapy may be considered afterALT has returned to normal.
• IfALT remains elevated check for the other reasons.
How often should CK be measured in patients taking lipid-lowering drugs?
Pre-treatment
• Before starting therapy.
• If baseline CK is 4x ULN,do not start drug therapy;recheck.
Monitoring:
• Routine monitoring of CK is not necessary.
• Check CK if patient develops myalgia.
Be alert regarding myopathy and CK elevation in patients at risk such as:elderly patients,concomitant interfering therapy,multiple medications,liver or renal
disease or sport athletes.
What if CK becomes elevated in a person taking lipid-lowering drugs?
Re-evaluate indication for statin treatment.
If ≥4 x ULN:
• If CK >10x ULN:stop treatment,check renal function and monitor CK every 2 weeks.
• If CK <10x ULN:if no symptoms,continue lipid-lowering therapy while monitoring CK.
• If CK <10x ULN:if symptoms present,stop statin and monitor normalization of CK,before re-challenge with a lower statin dose.
• Consider the possibility of transient CK elevation for other reasons such as exertion.
• Consider myopathy if CK remains elevated.
• Consider combination therapy or an alternative drug.
If <4 x ULN:
• If no muscle symptoms,continue statin (patient should be alerted to report symptoms;check CK).
• If muscle symptoms,monitor symptoms and CK regularly.
• If symptoms persist,stop statin and re-evaluate symptoms after 6 weeks;re-evaluate indication for statin treatment.
• Consider re-challenge with the same or another statin.
• Consider low-dose statin,alternate day or once/twice weekly dosing regimen or combination therapy.
For details on CK elevation and treatment of muscular symptoms during statin treatment see algorithm in supplementary figure C.
ACS ¼ acute coronary syndrome; ALT ¼ alanine aminotransferase; CK ¼ creatine kinase; ULN ¼ upper limit of normal.
ESC/EAS Guidelines3050
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
Symptomatic & CK <4 X ULN CK ≥4 X ULN +/- rhabdomyolisis
2–4 weeks washout of statin
Symptoms persist:
statin re-challenge
Symptom-free:
continue statin
Symptoms re-occur
1) Low-dose third efficacious
(potent)a
statin;
2) Efficaciousa
statin with
alternate day or once/twice
weekly dosing regimen
1) Low-dose second efficaciousa
statin;
2) Efficaciousa
statin with
alternate day or once/twice
weekly dosing regimen
Symptoms improve:
second statin at usual or
starting dose
6 weeks washout of statin until normalisation
of CK: creatinine and symptoms
Consider if statin-attributed muscle symptoms favour statin continuation / reinitiation
Aim: achieve LDL-C goal* with maximally tolerated dose of statin
If still not at goal: consider additional (future) novel therapies: PCSK9 monoclonal antibody therapy, CETP inhibitor
Ezetimibe
B + fibrate (not gemfibrozil) A + BA + bile acid absorption inhibitor
CETP = cholesteryl ester transfer protein; CK = creatine kinase; LDL-C= low-density lipoprotein cholesterol; PCKS9 = propotein onvertase subtilisin/kesin type 9; ULN = upper limit
of the normal range.
Efficacious statin such as atorvastatin or rosuvastatin.a
*Reiner Z et al. (2011).
Web Figure C Algorithm for treatment of muscular symptoms during statin treatment.211
.
ESC/EAS Guidelines 3051
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
Box 11 includes some useful techniques when counselling patients
for behavioural change.
In addition, it is important to be aware of the following barriers to
change:
† Healthy choices are not always easy choices.
† Socio-economic status and cultural and environmental factors
inﬂuence behaviour change.
† Your agenda for change as a health professional may conﬂict with
that of the person you are trying to help.
† Helping people to change requires dedicated time from the
health professional to provide support and follow-up.
† People may have feelings of ambivalence towards changing
behaviour that need exploring.
11.2 Adhering to medications
Despite a wealth of evidence on the efﬁcacy and effectiveness of
statins in both primary and secondary prevention, adherence
remains a consistent barrier, with rates of ,50% demonstrated
in several studies. Adherence declines over the duration of
treatment450 –454
; however, this is truer in patients treated for primary
compared with secondary prevention of CVD, with reported
rates of up to 77% discontinuing their statins within 2 years. Adherence
is better in patients recruited to clinical trials compared with
those treated in the real world.455,456
Not surprisingly, this nonadherence
has an impact on healthcare costs, morbidity, hospital
readmissions and mortality.457 – 461
Poor adherence rates are not
only limited to statins but are also true of other lipid-lowering drugs
and all medications used to prevent CVD, as demonstrated in a systematic
review and meta-analysis.462
The reasons for non-adherence are complex and include misconceptions
about tolerability on the part of both patients and professionals
alike. These barriers prevent patients from gaining the
maximum beneﬁt from their treatment.
In the UK in 2014, controversy was sparked among general practitioners
(GPs) and other physicians463
in relation to the recent updated
recommendation from NICE to offer atorvastatin 20 mg for
the primary prevention of CVD to people who have an estimated
≥10% absolute 10-year risk of developing CVD using the QRISK2
assessment tool (http://www.nice.org.uk/guidance/cg181). Together
with the additional controversy generated by Abramson et al.464,465
regarding their analysis of the adverse effects of statins, which was
subsequently corrected, it is not surprising that GPs, in particular,
have a certain degree of reluctance to proceed with the NICE strategy.
If there is a lack of local consensus on the prescription of statins
in primary prevention, then GPs may be less inclined to prescribe
them, let alone encourage patients to adhere to their statin therapy,
even in the face of minor adverse effects.
Various empirical models of health behaviour and behaviour
change theory have been shown to predict adherence, including
the Theory of Planned Behaviour466
and the Health Belief Model.467
Studies that investigated adherence to medications in long-term
conditions identiﬁed factors such as high susceptibility, severity of
the condition, strong intentions and high self-efﬁcacy as being
associated with good adherence, while poor lifestyle habits and
low perceived behavioural control were associated with poor
adherence.468,469
However, these theoretical models are limited in
that they do not take into account important social, economic, health
system and therapy-related factors. Most recently, the COM-B
(Capability, Opportunity and Motivation) theoretical model,470
developed
by Michie et al.,471
which takes a broader look at factors
inﬂuencing adherence, proposed a framework for assessing and addressing
adherence, taking the interaction between capability (deﬁned
as both the psychological and physical capacity of an individual
to engage in a behaviour), opportunities (deﬁned as factors outside
the control of an individual) and their motivation to do so.
Predictors of non-adherence with statins have been identiﬁed450,472
– 474
and include their use in individuals for primary prevention
as compared with their use in patients with disease or
with multiple risk factors, lower income, being elderly, complex
polypharmacy, cost and forgetfulness due to a lack of symptoms
and psychological co-morbidities. In addition, reasons for reluctance
to collect a ﬁrst prescription of statin medication were investigated
in a cross-sectional telephone survey conducted in California from
recruits to an RCT.475
The most commonly reported reasons included
general concerns about the medication, wanting to try lifestyle
measures ﬁrst and fear of adverse effects; however, a
signiﬁcant proportion reported ﬁnancial hardship, a lack of understanding
of why they needed to take the medication and what the
medication was for (indicating a need to address the patient–professional
relationship and poor health literacy). Health literacy is deﬁned
as ‘the degree to which individuals have the capacity to obtain,
process and understand basic health info and services needed to
make appropriate health decisions’ (http://nnlm.gov/outreach/
consumer/hlthlit.html).
Poor health literacy is of particular concern in regard to medication
adherence.475
Elderly patients and those with low socioeconomic
status and chronic health conditions may be especially
vulnerable. These patients may get confused, especially when their
regimens are complex and include many drugs (polypharmacy) that
need to be taken on more than one occasion per day. Important
steps to empower patients to get more beneﬁt from health interventions
include the following476
:
1. Use good interpersonal skills (good eye contact, warm manner)
and an empathetic, non-judgmental attitude.
2. Provide clear and simple instructions on a drug regimen backed up
with written instructions, which can also be seen by a spouse or
caregiver.
Box 11 Hints to aid adherence to lifestyle changes
1. Explore motivation and identify ambivalence. Weigh pros and cons
discussion.
2. Offer support and establish an alliance with the patient and his/her
family.
3. Involve the partner, other household members or caregiver who may
5. Tailor advice to an individual patient’s culture,habits and situation.
6. Use SMART goal setting–negotiate goals for change that are
Specific, Measurable, Achievable, Realistic and Timely. Follow up on
goals and record progress on a shared record.
4. Use the OARS method (Open-ended questions, Affirmation,
Reflective listening, Summarising; http://www.smartrecovery.org/
resources/UsingMIinSR.pdf) when discussing behaviour changes.
for change, assess and build self-efficacy and confidence, avoid circular
be influential in the lifestyle of the patient.
ESC/EAS Guidelines3052
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
3. Speak slowly in plain language and avoid medical jargon when
giving instructions.
4. Limit the number of instructions to no more than three key
points—principle of ‘need to know’ (Figure 8).
5. Use ‘teachback’ to conﬁrm understanding; e.g. ‘I want to make sure
that I explained things clearly. Let’s review what we discussed. What
are the three strategies that will help keep your cholesterol down?’
6. Use supplemental materials, e.g. images, videos and audio sources,
to improve recall (Figure 9).
7. Encourage questions and discussion—enlist the family or others
important to the individual.
8. Motivational interviewing skills may be helpful in communicating
with patients who are ambivalent or seem against starting or
continuing with medications:37,477
(a) Counsel patients using the OARS method (Box 11).
(b) Use the ‘elicit–provide–elicit’ model to tailor the information
you give (elicit what the patient wants to know, provide that
Need to know and do
e.g. Important information about diagnosis,
key treatment and management of prescribed medications
Nice to know and do
Information that may be covered but can wait for
a second consultation
Not necessary now, do later
web-based resources, about additional services
that can be provided
e.g. Provide information, using leaflets, booklets or
Figure 8 Prioritising information when educating patients.
Names of pills
Lisinopril
20 mg
1 pill once a day
Simvastatin
40 mg
1 pill at bedtime
Metformin
500 mg
2 pills twice a day
Gabapentin
300 mg
1 pill
every 8 hours
Aspirin EC
81 mg
1 pill once a day
What it's for
Morning/Breakfast
Heart
Afternoon/Lunch Evening/Dinner Night/Bedtime
Nerve pain
Diabetes
Cholesterol
Blood pressure
20
500 500
300 300 300
40
Figure 9 Images to improve recall.
ESC/EAS Guidelines 3053
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
information, elicit from the patient how they can use this new
knowledge to their beneﬁt).
(c) Acknowledge and reﬂect your patient’s resistance.
(d) Support your patient’s autonomy to make their own decisions
about their health and treatment.
(e) Explore your patient’s ambivalence to adhere to their
treatment.
(f) Develop a plan of action together and share decision-making.
9. Build self-efﬁcacy and conﬁdence, drawing on social learning
theory.478
Being able to identify patients with low health literacy is important.
Indicators may include seeking help when an illness is already
advanced, inarticulacy in explaining concerns, making excuses like
‘I forgot my glasses’ to cover for the shame associated with illiteracy,
being passive or aggressive and missing appointments.
Interventions to improve adherence have been reviewed in a Cochrane
review from 2010,479
which looked at interventions to improve
adherence to all forms of lipid-lowering therapy, including
reminders, simpliﬁcation of drug regimens and provision of information
and education. Most effective was reminders, such as setting
alarms, connecting medication-taking to other tasks to trigger memory
and phone reminders from nurses. Reminder systems have the
potential to be developed with the help of innovations in technology,
like the use of text messaging, the Internet and applications
for mobile phones or tablets to assist in self-monitoring and management.
Adherence research is weak in this area, mainly because
it has not kept abreast of the rapid developments in technology;480
however, these methods may come into their own in the future with
a stronger knowledge base.
Prescription of a statin should include a shared decision-making ap-
proach481
that engages the patient in a discussion before initiating
treatment, especially when it is being considered for primary prevention
of CVD. This discussion should be based on risk estimation and
adequate communication of this risk to patients. Involving the patient
in such a way is likely to be empowering and motivate adherence. This
discussion is not exclusively about the prescription of a statin to manage
lipids; a comprehensive approach includes addressing all lifestyle
and other biomedical factors that contribute to CV risk.
Once treatment has been prescribed, communication should focus
on conveying achievements in reaching goals, assessment of adherence
and possible reasons for non-adherence, such as adverse
effects. In relation to lipid-lowering medications, and statins in particular,
misconceptions and misleading media reports are in abundance.
Many patients report adverse effects of statins to their GPs
and this may be because of an increased likelihood to anticipate
them. However, a recent large review of RCTs213
found that in 83
880 patients receiving blinded placebo-controlled statin therapy,
few reported adverse effects were actually due to the drug. This
study calculated the PSN, deﬁned as the proportion of symptoms
not attributable to its pharmacological action, in order to provide
GPs with a clear metric to use in advising their patients on whether
reported symptoms are genuinely likely to be pharmacologically
caused by the statin or not.
Recently, promising results for improving adherence have been
demonstrated in the use of a ﬁxed-dose combination (FDC) drug
or ‘polypill’ in both primary and secondary prevention. The Use
of a Multidrug Pill In Reducing cardiovascular Events (UMPIRE)
RCT482
compared an FDC containing aspirin, statin and two blood
pressure–lowering agents with usual care in both primary and secondary
prevention in 2004 randomized patients in India and Europe.
At 15 months, statistically signiﬁcant differences between intervention
and usual care were seen in self-reported adherence and changes in
systolic blood pressure and LDL-C. The Fixed-Dose Combination
Drug for Secondary Cardiovascular Prevention (FOCUS) study483
had a cross-sectional ﬁrst phase, which identiﬁed factors contributing
to non-adherence after MI in 2118 patients from ﬁve countries in
South America and Europe. In the second phase, 695 patients from
the ﬁrst phase were randomized to receive either a polypill containing
aspirin, statin and ramipril in varying doses or were given the three
drugs separately. Adherence was measured with the self-reported
Morisky–Green questionnaire and pill counts and was statistically signiﬁcantly
superior in the intervention group compared with usual
care at 9 months. In phase 1, factors associated with non-adherence
were younger age, depression, complex regimen, poorer health insurance
coverage and low social support.
Given the beneﬁts for adherence demonstrated with simpliﬁed
dosing reported in a Cochrane overview of interventions to improve
safe and effective medicines use by consumers,484
it makes
sense that a pill that contains multiple medications in one tablet
will enhance adherence. This overview also found that the use of
self-management or self-monitoring programmes, as well as a regular
pharmacy review of prescribed medications with a view to taking
out unnecessary medications, was helpful.
Many of the studies included in the Cochrane review of interventions
to improve medication adherence480
drew on the support of
allied professionals such as nurses and pharmacists to deliver complex
interventions, which may include telephone follow-up, interim
appointments and monitoring of repeat prescriptions. The reviewed
interventions may be difﬁcult to replicate in everyday clinical care
due to the cost and the availability of personnel. Drawing on the
support of non-professional people within the social context of
the patient, such as spouses, other family members, caregivers or
other key ﬁgures, as well as lay groups in the community, may prove
to be a cost-effective way to improve adherence.
Box 12 lists a number of tips to use when prescribing multiple
medications to patients in order to help them adhere.
Box 12 Tips to aid adherence to multiple drug
therapies
1. ‘Agree’ on rather than ‘dictate’ a drug regimen to your patient and
tailor it to his/her personal lifestyle and needs.
2. Back up verbal instructions with clear written instructions.
3.
where available.
4. Perform a regular review of medicines to minimize polypharmacy (or
ask the pharmacist to assist).
5. Encourage self-monitoring and use cues and technologies to act as
reminders.
6. Provide information on common side effects and discuss management
strategies.
7. Involve the partner, other family members or the caregiver in the
patient’s treatment.
Simplify the dosing regimen and consider a fixed dose combination pill
ESC/EAS Guidelines3054
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
12. To do and not to do messages from the Guidelines
Recommendations Classa
Level b
Recommendations for risk estimation
Total risk estimation using a risk estimation system such as SCORE is recommended for asymptomatic adults >40 years of age
without evidence of CVD, diabetes, CKD or familial hypercholesterolaemia.
I C
High and very high-risk individuals can be detected on the basis of documented CVD, diabetes mellitus, moderate to severe renal
disease, very high levels of individual risk factors , familial hypercholesterolaemia or a high SCORE risk and are a high priority for
intensive advice with regard to all risk factors.
I C
Recommendations for lipid analyses in cardiovascular disease risk estimation
TC is to be used for the estimation of total CV risk by means of the SCORE system. I C
LDL-C is recommended to be used as the primary lipid analysis for screening, risk estimation, diagnosis and management. HDL-C is
a strong independent risk factor and is recommended to be used in the HeartScore algorithm.
I C
Non-HDL-C is a strong independent risk factor and should be considered as a risk marker, especially in subjects with high TG. I C
Recommendations for lipid analyses for characterization of dyslipidaemias before treatment
LDL-C has to be used as the primary lipid analysis. I C
It is recommended to analyse HDL-C before treatment. I C
TG adds information about risk, and is indicated for diagnosis and choice of treatment. I C
Non-HDL-C is recommended to be calculated, especially in subjects with high TG. I C
Recommendations for lipid analyses as treatment targets in the prevention of cardiovascular disease
LDL-C is recommended as the primary target for treatment. I A
HDL-C is not recommended as a target for treatment. III A
The ratios apoB/apoA1 and non-HDL-C/HDL-C are not recommended as targets for treatment. III B
Recommendations for treatment goals for low-density lipoprotein-cholesterol
In patients at VERY HIGH CV riskc
, an LDL-C goal of <1.8 mmol/L (70 mg/dL), or a reduction of at least 50% if the baseline LDL-Cd
is
between 1.8 and 3.5 mmol/L (70 and 135 mg/dL) is recommended.
I B
In patients at HIGH CV riskc
, an LDL-C goal of <2.6 mmol/L (100 mg/dL), or a reduction of at least 50% if the baseline LDL-Cd
is
between 2.6 and 5.2 mmol/L (100 and 200 mg/dL) is recommended.
I B
Recommendations for the pharmacological treatment of hypercholesterolaemia
Prescribe statin up to the highest recommended dose or highest tolerable dose to reach the goal. I A
Recommendations for the detection and treatment of patients with heterozygous familial hypercholesterolaemia
FH is recommended to be suspected in patients with CHD before the age of 55 years for men and 60 years for women, in subjects
with relatives with premature fatal or non-fatal CVD, in subjects with relatives having tendon xanthomas, and in subjects with
severely elevated LDL-C [in adults >5 mmol/L (190 mg/dL), in children >4 mmol/L (150 mg/dL)].
I C
Family cascade screening is recommended to be performed when an index case of FH is diagnosed. I C
FH patients are recommended to be treated with intense-dose statin, often in combination with ezetimibe. I C
In children, testing is recommended from age 5 years, or earlier if homozygous FH is suspected. I C
Recommendations for the treatment of dyslipidaemia in older adults
Treatment with statins is recommended for older adults with established CVD in the same way as for younger patients. I A
Recommendations for the treatment of dyslipidaemia in diabetes
In all patients with type I diabetes and in the presence of microalbuminuria and/or renal disease, LDL-C lowering (at least 50%) with
statins as the first choice is recommended irrespective of the baseline LDL-C concentration. I C
In patients with type 2 diabetes and CVD or CKD, and in those without CVD who are >40 years of age with one or more other
CVD risk factors or markers of target organ damage, the recommended goal for LDL-C is <1.8 mmol/L (< 70 mg/dL) and
the secondary goal for non-HDL-C is <2.6 mmol/L (< 100 mg/dL) and for apoB is <80 mg/dL.
I B
In all patients with type 2 diabetes and no additional risk factors and/or evidence of target organ damage, LDL-C <2.6 mmol/L
(<100 mg/dL) is the primary goal. Non-HDL-C <3.4 mmol/L (<130 mg/dL) and apoB <100 mg/dL are the secondary goals.
I B
Recommendation for lipid-lowering therapy in patients with acute coronary syndrome and patients undergoing percutaneous
coronary intervention
It is recommended to initiate or continue high dose statins early after admission in all ACS patients without contra-indication or
history of intolerance, regardless of initial LDL-C values.
I A
continued
ESC/EAS Guidelines 3055
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
13. Appendix
ESC Committee for Practice Guidelines (CPG): Jose Luis
Zamorano (Chairperson) (Spain), Victor Aboyans (France), Stephan
Achenbach (Germany), Stefan Agewall (Norway), Lina Badimon
(Spain), Gonzalo Baro´n-Esquivias (Spain), Helmut Baumgartner
(Germany), Jeroen J. Bax (The Netherlands), He´ctor Bueno (Spain),
Scipione Carerj (Italy), Veronica Dean (France), Çetin Erol (Turkey),
Donna Fitzsimons (UK), Oliver Gaemperli (Switzerland), Paulus
Kirchhof (UK/Germany), Philippe Kolh (Belgium), Patrizio Lancellotti
(Belgium), Gregory Y. H. Lip (UK), Petros Nihoyannopoulos (UK),
Massimo F. Piepoli (Italy), Piotr Ponikowski (Poland), Marco Rofﬁ
(Switzerland), Adam Torbicki (Poland), Anto´nio Vaz Carneiro
(Portugal), Stephan Windecker (Switzerland).
ESC National Cardiac Societies actively involved in the review
process of the 2016 ESC/EAS Guidelines for the management
of dyslipidaemias:
Armenia: Armenian Cardiologists Association, Parounak
H. Zelveian; Austria: Austrian Society of Cardiology, Peter Siostrzonek;
Azerbaijan: Azerbaijan Society of Cardiology, Firdovsi Ibrahimov;
Belarus: Belorussian Scientiﬁc Society of Cardiologists,
Volha Sujayeva; Belgium: Belgian Society of Cardiology, Marc
J. Claeys; Bosnia and Herzegovina: Association of Cardiologists
of Bosnia and Herzegovina, Belma Pojskic´; Bulgaria: Bulgarian
Society of Cardiology, Arman Postadzhiyan; Croatia: Croatian
Cardiac Society, Davor Milicˇic´; Cyprus: Cyprus Society of Cardiology,
George C. Georgiou; Czech Republic: Czech Society of
Cardiology, Hana Rosolova; Denmark: Danish Society of Cardiology,
Christian Klausen; Estonia: Estonian Society of Cardiology,
Margus Viigimaa; Finland: Finnish Cardiac Society, Kari Kervinen;
Former Yugoslav Republic of Macedonia: Macedonian FYR
Society of Cardiology, Sasko Kedev; France: French Society of Cardiology,
Jean Ferrie`res; Georgia: Georgian Society of Cardiology,
Shalva Petriashvili; Germany: German Cardiac Society, Ulrich
Kintscher; Greece: Hellenic Cardiological Society, Loukianos Rallidis;
Hungary: Hungarian Society of Cardiology, Ro´bert Ga´bor Kiss;
Iceland: Icelandic Society of Cardiology, Thorarinn Guðnason;
Ireland: Irish Cardiac Society, Vincent Maher; Israel: Israel Heart
Society, Yaakov Henkin; Italy: Italian Federation of Cardiology, Gian
Francesco Mureddu; Kazakhstan: Association of Cardiologists of
Kazakhstan, Aisulu Mussagaliyeva; Kosovo: Kosovo Society of
Cardiology, Pranvera Ibrahimi; Kyrgyzstan: Kyrgyz Society of
Cardiology, Erkin Mirrakhimov; Latvia: Latvian Society of Cardiology,
Gustavs Latkovskis; Libya: Libyan Cardiac Society, Hisham
Ben Lamin; Lithuania: Lithuanian Society of Cardiology, Rimvydas
Slapikas; Luxembourg: Luxembourg Society of Cardiology,
Laurent Visser; Malta: Maltese Cardiac Society, Philip Dingli;
Moldova: Moldavian Society of Cardiology, Victoria Ivanov;
To do or not to do lipid guidelines (continued)
Recommendations Classa
Level b
Recommendations for the treatment of dyslipidaemia in heart failure or valvular disease
Cholesterol lowering therapy with statins is not recommended (but is not harmful either) in patients with heart failure in the
absence of other indications for their use.
III A
Cholesterol-lowering treatment is not recommended in patients with aortic valvular stenosis without CAD in the absence of other
indications for their use.
III A
Recommendations for the treatment of dyslipidaemia in autoimmune diseases
The universal use of lipid-lowering drugs is not recommended. III C
Recommendations for lipid management in patients with moderate to severe chronic kidney disease
Patients with stage 3–5 CKD have to be considered at high or very high CV risk. I A
The use of statins or statin/ezetimibe combination is indicated in patients with non-dialysis-dependent CKD. I A
In patients with dialysis-dependent CKD and free of atherosclerotic CVD, statins should not be initiated. III A
Recommendations for lipid-lowering drugs in patients with peripheral arterial disease (including carotid artery disease)
PAD is a very high-risk condition and lipid-lowering therapy (mostly statins) is recommended in these patients. I A
Recommendations for lipid-lowering drugs for primary and secondary prevention of stroke
Statin therapy to reach established treatment goals is recommended in patients at high or very high CV risk for primary prevention
of stroke.
I A
Lipid-lowering therapy is recommended in patients with other manifestations of CVD for primary prevention of stroke. I A
Intensive statin therapy is recommended in patients with a history of non-cardioembolic ischaemic stroke or TIA for secondary
prevention of stroke.
I A
a
Class of recommendation.
b
Level of evidence.
ESC/EAS Guidelines3056
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
The Netherlands: Netherlands Society of Cardiology, Janneke
Wittekoek; Norway: Norwegian Society of Cardiology, Anders
Hovland; Poland: Polish Cardiac Society, Andrzej Rynkiewicz;
Portugal: Portuguese Society of Cardiology, Quiteria Rato; Russian
Federation: Russian Society of Cardiology, Marat Ezhov; San
Marino: San Marino Society of Cardiology, Marco Zavatta; Serbia:
Cardiology Society of Serbia, Milan A. Nedeljkovic; Slovakia: Slovak
Society of Cardiology, Daniel Pella; Slovenia: Slovenian Society of Cardiology,
Zlatko Fras; Spain: Spanish Society of Cardiology, Domingo
Marzal; Sweden: Swedish Society of Cardiology, Lennart Nilsson;
Switzerland: Swiss Society of Cardiology, Francois Mach; Tunisia:
Tunisian Society of Cardiology and Cardio-Vascular Surgery, Faouzi Addad;
Turkey: Turkish Society of Cardiology, Meral Kayıkcıoglu;
Ukraine: Ukrainian Association of Cardiology, Olena Mitchenko;
United Kingdom: British Cardiovascular Society, David Wald.
14. References
1. Townsend N, Nichols M, Scarborough P, Rayner M. Cardiovascular disease in
Europe—epidemiological update 2015. Eur Heart J 2015;36:2696–705.
2. Cooney MT, Dudina A, Whincup P, Capewell S, Menotti A, Jousilahti P, Njølstad I,
Oganov R, Thomsen T, Tverdal A, Wedel H, Wilhelmsen L, Graham I. Reevaluating
the Rose approach: comparative beneﬁts of the population and highrisk
preventive strategies. Eur J Cardiovasc Prev Rehabil 2009;16:541–549.
3. Liu K, Daviglus ML, Loria CM, Colangelo LA, Spring B, Moller AC,
Lloyd-Jones DM. Healthy lifestyle through young adulthood and the presence
of low cardiovascular disease risk proﬁle in middle age: the Coronary Artery
Risk Development in (Young) Adults (CARDIA) study. Circulation 2012;125:
996–1004.
4. Ezzati M, Lopez AD, Rodgers A, Murray CJL. Comparative quantiﬁcation of health
risks: global and regional burden of disease attributable to selected major risk factors.
Geneva: World Health Organization, 2004.
5. World Health Organization. Global status report on noncommunicable diseases
2010. Geneva: World Health Organization, 2011.
6. Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren M, Albus C,
Benlian P, Boysen G, Cifkova R, Deaton C, Ebrahim S, Fisher M, Germano G,
Hobbs R, Hoes A, Karadeniz S, Mezzani A, Prescott E, Ryden L, Scherer M,
Syva¨nne M, Scholte op Reimer WJ, Vrints C, Wood D, Zamorano JL, Zannad F.
European Guidelines on cardiovascular disease prevention in clinical practice
(version 2012). The Fifth Joint Task Force of the European Society of Cardiology
and Other Societies on Cardiovascular Disease Prevention in Clinical Practice
(constituted by representatives of nine societies and by invited experts). Eur Heart
J 2012;33:1635–1701.
7. Mistry H, Morris S, Dyer M, Kotseva K, Wood D, Buxton M. Cost-effectiveness of
a European preventive cardiology programme in primary care: a Markov modelling
approach. BMJ Open 2012 Oct 11;2. pii: e001029.
8. Nichols M, Townsend N, Luengo-Fernandez R, Leal J, Gray A, Scarborough P,
Rayner M. European Cardiovascular Disease Statistics, 2012. Brussels: European
Heart Network, 2012.
9. Heidenreich PA, Trogdon JG, Khavjou OA, Butler J, Dracup K, Ezekowitz MD,
Finkelstein EA, Hong Y, Johnston SC, Khera A, Lloyd-Jones DM, Nelson SA,
Nichol G, Orenstein D, Wilson PW, Woo YJ. Forecasting the future of cardiovascular
disease in the United States: a policy statement from the American Heart
Association. Circulation 2011;123:933–944.
10. McConnachie A, Walker A, Robertson M, Marchbank L, Peacock J, Packard CJ,
Cobbe SM, Ford I. Long-term impact on healthcare resource utilization of statin
treatment, and its cost effectiveness in the primary prevention of cardiovascular
disease: a record linkage study. Eur Heart J 2014;35:290–298.
11. Ward S, Lloyd Jones M, Pandor A, Holmes M, Ara R, Ryan A, Yeo W, Payne N. A
systematic review and economic evaluation of statins for the prevention of coronary
events. Health Technol Assess 2007;11:1–160, iii–iv.
12. Plans-Rubio P. The cost effectiveness of statin therapies in Spain in 2010, after the
introduction of generics and reference prices. Am J Cardiovasc Drugs 2010;10:
369–382.
13. Bjorck L, Rosengren A, Bennett K, Lappas G, Capewell S. Modelling the decreasing
coronary heart disease mortality in Sweden between 1986 and 2002. Eur Heart J
2009;30:1046–1056.
14. Aspelund T, Gudnason V, Magnusdottir BT, Andersen K, Sigurdsson G,
Thorsson B, Steingrimsdottir L, Critchley J, Bennett K, O’Flaherty M,
Capewell S. Analysing the large decline in coronary heart disease mortality in
the Icelandic population aged 25–74 between the years 1981 and 2006. PLoS
One 2010;5:e13957.
15. Pereira M, Azevedo A, Lunet N, Carreira H, O’Flaherty M, Capewell S, Bennett K.
Explaining the decline in coronary heart disease mortality in Portugal between
1995 and 2008. Circ Cardiovasc Qual Outcomes 2013;6:634–642.
16. Unal B, Sozmen K, Arik H, Gerceklioglu G, Altun DU, Simsek H, Doganay S,
Demiral Y, Aslan O¨ , Bennett K, O’Flaherty M, Capewell S, Critchley J. Explaining
the decline in coronary heart disease mortality in Turkey between 1995 and 2008.
BMC Public Health 2013;13:1135.
17. Roth GA, Forouzanfar MH, Moran AE, Barber R, Nguyen G, Feigin VL, Naghavi M,
Mensah GA, Murray CJ. Demographic and epidemiologic drivers of global cardiovascular
mortality. N Engl J Med 2015;372:1333–1341.
18. Cobiac LJ, Magnus A, Lim S, Barendregt JJ, Carter R, Vos T. Which interventions
offer best value for money in primary prevention of cardiovascular disease? PLoS
One 2012;7:e41842.
19. Collins M, Mason H, O’Flaherty M, Guzman-Castillo M, Critchley J, Capewell S. An
economic evaluation of salt reduction policies to reduce coronary heart disease in
England: a policy modeling study. Value Health 2014;17:517–524.
20. Mason H, Shoaibi A, Ghandour R, O’Flaherty M, Capewell S, Khatib R, Jabr S,
Unal B, So¨zmen K, Arfa C, Aissi W, Ben Romdhane H, Fouad F, Al-Ali R,
Husseini A. A cost effectiveness analysis of salt reduction policies to reduce coronary
heart disease in four Eastern Mediterranean countries. PLoS One 2014;9:
e84445.
21. O’Keeffe C, Kabir Z, O’Flaherty M, Walton J, Capewell S, Perry IJ. Modelling the
impact of speciﬁc food policy options on coronary heart disease and stroke
deaths in Ireland. BMJ Open 2013;3. pii: e002837.
22. Moreira PV, Baraldi LG, Moubarac JC, Monteiro CA, Newton A, Capewell S,
O’Flaherty M. Comparing different policy scenarios to reduce the consumption
of ultra-processed foods in UK: impact on cardiovascular disease mortality using
a modelling approach. PLoS One 2015;10:e0118353.
23. Neyt M, De Laet C, Van Brabandt H, Franco O, Ramaekers D. Cost-effectiveness
of statins in the primary prevention of cardiovascular disease: a systematic review
and economic analysis for Belgium. Acta Cardiol 2009;64:1–10.
24. Peura P, Martikainen J, Soini E, Hallinen T, Niskanen L. Cost-effectiveness of statins
in the prevention of coronary heart disease events in middle-aged Finnish men.
Curr Med Res Opin 2008;24:1823–1832.
25. Ito MK, Nanchen D, Rodondi N, Paccaud F, Waeber G, Vollenweider P,
Marques-Vidal P. Statins for cardiovascular prevention according to different
strategies: a cost analysis. Am J Cardiovasc Drugs 2011;11:33–44.
26. Stevanovic J, O’Prinsen AC, Verheggen BG, Schuiling-Veninga N, Postma MJ,
Pechlivanoglou P. Economic evaluation of primary prevention of cardiovascular
diseases in mild hypertension: a scenario analysis for the Netherlands. Clin Ther
2014;36:368–384.e5.
27. Wisloff T, Selmer RM, Halvorsen S, Fretheim A, Norheim OF, Kristiansen IS.
Choice of generic antihypertensive drugs for the primary prevention of cardiovascular
disease—a cost-effectiveness analysis. BMC Cardiovasc Disord 2012;12:26.
28. Banegas JR, Lopez-Garcia E, Dallongeville J, Guallar E, Halcox JP, Borghi C,
Masso´-Gonza´lez EL, Jime´nez FJ, Perk J, Steg PG, De Backer G,
Rodrı´guez-Artalejo F. Achievement of treatment goals for primary prevention
of cardiovascular disease in clinical practice across Europe: the EURIKA study.
Eur Heart J 2011;32:2143–2152.
29. Kotseva K, Wood D, De Backer G, De Bacquer D, Pyorala K, Reiner Z, Keil U.
EUROASPIRE III. Management of cardiovascular risk factors in asymptomatic
high-risk patients in general practice: cross-sectional survey in 12 European countries.
Eur J Cardiovasc Prev Rehabil 2010;17:530–540.
30. Cherry SB, Benner JS, Hussein MA, Tang SS, Nichol MB. The clinical and economic
burden of nonadherence with antihypertensive and lipid-lowering therapy in
hypertensive patients. Value Health 2009;12:489–497.
31. Corrao G, Scotti L, Zambon A, Baio G, Nicotra F, Conti V, Capri S, Tragni E,
Merlino L, Catapano AL, Mancia G. Cost-effectiveness of enhancing adherence
to therapy with statins in the setting of primary cardiovascular prevention. Evidence
from an empirical approach based on administrative databases. Atherosclerosis
2011;217:479–485.
32. Dragomir A, Cote R, Roy L, Blais L, Lalonde L, Berard A, Perreault S. Impact of
adherence to antihypertensive agents on clinical outcomes and hospitalization
costs. Med Care 2010;48:418–425.
33. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%.
BMJ 2003;326:1419.
34. Gaziano TA, Opie LH, Weinstein MC. Cardiovascular disease prevention with a
multidrug regimen in the developing world: a cost-effectiveness analysis. Lancet
2006:368:679–686.
35. van Gils PF, Over EA, Hamberg-van Reenen HH, de Wit GA, van den Berg M,
Schuit AJ, Engelfriet PM. The polypill in the primary prevention of cardiovascular
disease: cost-effectiveness in the Dutch population. BMJ Open 2011;1:e000363.
ESC/EAS Guidelines 3057
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
36. Frieden TR. A framework for public health action: the health impact pyramid.
Am J Public Health 2010;100:590–595.
37. Brown MT, Bussell JK. Medication adherence: WHO cares? Mayo Clin Proc 2011;
86:304–314.
38. National Institute for Health and Care Excellence. NICE Public Health Guidance
25. June 2010. https://www.nice.org.uk/guidance/ph25.
39. Capewell S, Ford ES, Croft JB, Critchley JA, Greenlund KJ, Labarthe DR. Cardiovascular
risk factor trends and potential for reducing coronary heart disease mortality
in the United States of America. Bull World Health Org 2010;88:120–130.
40. Mozaffarian D, Capewell S. United Nations’ dietary policies to prevent cardiovascular
disease. BMJ 2011;343:d5747.
41. D’Agostino RB Sr, Vasan RS, Pencina MJ, Wolf PA, Cobain M, Massaro JM,
Kannel WB. General cardiovascular risk proﬁle for use in primary care: the
Framingham Heart Study. Circulation 2008;117:743–753.
42. Conroy RM, Pyorala K, Fitzgerald AP, Sans S, Menotti A, De Backer G, De
Bacquer D, Ducimetie`re P, Jousilahti P, Keil U, Njølstad I, Oganov RG,
Thomsen T, Tunstall-Pedoe H, Tverdal A, Wedel H, Whincup P, Wilhelmsen L,
Graham IM. Estimation of ten-year risk of fatal cardiovascular disease in Europe:
the SCORE project. Eur Heart J 2003;24:987–1003.
43. Woodward M, Brindle P, Tunstall-Pedoe H. Adding social deprivation and family
history to cardiovascular risk assessment: the ASSIGN score from the Scottish
Heart Health Extended Cohort (SHHEC). Heart 2007;93:172–176.
44. Hippisley-Cox J, Coupland C, Vinogradova Y, Robson J, Minhas R, Sheikh A,
Brindle P. Predicting cardiovascular risk in England and Wales: prospective derivation
and validation of QRISK2. BMJ 2008;336:1475–1482.
45. Assmann G, Cullen P, Schulte H. Simple scoring scheme for calculating the risk of
acute coronary events based on the 10-year follow-up of the prospective cardiovascular
Munster (PROCAM) study. Circulation 2002;105:310–315.
46. Ridker PM, Paynter NP, Rifai N, Gaziano JM, Cook NR. C-reactive protein and
parental history improve global cardiovascular risk prediction: the Reynolds
Risk Score for men. Circulation 2008;118:2243–2251.
47. Ridker PM, Buring JE, Rifai N, Cook NR. Development and validation of improved
algorithms for the assessment of global cardiovascular risk in women: the
Reynolds Risk Score. JAMA 2007;297:611–619.
48. Ferrario M, Chiodini P, Chambless LE, Cesana G, Vanuzzo D, Panico S, Sega R,
Pilotto L, Palmieri L, Giampaoli S. Prediction of coronary events in a low incidence
population. Assessing accuracy of the CUORE Cohort Study prediction equation.
Int J Epidemiol 2005;34:413–421.
49. Goff DC Jr, Lloyd-Jones DM, Bennett G, Coady S, D’Agostino RB, Gibbons R,
Greenland P, Lackland DT, Levy D, O’Donnell CJ, Robinson JG, Schwartz JS,
Shero ST, Smith SC Jr, Sorlie P, Stone NJ, Wilson PW, Jordan HS, Nevo L,
Wnek J, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG,
Curtis LH, DeMets D, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ,
Sellke FW, Shen WK, Smith SC Jr, Tomaselli GF. 2013 ACC/AHA guideline
on the assessment of cardiovascular risk: a report of the American College
of Cardiology/American Heart Association Task Force on Practice Guidelines.
Circulation 2014;129(25 Suppl 2):S49–S73.
50. Hajifathalian K, Ueda P, Lu Y, Woodward M, Ahmadvand A, Aguilar-Salinas CA,
Azizi F, Cifkova R, Di Cesare M, Eriksen L, Farzadfar F, Ikeda N, Khalili D,
Khang YH, Lanska V, Leo´n-Mun˜oz L, Magliano D, Msyamboza KP, Oh K,
Rodrı´guez-Artalejo F, Rojas-Martinez R, Shaw JE, Stevens GA, Tolstrup J,
Zhou B, Salomon JA, Ezzati M, Danaei G. A novel risk score to predict cardiovascular
disease risk in national populations (Globorisk): a pooled analysis of prospective
cohorts and health examination surveys. Lancet Diabetes Endocrinol
2015;3:339–355.
51. Cooney MT, Dudina AL, Graham IM. Value and limitations of existing scores for
the assessment of cardiovascular risk: a review for clinicians. J Am Coll Cardiol 2009;
54:1209–1227.
52. Cooney MT, Dudina A, D’Agostino R, Graham IM. Cardiovascular risk-estimation
systems in primary prevention: do they differ? Do they make a difference? Can we
see the future? Circulation 2010;122:300–310.
53. Lloyd-Jones DM, Leip EP, Larson MG, D’Agostino RB, Beiser A, Wilson PW,
Wolf PA, Levy D. Prediction of lifetime risk for cardiovascular disease by risk
factor burden at 50 years of age. Circulation 2006;113:791–798.
54. Cooney MT, Selmer R, Lindman A, Tverdal A, Menotti A, Thomsen T,
DeBacker G, De Bacquer D, Tell GS, Njolstad I, Graham IM. Cardiovascular
risk estimation in older persons: SCORE O.P. Eur J Prev Cardiol 2016;23:
1093–1103.
55. Cooney MT, Dudina A, De Bacquer D, Wilhelmsen L, Sans S, Menotti A, De
Backer G, Jousilahti P, Keil U, Thomsen T, Whincup P, Graham IM. HDL cholesterol
protects against cardiovascular disease in both genders, at all ages and at all
levels of risk. Atherosclerosis 2009;206:611–616.
56. Cooney MT, Dudina A, De Bacquer D, Fitzgerald A, Conroy R, Sans S, Menotti A,
De Backer G, Jousilahti P, Keil U, Thomsen T, Whincup P, Graham I. How much
does HDL cholesterol add to risk estimation? A report from the SCORE Investigators.
Eur J Cardiovasc Prev Rehabil 2009;16:304–314.
57. Mortensen MB, Afzal S, Nordestgaard BG, Falk E. The high-density
lipoprotein-adjusted SCORE model worsens SCORE-based risk classiﬁcation in
a contemporary population of 30,824 Europeans: the Copenhagen General Population
Study. Eur Heart J 2015;36:2446–2453.
58. Kavousi M, Elias-Smale S, Rutten JH, Leening MJ, Vliegenthart R, Verwoert GC,
Krestin GP, Oudkerk M, de Maat MP, Leebeek FW, Mattace-Raso FU,
Lindemans J, Hofman A, Steyerberg EW, van der Lugt A, van den
Meiracker AH, Witteman JC. Evaluation of newer risk markers for coronary heart
disease risk classiﬁcation: a cohort study. Ann Intern Med 2012;156:438–444.
59. Yeboah J, McClelland RL, Polonsky TS, Burke GL, Sibley CT, O’Leary D, Carr JJ,
Goff DC, Greenland P, Herrington DM. Comparison of novel risk markers for improvement
in cardiovascular risk assessment in intermediate-risk individuals.
JAMA 2012;308:788–795.
60. Vlachopoulos C, Xaplanteris P, Aboyans V, Brodmann M, Cifkova R, Cosentino F,
De Carlo M, Gallino A, Landmesser U, Laurent S, Lekakis J, Mikhailidis DP,
Naka KK, Protogerou AD, Rizzoni D, Schmidt-Trucksa¨ss A, Van Bortel L,
Weber T, Yamashina A, Zimlichman R, Boutouyrie P, Cockcroft J, O’Rourke M,
Park JB, Schillaci G, Sillesen H, Townsend RR. The role of vascular biomarkers
for primary and secondary prevention. A position paper from the European Society
of Cardiology Working Group on peripheral circulation: endorsed by the
Association for Research into Arterial Structure and Physiology (ARTERY) Society.
Atherosclerosis 2015;241:507–532.
61. Boekholdt SM, Hovingh GK, Mora S, Arsenault BJ, Amarenco P, Pedersen TR,
LaRosa JC, Waters DD, DeMicco DA, Simes RJ, Keech AC, Colquhoun D,
Hitman GA, Betteridge DJ, Clearﬁeld MB, Downs JR, Colhoun HM, Gotto AM
Jr, Ridker PM, Grundy SM, Kastelein JJ. Very low levels of atherogenic lipoproteins
and the risk for cardiovascular events: a meta-analysis of statin trials. J Am Coll Cardiol
2014;64:485–494.
62. Brugts JJ, Yetgin T, Hoeks SE, Gotto AM, Shepherd J, Westendorp RG, de
Craen AJ, Knopp RH, Nakamura H, Ridker P, van Domburg R, Deckers JW.
The beneﬁts of statins in people without established cardiovascular disease but
with cardiovascular risk factors: meta-analysis of randomised controlled trials.
BMJ 2009;338:b2376.
63. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H,
Lewis BS, Ophuis TO, Jukema JW, De Ferrari GM, Ruzyllo W, De Lucca P, Im K,
Bohula EA, Reist C, Wiviott SD, Tershakovec AM, Musliner TA, Braunwald E,
Califf RM. Ezetimibe added to statin therapy after acute coronary syndromes. N
Engl J Med 2015;372:2387–2397.
64. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L,
Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J,
Collins R. Efﬁcacy and safety of more intensive lowering of LDL cholesterol: a
meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet
2010;376:1670–1681.
65. Cholesterol Treatment Trialists’ (CTT) Collaboration, Fulcher J, O’Connell R,
Voysey M, Emberson J, Blackwell L, Mihaylova B, Simes J, Collins R, Kirby A,
Colhoun H, Braunwald E, La Rosa J, Pedersen TR, Tonkin A, Davis B, Sleight P,
Franzosi MG, Baigent C, Keech A. Efﬁcacy and safety of LDL-lowering therapy
among men and women: meta-analysis of individual data from 174,000 participants
in 27 randomised trials. Lancet 2015;385:1397–1405.
66. Cholesterol Treatment Trialists’ (CTT) Collaborators, Mihaylova B, Emberson J,
Blackwell L, Keech A, Simes J, Barnes EH, Voysey M, Gray A, Collins R, Baigent C.
The effects of lowering LDL cholesterol with statin therapy in people at low risk of
vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet
2012;380:581–590.
67. Hegele RA, Ginsberg HN, Chapman MJ, Nordestgaard BG, Kuivenhoven JA,
Averna M, Bore´n J, Bruckert E, Catapano AL, Descamps OS, Hovingh GK,
Humphries SE, Kovanen PT, Masana L, Pajukanta P, Parhofer KG, Raal FJ,
Ray KK, Santos RD, Stalenhoef AF, Stroes E, Taskinen MR, Tybjærg-Hansen A,
Watts GF, Wiklund O. The polygenic nature of hypertriglyceridaemia: implications
for deﬁnition, diagnosis, and management. Lancet Diabetes Endocrinol 2014;
2:655–666.
68. Mills EJ, Rachlis B, Wu P, Devereaux PJ, Arora P, Perri D. Primary prevention of
cardiovascular mortality and events with statin treatments: a network
meta-analysis involving more than 65,000 patients. J Am Coll Cardiol 2008;52:
1769–1781.
69. Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ, Holme I,
Larsen ML, Bendiksen FS, Lindahl C, Szarek M, Tsai J. High-dose atorvastatin vs
usual-dose simvastatin for secondary prevention after myocardial infarction: the
IDEAL study: a randomized controlled trial. JAMA 2005;294:2437–2445.
70. SPRINT Research Group, Wright JT Jr, Williamson JD, Whelton PK, Snyder JK,
Sink KM, Rocco MV, Reboussin DM, Rahman M, Oparil S, Lewis CE,
Kimmel PL, Johnson KC, Goff DC Jr, Fine LJ, Cutler JA, Cushman WC,
ESC/EAS Guidelines3058
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
Cheung AK, Ambrosius WT. A randomized trial of intensive versus standard
blood-pressure control. N Engl J Med 2015;373:2103–2116.
71. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH,
Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS,
Shero ST, Smith SC Jr, Watson K, Wilson PW, Eddleman KM, Jarrett NM,
LaBresh K, Nevo L, Wnek J, Anderson JL, Halperin JL, Albert NM, Bozkurt B,
Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ, Ohman EM,
Pressler SJ, Sellke FW, Shen WK, Smith SC Jr, Tomaselli GF. 2013 ACC/AHA
guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular
risk in adults: a report of the American College of Cardiology/American
Heart Association Task Force on Practice Guidelines. Circulation 2014;129(25
Suppl 2):S1–S45.
72. Langlois MR, Descamps OS, van der Laarse A, Weykamp C, Baum H, Pulkki K, von
Eckardstein A, De Bacquer D, Bore´n J, Wiklund O, Laitinen P, Oosterhuis WP,
Cobbaert C. Clinical impact of direct HDLc and LDLc method bias in hypertriglyceridemia.
A simulation study of the EAS-EFLM Collaborative Project Group. Atherosclerosis
2014;233:83–90.
73. Kolovou GD, Mikhailidis DP, Kovar J, Lairon D, Nordestgaard BG, Ooi TC,
Perez-Martinez P, Bilianou H, Anagnostopoulou K, Panotopoulos G. Assessment
and clinical relevance of non-fasting and postprandial triglycerides: an expert panel
statement. Curr Vasc Pharmacol 2011;9:258–270.
74. Mihas C, Kolovou GD, Mikhailidis DP, Kovar J, Lairon D, Nordestgaard BG,
Ooi TC, Perez-Martinez P, Bilianou H, Anagnostopoulou K, Panotopoulos G.
Diagnostic value of postprandial triglyceride testing in healthy subjects: a
meta-analysis. Curr Vasc Pharmacol 2011;9:271–280.
75. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014;
384:626–635.
76. Jorgensen AB, Frikke-Schmidt R, West AS, Grande P, Nordestgaard BG,
Tybjaerg-Hansen A. Genetically elevated non-fasting triglycerides and calculated
remnant cholesterol as causal risk factors for myocardial infarction. Eur Heart J
2013;34:1826–1833.
77. Langsted A, Nordestgaard BG. Nonfasting lipids, lipoproteins, and apolipoproteins
in individuals with and without diabetes: 58 434 individuals from the Copenhagen
General Population Study. Clin Chem 2011;57:482–489.
78. Marti-Soler H, Gubelmann C, Aeschbacher S, Alves L, Bobak M, Bongard V,
Clays E, de Gaetano G, Di Castelnuovo A, Elosua R, Ferrieres J, Guessous I,
Igland J, Jørgensen T, Nikitin Y, O’Doherty MG, Palmieri L, Ramos R, Simons J,
Sulo G, Vanuzzo D, Vila J, Barros H, Borglykke A, Conen D, De Bacquer D,
Donfrancesco C, Gaspoz JM, Giampaoli S, Giles GG, Iacoviello L, Kee F,
Kubinova R, Malyutina S, Marrugat J, Prescott E, Ruidavets JB, Scragg R,
Simons LA, Tamosiunas A, Tell GS, Vollenweider P, Marques-Vidal P. Seasonality
of cardiovascular risk factors: an analysis including over 230 000 participants in 15
countries. Heart 2014;100:1517–1523.
79. Rabar S, Harker M, O’Flynn N, Wierzbicki AS, Guideline Development Group.
Lipid modiﬁcation and cardiovascular risk assessment for the primary and secondary
prevention of cardiovascular disease: summary of updated NICE guidance.
BMJ 2014;349:g4356.
80. JBS3. Joint British Societies’ consensus recommendations for the prevention of
cardiovascular disease (JBS3). Heart 2014;100(Suppl 2):ii1–ii67.
81. Knopfholz J, Disserol CC, Pierin AJ, Schirr FL, Streisky L, Takito LL, Massucheto
Ledesma P, Faria-Neto JR, Olandoski M, da Cunha CL, Bandeira AM. Validation of
the Friedewald formula in patients with metabolic syndrome. Cholesterol 2014;
2014:261878.
82. National Institute for Health and Care Excellence. Lipid modiﬁcation: cardiovascular
risk assessment and the modiﬁcation of blood lipids for the primary and secondary
prevention of cardiovascular disease. London: National Institute for
Health and Care Excellence, 2014.
83. Emerging Risk Factors Collaboration, Di Angelantonio E, Gao P, Pennells L,
Kaptoge S, Caslake M, Thompson A, Butterworth AS, Sarwar N, Wormser D,
Saleheen D, Ballantyne CM, Psaty BM, Sundstro¨m J, Ridker PM, Nagel D,
Gillum RF, Ford I, Ducimetiere P, Kiechl S, Koenig W, Dullaart RP, Assmann G,
D’Agostino RB Sr, Dagenais GR, Cooper JA, Kromhout D, Onat A,
Tipping RW, Go´mez-de-la-Ca´mara A, Rosengren A, Sutherland SE, Gallacher J,
Fowkes FG, Casiglia E, Hofman A, Salomaa V, Barrett-Connor E, Clarke R,
Brunner E, Jukema JW, Simons LA, Sandhu M, Wareham NJ, Khaw KT,
Kauhanen J, Salonen JT, Howard WJ, Nordestgaard BG, Wood AM, Thompson
SG, Boekholdt SM, Sattar N, Packard C, Gudnason V, Danesh J. Lipid-related
markers and cardiovascular disease prediction. JAMA 2012;307:2499–2506.
84. Boekholdt SM, Arsenault BJ, Mora S, Pedersen TR, LaRosa JC, Nestel PJ, Simes RJ,
Durrington P, Hitman GA, Welch KM, DeMicco DA, Zwinderman AH,
Clearﬁeld MB, Downs JR, Tonkin AM, Colhoun HM, Gotto AM Jr, Ridker PM,
Kastelein JJ. Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein
B levels with risk of cardiovascular events among patients treated with
statins: a meta-analysis. JAMA 2012;307:1302–1309.
85. Robinson JG, Wang S, Jacobson TA. Meta-analysis of comparison of effectiveness
of lowering apolipoprotein B versus low-density lipoprotein cholesterol and
nonhigh-density lipoprotein cholesterol for cardiovascular risk reduction in randomized
trials. Am J Cardiol 2012;110:1468–1476.
86. Varbo A, Benn M, Tybjaerg-Hansen A, Jorgensen AB, Frikke-Schmidt R,
Nordestgaard BG. Remnant cholesterol as a causal risk factor for ischemic heart
disease. J Am Coll Cardiol 2013;61:427–436.
87. Triglyceride Coronary Disease Genetics, Consortium and Emerging Risk Factors
Collaboration, Sarwar N, Sandhu MS, Ricketts SL, Butterworth AS, Di
Angelantonio E, Boekholdt SM, Ouwehand W, Watkins H, Samani NJ,
Saleheen D, Lawlor D, Reilly MP, Hingorani AD, Talmud PJ, Danesh J. Triglyceridemediated
pathways and coronary disease: collaborative analysis of 101 studies.
Lancet 2010;375:1634–1639.
88. Do R, Willer CJ, Schmidt EM, Sengupta S, Gao C, Peloso GM, Gustafsson S,
Kanoni S, Ganna A, Chen J, Buchkovich ML, Mora S, Beckmann JS,
Bragg-Gresham JL, Chang HY, Demirkan A, Den Hertog HM, Donnelly LA,
Ehret GB, Esko T, Feitosa MF, Ferreira T, Fischer K, Fontanillas P, Fraser RM,
Freitag DF, Gurdasani D, Heikkila¨ K, Hyppo¨nen E, Isaacs A, Jackson AU,
Johansson A, Johnson T, Kaakinen M, Kettunen J, Kleber ME, Li X, Luan J,
Lyytika¨inen LP, Magnusson PK, Mangino M, Mihailov E, Montasser ME,
Mu¨ller-Nurasyid M, Nolte IM, O’Connell JR, Palmer CD, Perola M,
Petersen AK, Sanna S, Saxena R, Service SK, Shah S, Shungin D, Sidore C,
Song C, Strawbridge RJ, Surakka I, Tanaka T, Teslovich TM, Thorleifsson G, Van
den Herik EG, Voight BF, Volcik KA, Waite LL, Wong A, Wu Y, Zhang W,
Absher D, Asiki G, Barroso I, Been LF, Bolton JL, Bonnycastle LL, Brambilla P,
Burnett MS, Cesana G, Dimitriou M, Doney AS, Do¨ring A, Elliott P, Epstein SE,
Eyjolfsson GI, Gigante B, Goodarzi MO, Grallert H, Gravito ML, Groves CJ,
Hallmans G, Hartikainen AL, Hayward C, Hernandez D, Hicks AA, Holm H,
Hung YJ, Illig T, Jones MR, Kaleebu P, Kastelein JJ, Khaw KT, Kim E, Klopp N,
Komulainen P, Kumari M, Langenberg C, Lehtima¨ki T, Lin SY, Lindstro¨m J,
Loos RJ, Mach F, McArdle WL, Meisinger C, Mitchell BD, Mu¨ller G, Nagaraja R,
Narisu N, Nieminen TV, Nsubuga RN, Olafsson I, Ong KK, Palotie A,
Papamarkou T, Pomilla C, Pouta A, Rader DJ, Reilly MP, Ridker PM,
Rivadeneira F, Rudan I, Ruokonen A, Samani N, Scharnagl H, Seeley J,
Silander K, Stancˇa´kova´ A, Stirrups K, Swift AJ, Tiret L, Uitterlinden AG, van
Pelt LJ, Vedantam S, Wainwright N, Wijmenga C, Wild SH, Willemsen G,
Wilsgaard T, Wilson JF, Young EH, Zhao JH, Adair LS, Arveiler D, Assimes TL,
Bandinelli S, Bennett F, Bochud M, Boehm BO, Boomsma DI, Borecki IB,
Bornstein SR, Bovet P, Burnier M, Campbell H, Chakravarti A, Chambers JC,
Chen YD, Collins FS, Cooper RS, Danesh J, Dedoussis G, de Faire U,
Feranil AB, Ferrie`res J, Ferrucci L, Freimer NB, Gieger C, Groop LC,
Gudnason V, Gyllensten U, Hamsten A, Harris TB, Hingorani A, Hirschhorn JN,
Hofman A, Hovingh GK, Hsiung CA, Humphries SE, Hunt SC, Hveem K,
Iribarren C, Ja¨rvelin MR, Jula A, Ka¨ho¨nen M, Kaprio J, Kesa¨niemi A, Kivimaki M,
Kooner JS, Koudstaal PJ, Krauss RM, Kuh D, Kuusisto J, Kyvik KO, Laakso M,
Lakka TA, Lind L, Lindgren CM, Martin NG, Ma¨rz W, McCarthy MI,
McKenzie CA, Meneton P, Metspalu A, Moilanen L, Morris AD, Munroe PB,
Njølstad I, Pedersen NL, Power C, Pramstaller PP, Price JF, Psaty BM,
Quertermous T, Rauramaa R, Saleheen D, Salomaa V, Sanghera DK, Saramies J,
Schwarz PE, Sheu WH, Shuldiner AR, Siegbahn A, Spector TD, Stefansson K,
Strachan DP, Tayo BO, Tremoli E, Tuomilehto J, Uusitupa M, van Duijn CM,
Vollenweider P, Wallentin L, Wareham NJ, Whitﬁeld JB, Wolffenbuttel BH,
Altshuler D, Ordovas JM, Boerwinkle E, Palmer CN, Thorsteinsdottir U,
Chasman DI, Rotter JI, Franks PW, Ripatti S, Cupples LA, Sandhu MS, Rich SS,
Boehnke M, Deloukas P, Mohlke KL, Ingelsson E, Abecasis GR, Daly MJ,
Neale BM, Kathiresan S. Common variants associated with plasma triglycerides
and risk for coronary artery disease. Nat Genet 2013;45:1345–1352.
89. Holmes MV, Asselbergs FW, Palmer TM, Drenos F, Lanktree MB, Nelson CP,
Dale CE, Padmanabhan S, Finan C, Swerdlow DI, Tragante V, van Iperen EP,
Sivapalaratnam S, Shah S, Elbers CC, Shah T, Engmann J, Giambartolomei C,
White J, Zabaneh D, Sofat R, McLachlanS; UCLEB consortium, Doevendans PA,
Balmforth AJ, Hall AS, North KE, Almoguera B, Hoogeveen RC, Cushman M,
Fornage M, Patel SR, Redline S, Siscovick DS, Tsai MY, Karczewski KJ,
Hofker MH, Verschuren WM, Bots ML, van der Schouw YT, Melander O,
Dominiczak AF, Morris R, Ben-Shlomo Y, Price J, Kumari M, Baumert J,
Peters A, Thorand B, Koenig W, Gaunt TR, Humphries SE, Clarke R,
Watkins H, Farrall M, Wilson JG, Rich SS, de Bakker PI, Lange LA, Davey
Smith G, Reiner AP, Talmud PJ, Kivima¨ki M, Lawlor DA, Dudbridge F,
Samani NJ, Keating BJ, Hingorani AD, Casas JP. Mendelian randomization of blood
lipids for coronary heart disease. Eur Heart J 2015;36:539–550.
90. Emerging Risk Factors Collaboration, Di Angelantonio E, Sarwar N, Perry P,
Kaptoge S, Ray KK, Thompson A, Wood AM, Lewington S, Sattar N,
Packard CJ, Collins R, Thompson SG, Danesh J. Major lipids, apolipoproteins,
and risk of vascular disease. JAMA 2009;302:1993–2000.
ESC/EAS Guidelines 3058a
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
91. Haase CL, Tybjærg-Hansen A, Grande P, Frikke-Schmidt R. Genetically elevated
apolipoprotein A-I, high-density lipoprotein cholesterol levels, and risk of ischemic
heart disease. J Clin Endocrinol Metab 2010;95:E500–510.
92. Voight BF, Peloso GM, Orho-Melander M, Frikke-Schmidt R, Barbalic M,
Jensen MK, Hindy G, Ho´lm H, Ding EL, Johnson T, Schunkert H, Samani NJ,
Clarke R, Hopewell JC, Thompson JF, Li M, Thorleifsson G, Newton-Cheh C,
Musunuru K, Pirruccello JP, Saleheen D, Chen L, Stewart A, Schillert A,
Thorsteinsdottir U, Thorgeirsson G, Anand S, Engert JC, Morgan T, Spertus J,
Stoll M, Berger K, Martinelli N, Girelli D, McKeown PP, Patterson CC,
Epstein SE, Devaney J, Burnett MS, Mooser V, Ripatti S, Surakka I,
Nieminen MS, Sinisalo J, Lokki ML, Perola M, Havulinna A, de Faire U,
Gigante B, Ingelsson E, Zeller T, Wild P, de Bakker PI, Klungel OH, Maitland-van
der Zee AH, Peters BJ, de Boer A, Grobbee DE, Kamphuisen PW, Deneer VH,
Elbers CC, Onland-Moret NC, Hofker MH, Wijmenga C, Verschuren WM,
Boer JM, van der Schouw YT, Rasheed A, Frossard P, Demissie S, Willer C,
Do R, Ordovas JM, Abecasis GR, Boehnke M, Mohlke KL, Daly MJ, Guiducci C,
Burtt NP, Surti A, Gonzalez E, Purcell S, Gabriel S, Marrugat J, Peden J,
Erdmann J, Diemert P, Willenborg C, Ko¨nig IR, Fischer M, Hengstenberg C,
Ziegler A, Buysschaert I, Lambrechts D, Van de Werf F, Fox KA, El
Mokhtari NE, Rubin D, Schrezenmeir J, Schreiber S, Scha¨fer A, Danesh J,
Blankenberg S, Roberts R, McPherson R, Watkins H, Hall AS, Overvad K,
Rimm E, Boerwinkle E, Tybjaerg-Hansen A, Cupples LA, Reilly MP,
Melander O, Mannucci PM, Ardissino D, Siscovick D, Elosua R, Stefansson K,
O’Donnell CJ, Salomaa V, Rader DJ, Peltonen L, Schwartz SM, Altshuler D,
Kathiresan S. Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian
randomisation study. Lancet 2012;380:572–580.
93. Khera AV, Cuchel M, de la Llera-Moya M, Rodrigues A, Burke MF, Jafri K,
French BC, Phillips JA, Mucksavage ML, Wilensky RL, Mohler ER, Rothblat GH,
Rader DJ. Cholesterol efﬂux capacity, high-density lipoprotein function, and atherosclerosis.
N Engl J Med 2011;364:127–135.
94. Li XM, Tang WH, Mosior MK, Huang Y, Wu Y, Matter W, Gao V, Schmitt D,
Didonato JA, Fisher EA, Smith JD, Hazen SL. Paradoxical association of enhanced
cholesterol efﬂux with increased incident cardiovascular risks. Arterioscler Thromb
Vasc Biol 2013;33:1696–1705.
95. Rohatgi A, Khera A, Berry JD, Givens EG, Ayers CR, Wedin KE, Neeland IJ,
Yuhanna IS, Rader DR, de Lemos JA, Shaul PW. HDL cholesterol efﬂux capacity
and incident cardiovascular events. N Engl J Med 2014;371:2383–2393.
96. Sarwar N, Danesh J, Eiriksdottir G, Sigurdsson G, Wareham N, Bingham S,
Boekholdt SM, Khaw KT, Gudnason V. Triglycerides and the risk of coronary
heart disease: 10,158 incident cases among 262,525 participants in 29 Western
prospective studies. Circulation 2007;115:450–458.
97. Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular
disease independent of high-density lipoprotein cholesterol level: a
meta-analysis of population-based prospective studies. J Cardiovasc Risk 1996;3:
213–219.
98. Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM. Fasting compared with
nonfasting triglycerides and risk of cardiovascular events in women. JAMA 2007;
298:309–316.
99. Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides
and risk of myocardial infarction, ischemic heart disease, and death in men and
women. JAMA 2007;298:299–308.
100. Charlton-Menys V, Betteridge DJ, Colhoun H, Fuller J, France M, Hitman GA,
Livingstone SJ, Neil HA, Newman CB, Szarek M, DeMicco DA, Durrington PN.
Targets of statin therapy: LDL cholesterol, non-HDL cholesterol, and apolipoprotein
B in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study
(CARDS). Clin Chem 2009;55:473–480.
101. Ingelsson E, Schaefer EJ, Contois JH, McNamara JR, Sullivan L, Keyes MJ,
Pencina MJ, Schoonmaker C, Wilson PW, D’Agostino RB, Vasan RS. Clinical utility
of different lipid measures for prediction of coronary heart disease in men and
women. JAMA 2007;298:776–785.
102. Taskinen MR, Barter PJ, Ehnholm C, Sullivan DR, Mann K, Simes J, Best JD,
Hamwood S, Keech AC. Ability of traditional lipid ratios and apolipoprotein ratios
to predict cardiovascular risk in people with type 2 diabetes. Diabetologia 2010;53:
1846–1855.
103. Sniderman AD, Williams K, Contois JH, Monroe HM, McQueen MJ, de Graaf J,
Furberg CD. A meta-analysis of low-density lipoprotein cholesterol,
non-high-density lipoprotein cholesterol, and apolipoprotein B as markers of cardiovascular
risk. Circ Cardiovasc Qual Outcomes 2011;4:337–345.
104. Onat A, Hergenc¸ G, Sansoy V, Fobker M, Ceyhan K, Toprak S, Assmann G. Apolipoprotein
C-III, a strong discriminant of coronary risk in men and a determinant
of the metabolic syndrome in both genders. Atherosclerosis 2003;168:81–89.
105. Sacks FM, Alaupovic P, Moye LA, Cole TG, Sussex B, Stampfer MJ, Pfeffer MA,
Braunwald E. VLDL, apolipoproteins B, CIII, and E, and risk of recurrent coronary
events in the Cholesterol and Recurrent Events (CARE) trial. Circulation 2000;102:
1886–1892.
106. TG and HDL Working Group of the Exome Sequencing Project, National Heart,
Lung, and Blood Institute, Crosby J, Peloso GM, Auer PL, Crosslin DR, Stitziel NO,
Lange LA, Lu Y, Tang ZZ, Zhang H, Hindy G, Masca N, Stirrups K, Kanoni S, Do R,
Jun G, Hu Y, Kang HM, Xue C, Goel A, Farrall M, Duga S, Merlini PA, Asselta R,
Girelli D, Olivieri O, Martinelli N, Yin W, Reilly D, Speliotes E, Fox CS, Hveem K,
Holmen OL, Nikpay M, Farlow DN, Assimes TL, Franceschini N, Robinson J,
North KE, Martin LW, DePristo M, Gupta N, Escher SA, Jansson JH, Van
Zuydam N, Palmer CN, Wareham N, Koch W, Meitinger T, Peters A, Lieb W,
Erbel R, Konig IR, Kruppa J, Degenhardt F, Gottesman O, Bottinger EP,
O’Donnell CJ, Psaty BM, Ballantyne CM, Abecasis G, Ordovas JM, Melander O,
Watkins H, Orho-Melander M, Ardissino D, Loos RJ, McPherson R, Willer CJ,
Erdmann J, Hall AS, Samani NJ, Deloukas P, Schunkert H, Wilson JG,
Kooperberg C, Rich SS, Tracy RP, Lin DY, Altshuler D, Gabriel S,
Nickerson DA, Jarvik GP, Cupples LA, Reiner AP, Boerwinkle E, Kathiresan S.
Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N
Engl J Med 2014;371:22–31.
107. Jorgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A.
Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N
Engl J Med 2014;371:32–41.
108. Graham MJ, Lee RG, Bell TA 3rd, Fu W, Mullick AE, Alexander VJ, Singleton W,
Viney N, Geary R, Su J, Baker BF, Burkey J, Crooke ST, Crooke RM. Antisense
oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in
rodents, nonhuman primates, and humans. Circ Res 2013;112:1479–1490.
109. Nordestgaard BG, Chapman MJ, Ray K, Bore´n J, Andreotti F, Watts GF,
Ginsberg H, Amarenco P, Catapano A, Descamps OS, Fisher E, Kovanen PT,
Kuivenhoven JA, Lesnik P, Masana L, Reiner Z, Taskinen MR, Tokgo¨zoglu L,
Tybjærg-Hansen A. Lipoprotein(a) as a cardiovascular risk factor: current status.
Eur Heart J 2010;31:2844–2853.
110. Kamstrup PR, Tybjaerg-Hansen A, Nordestgaard BG. Elevated lipoprotein(a) and
risk of aortic valve stenosis in the general population. J Am Coll Cardiol 2014;63:
470–477.
111. Kronenberg F, Utermann G. Lipoprotein(a): resurrected by genetics. J Intern Med
2013;273:6–30.
112. Marcovina SM, Koschinsky ML, Albers JJ, Skarlatos S. Report of the National
Heart, Lung, and Blood Institute Workshop on Lipoprotein(a) and Cardiovascular
Disease: recent advances and future directions. Clin Chem 2003;49:1785–1796.
113. Willeit P, Kiechl S, Kronenberg F, Witztum JL, Santer P, Mayr M, Xu Q, Mayr A,
Willeit J, Tsimikas S. Discrimination and net reclassiﬁcation of cardiovascular risk
with lipoprotein(a): prospective 15-year outcomes in the Bruneck Study. J Am Coll
Cardiol 2014;64:851–860.
114. Kamstrup PR, Tybjaerg-Hansen A, Nordestgaard BG. Extreme lipoprotein(a) levels
and improved cardiovascular risk prediction. J Am Coll Cardiol 2013;61:
1146–1156.
115. Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, Stroes ES,
Langslet G, Raal FJ, El Shahawy M, Koren MJ, Lepor NE, Lorenzato C, Pordy R,
Chaudhari U, Kastelein JJ. Efﬁcacy and safety of alirocumab in reducing lipids
and cardiovascular events. N Engl J Med 2015;372:1489–1499.
116. Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J,
Ballantyne CM, Somaratne R, Legg J, Wasserman SM, Scott R, Koren MJ,
Stein EA. Efﬁcacy and safety of evolocumab in reducing lipids and cardiovascular
events. N Engl J Med 2015;727:1500–1509.
117. Seed M, O’Connor B, Perombelon N, O’Donnell M, Reaveley D, Knight BL. The
effect of nicotinic acid and acipimox on lipoprotein(a) concentration and turnover.
Atherosclerosis 1993;101:61–68.
118. Packard CJ. Small dense low-density lipoprotein and its role as an independent
predictor of cardiovascular disease. Curr Opin Lipidol 2006;17:412–417.
119. Mora S, Szklo M, Otvos JD, Greenland P, Psaty BM, Goff DC Jr, O’Leary DH,
Saad MF, Tsai MY, Sharrett AR. LDL particle subclasses, LDL particle size, and carotid
atherosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis
2007;192:211–217.
120. Whitﬁeld JB. Genetic insights into cardiometabolic risk factors. Clin Biochem Rev
2014;35:15–36.
121. Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L,
Descamps OS, Wiklund O, Hegele RA, Raal FJ, Defesche JC, Wiegman A,
Santos RD, Watts GF, Parhofer KG, Hovingh GK, Kovanen PT, Boileau C,
Averna M, Bore´n J, Bruckert E, Catapano AL, Kuivenhoven JA, Pajukanta P,
Ray K, Stalenhoef AF, Stroes E, Taskinen MR, Tybjærg-Hansen A. Familial hypercholesterolaemia
is underdiagnosed and undertreated in the general population:
guidance for clinicians to prevent coronary heart disease: consensus statement of
the European Atherosclerosis Society. Eur Heart J 2013;34:3478–3490a.
122. Futema M, Shah S, Cooper JA, Li K, Whittall RA, Shariﬁ M, Goldberg O, Drogari E,
Mollaki V, Wiegman A, Defesche J, D’Agostino MN, D’Angelo A, Rubba P,
Fortunato G, Walus´-Miarka M, Hegele RA, Aderayo Bamimore M, Durst R,
Leitersdorf E, Mulder MT, Roeters van Lennep JE, Sijbrands EJ, Whittaker JC,
Talmud PJ, Humphries SE. Reﬁnement of variant selection for the LDL cholesterol
ESC/EAS Guidelines3058b
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
genetic risk score in the diagnosis of the polygenic form of clinical familial hypercholesterolemia
and replication in samples from 6 countries. Clin Chem 2015;61:
231–238.
123. Soran H, Schoﬁeld JD, Durrington PN. Cholesterol, not just cardiovascular risk, is
important in deciding who should receive statin treatment. Eur Heart J 2015;36:
2975–2983.
124. Holme I, Cater NB, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ,
Larsen ML, Lindahl C, Pedersen TR. Lipoprotein predictors of cardiovascular
events in statin-treated patients with coronary heart disease. Insights from the Incremental
Decrease In End-points Through Aggressive Lipid-lowering Trial
(IDEAL). Ann Med 2008;40:456–464.
125. European Association for Cardiovascular Prevention & Rehabilitation, Reiner Z,
Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, Agewall S,
Alegria E, Chapman MJ, Durrington P, Erdine S, Halcox J, Hobbs R, Kjekshus J,
Filardi PP, Riccardi G, Storey RF, Wood D. ESC/EAS Guidelines for the management
of dyslipidaemias: the Task Force for the management of dyslipidaemias of
the European Society of Cardiology (ESC) and the European Atherosclerosis
Society (EAS). Eur Heart J 2011;32:1769–1818.
126. Hsia J, MacFadyen JG, Monyak J, Ridker PM. Cardiovascular event reduction and
adverse events among subjects attaining low-density lipoprotein cholesterol
,50 mg/dl with rosuvastatin. The JUPITER trial (Justiﬁcation for the Use of Statins
in Prevention: an Intervention Trial Evaluating Rosuvastatin). J Am Coll Cardiol
2011;57:1666–1675.
127. Tight blood pressure control and risk of macrovascular and microvascular complications
in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group.
BMJ 1998;317:703–713.
128. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM,
Greten H, Kastelein JJ, Shepherd J, Wenger NK. Intensive lipid lowering with atorvastatin
in patients with stable coronary disease. N Engl J Med 2005;352:
1425–1435.
129. LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease: a
meta-analysis of randomized controlled trials. JAMA 1999;282:2340–2346.
130. Thompson A, Danesh J. Associations between apolipoprotein B, apolipoprotein
AI, the apolipoprotein B/AI ratio and coronary heart disease: a literature-based
meta-analysis of prospective studies. J Intern Med 2006;259:481–492.
131. Robinson JG, Wang S, Smith BJ, Jacobson TA. Meta-analysis of the relationship between
non-high-density lipoprotein cholesterol reduction and coronary heart disease
risk. J Am Coll Cardiol 2009;53:316–322.
132. Dalen JE, Devries S. Diets to prevent coronary heart disease 1957–2013: what
have we learned? Am J Med 2014;127:364–369.
133. Eckel RH, Jakicic JM, Ard JD, de Jesus JM, Houston Miller N, Hubbard VS, Lee IM,
Lichtenstein AH, Loria CM, Millen BE, Nonas CA, Sacks FM, Smith SC Jr,
Svetkey LP, Wadden TA, Yanovski SZ, Kendall KA, Morgan LC, Trisolini MG,
Velasco G, Wnek J, Anderson JL, Halperin JL, Albert NM, Bozkurt B,
Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ, Ohman EM,
Pressler SJ, Sellke FW, Shen WK, Smith SC Jr, Tomaselli GF. 2013 AHA/ACC
guideline on lifestyle management to reduce cardiovascular risk: a report of the
American College of Cardiology/American Heart Association Task Force on
Practice Guidelines. Circulation 2014;129(25 Suppl 2):S76–S99.
134. Mente A, de Koning L, Shannon HS, Anand SS. A systematic review of the evidence
supporting a causal link between dietary factors and coronary heart disease.
Arch Intern Med 2009;169:659–669.
135. Chowdhury R, Warnakula S, Kunutsor S, Crowe F, Ward HA, Johnson L,
Franco OH, Butterworth AS, Forouhi NG, Thompson SG, Khaw KT,
Mozaffarian D, Danesh J, Di Angelantonio E. Association of dietary, circulating,
and supplement fatty acids with coronary risk: a systematic review and
meta-analysis. Ann Intern Med 2014;160:398–406.
136. Mozaffarian D, Micha R, Wallace S. Effects on coronary heart disease of increasing
polyunsaturated fat in place of saturated fat: a systematic review and meta-analysis
of randomized controlled trials. PLoS Med 2010;7:e1000252.
137. Estruch R, Ros E, Salas-Salvado´ J, Covas MI, Corella D, Aro´s F, Go´mez-Gracia E,
Ruiz-Gutie´rrez V, Fiol M, Lapetra J, Lamuela-Raventos RM, Serra-Majem L,
Pinto´ X, Basora J, Mun˜oz MA, Sorlı´ JV, Martı´nez JA, Martı´nez-Gonza´lez MA. Primary
prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med
2013;368:1279–1290.
138. de Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N. Mediterranean
diet, traditional risk factors, and the rate of cardiovascular complications after
myocardial infarction: ﬁnal report of the Lyon Diet Heart Study. Circulation
1999;99:779–785.
139. Mozaffarian D, Aro A, Willett WC. Health effects of trans-fatty acids:
experimental and observational evidence. Eur J Clin Nutr 2009;63(Suppl 2):
S5–S21.
140. Brown L, Rosner B, Willett WW, Sacks FM. Cholesterol-lowering effects of dietary
ﬁber: a meta-analysis. Am J Clin Nutr 1999;69:30–42.
141. Hollaender PL, Ross AB, Kristensen M. Whole-grain and blood lipid changes in
apparently healthy adults: a systematic review and meta-analysis of randomized
controlled studies. Am J Clin Nutr 2015;102:556–572.
142. Gylling H, Plat J, Turley S, Ginsberg HN, Ellega˚rd L, Jessup W, Jones PJ,
Lu¨tjohann D, Maerz W, Masana L, Silbernagel G, Staels B, Bore´n J,
Catapano AL, De Backer G, Deanﬁeld J, Descamps OS, Kovanen PT,
Riccardi G, Tokgo¨zoglu L, Chapman MJ. Plant sterols and plant stanols in the management
of dyslipidaemia and prevention of cardiovascular disease. Atherosclerosis
2014;232:346–360.
143. Musa-Veloso K, Poon TH, Elliot JA, Chung C. A comparison of the
LDL-cholesterol lowering efﬁcacy of plant stanols and plant sterols over a continuous
dose range: results of a meta-analysis of randomized, placebo-controlled
trials. Prostaglandins Leukot Essent Fatty Acids 2011;85:9–28.
144. Lu Z, Kou W, Du B, Wu Y, Zhao S, Brusco OA, Morgan JM, Capuzzi DM. Effect of
Xuezhikang, an extract from red yeast Chinese rice, on coronary events in a Chinese
population with previous myocardial infarction. Am J Cardiol 2008;101:
1689–1693.
145. Gordon RY, Cooperman T, Obermeyer W, Becker DJ. Marked variability of monacolin
levels in commercial red yeast rice products: buyer beware. Arch Intern Med
2010;170:1722–1727.
146. Li Y, Jiang L, Jia Z, Xin W, Yang S, Yang Q, Wand L. A meta-analysis of red yeast
rice: an effective and relatively safe alternative approach for dyslipidemia. PLoS One
2014;9:e98611.
147. Dattilo AM, Kris-Etherton PM. Effects of weight reduction on blood lipids and lipoproteins:
a meta-analysis. Am J Clin Nutr 1992;56:320–328.
148. Nordmann AJ, Nordmann A, Briel M, Keller U, Yancy WS Jr, Brehm BJ,
Bucher HC. Effects of low-carbohydrate vs low-fat diets on weight loss and
cardiovascular risk factors: a meta-analysis of randomized controlled trials. Arch
Intern Med 2006;166:285–293.
149. Keys A. Serum cholesterol response to dietary cholesterol. Am J Clin Nutr 1984;40:
351–359.
150. Shaw K, Gennat H, O’Rourke P, Del Mar C. Exercise for overweight or obesity.
Cochrane Database Syst Rev 2006;4:CD003817.
151. Dewell A, Hollenbeck PL, Hollenbeck CB. Clinical review: a critical evaluation of
the role of soy protein and isoﬂavone supplementation in the control of plasma
cholesterol concentrations. J Clin Endocrinol Metab 2006;91:772–780.
152. Rimm EB, Williams P, Fosher K, Criqui M, Stampfer MJ. Moderate alcohol intake
and lower risk of coronary heart disease: meta-analysis of effects on lipids and
haemostatic factors. BMJ 1999;319:1523–1528.
153. Droste DW, Iliescu C, Vaillant M, Gantenbein M, De Bremaeker N, Lieunard C,
Velez T, Meyer M, Guth T, Kuemmerle A, Gilson G, Chioti A. A daily glass of red
wine associated with lifestyle changes independently improves blood lipids in patients
with carotid arteriosclerosis: results from a randomized controlled trial.
Nutr J 2013;12:147.
154. Yu-Poth S, Zhao G, Etherton T, Naglak M, Jonnalagadda S, Kris-Etherton PM. Effects
of the National Cholesterol Education Program’s Step I and Step II dietary
intervention programs on cardiovascular disease risk factors: a meta-analysis.
Am J Clin Nutr 1999;69:632–646.
155. Santos FL, Esteves SS, da Costa Pereira A, Yancy WS Jr, Nunes JP. Systematic review
and meta-analysis of clinical trials of the effects of low carbohydrate diets on
cardiovascular risk factors. Obes Rev 2012;13:1048–1066.
156. Rivellese AA, Maffettone A, Vessby B, Uusitupa M, Hermansen K, Berglund L,
Louheranta A, Meyer BJ, Riccardi G. Effects of dietary saturated, monounsaturated
and n-3 fatty acids on fasting lipoproteins, LDL size and post-prandial lipid
metabolism in healthy subjects. Atherosclerosis 2003;167:149–158.
157. Harris WS. n-3 fatty acids and serum lipoproteins: human studies. Am J Clin Nutr
1997;65(5 Suppl):1645S–1654S.
158. Stanhope KL, Schwarz JM, Keim NL, Griffen SC, Bremer AA, Graham JL,
Hatcher B, Cox CL, Dyachenko A, Zhang W, McGahan JP, Seibert A,
Krauss RM, Chiu S, Schaefer EJ, Ai M, Otokozawa S, Nakajima K, Nakano T,
Beysen C, Hellerstein MK, Berglund L, Havel PJ. Consuming fructose-sweetened,
not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases
insulin sensitivity in overweight/obese humans. J Clin Invest 2009;119:
1322–1334.
159. Kelishadi R, Mansourian M, Heidari-Beni M. Association of fructose consumption
and components of metabolic syndrome in human studies: a systematic review
and meta-analysis. Nutrition 2014;30:503–510.
160. Gayet-Boyer C, Tenenhaus-Aziza F, Prunet C, Marmonier C,
Malpuech-Brugere C, Lamarche B, Chardigney JM. Is there a linear relationship
between the dose of ruminant trans-fatty acids and cardiovascular risk markers
in healthy subjects: results from a systematic review and meta-regression of randomised
clinical trials. Br J Nutr 2014;112:1914–1922.
161. Kelley GA, Kelley KS. Impact of progressive resistance training on lipids and lipoproteins
in adults: another look at a meta-analysis using prediction intervals. Prev
Med 2009;49:473–475.
ESC/EAS Guidelines 3058c
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
162. Kastorini CM, Milionis HJ, Esposito K, Giugliano D, Goudevenos JA,
Panagiotakos DB. The effect of Mediterranean diet on metabolic syndrome and
its components: a meta-analysis of 50 studies and 534,906 individuals. J Am Coll
Cardiol 2011;57:1299–1313.
163. Maeda K, Noguchi Y, Fukui T. The effects of cessation from cigarette smoking on
the lipid and lipoprotein proﬁles: a meta-analysis. Prev Med 2003;37:283–290.
164. Poli A, Marangoni F, Paoletti R, Mannarino E, Lupattelli G, Notarbartolo A,
Aureli P, Bernini F, Cicero A, Gaddi A, Catapano A, Cricelli C, Gattone M,
Marrocco W, Porrini M, Stella R, Vanotti A, Volpe M, Volpe R, Cannella C,
Pinto A, Del Toma E, La Vecchia C, Tavani A, Manzato E, Riccardi G, Sirtori C,
Zambon A. Non-pharmacological control of plasma cholesterol levels. Nutr Metab
Cardiovasc Dis 2008;18:S1–S16.
165. Mensink RP, Zock PL, Kester AD, Katan MB. Effects of dietary fatty acids and carbohydrates
on the ratio of serum total to HDL cholesterol and on serum lipids
and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr 2003;
77:1146–1155.
166. Micha R, Khatibzadeh S, Shi P, Fahimi S, Lim S, Andrews KG, Engell RE, Powles J,
Ezzati M, Mozaffarian D. Global, regional, and national consumption levels of dietary
fats and oils in 1990 and 2010: a systematic analysis including 266 countryspeciﬁc
nutrition surveys. BMJ 2014;348:g2272.
167. Grifﬁn JD, Lichtenstein AH. Dietary cholesterol and plasma lipoprotein proﬁles:
randomized-controlled trials. Curr Nutr Rep 2013;2:274–282.
168. Ordovas JM. Genetic inﬂuences on blood lipids and cardiovascular disease risk:
tools for primary prevention. Am J Clin Nutr 2009;89:1509S–1517S.
169. Huffman KM, Hawk VH, Henes ST, Ocampo CI, Orenduff MC, Slentz CA,
Johnson JL, Houmard JA, Samsa GP, Kraus WE, Bales CW. Exercise effects on lipids
in persons with varying dietary patterns-does diet matter if they exercise? Responses
in Studies of a Targeted Risk Reduction Intervention through Deﬁned
Exercise I. Am Heart J 2012;164:117–124.
170. Vessby B, Uusitupa M, Hermansen K, Riccardi G, Rivellese AA, Tapsell LC,
Na¨lse´n C, Berglund L, Louheranta A, Rasmussen BM, Calvert GD, Maffetone A,
Pedersen E, Gustafsson IB, Storlien LH. Substituting dietary saturated for monounsaturated
fat impairs insulin sensitivity in healthy men and women: the
KANWU Study. Diabetologia 2001;44:312–319.
171. Rivellese AA, Giacco R, Annuzzi G, De Natale C, Patti L, Di Marino L, Minerva V,
Costabile G, Santangelo C, Masella R, Riccardi G. Effects of monounsaturated vs.
saturated fat on postprandial lipemia and adipose tissue lipases in type 2 diabetes.
Clin Nutr 2008;27:133–141.
172. Jacobson TA, Glickstein SB, Rowe JD, Soni PN. Effects of eicosapentaenoic acid
and docosahexaenoic acid on low-density lipoprotein cholesterol and other lipids:
a review. J Clin Lipidol 2012;6:5–18.
173. Liu S, Manson JE, Stampfer MJ, Holmes MD, Hu FB, Hankinson SE, Willett WC.
Dietary glycemic load assessed by food-frequency questionnaire in relation to
plasma high-density-lipoprotein cholesterol and fasting plasma triacylglycerols in
postmenopausal women. Am J Clin Nutr 2001;73:560–566.
174. De Natale C, Annuzzi G, Bozzetto L, Mazzarella R, Costabile G, Ciano O,
Riccardi G, Rivellese AA. Effects of a plant-based high-carbohydrate/high-ﬁber
diet versus high-monounsaturated fat/low-carbohydrate diet on postprandial
lipids in type 2 diabetic patients. Diabetes Care 2009;32:2168–2173.
175. Stanhope KL, Medici V, Bremer AA, Lee V, Lam HD, Nunez MV, Chen GX,
Keim NL, Havel PJ. A dose-response study of consuming high-fructose corn
syrup-sweetened beverages on lipid/lipoprotein risk factors for cardiovascular
disease in young adults. Am J Clin Nutr 2015;101:1144–1154.
176. Kraus WE, Houmard JA, Duscha BD, Knetzger KJ, Wharton MB, McCartney JS,
Bales CW, Henes S, Samsa GP, Otvos JD, Kulkarni KR, Slentz CA. Effects of the
amount and intensity of exercise on plasma lipoproteins. N Engl J Med 2002;347:
1483–1492.
177. Brien SE, Ronksley PE, Turner BJ, Mukamal KJ, Ghali WA. Effect of alcohol
consumption on biological markers associated with risk of coronary heart disease:
systematic review and meta-analysis of interventional studies. BMJ 2011;
342:d636.
178. Goff LM, Cowland DE, Hooper L, Frost GS. Low glycaemic index diets and blood
lipids: a systematic review and meta-analysis of randomised controlled trials. Nutr
Metab Cardiovasc Dis 2013;23:1–10.
179. Bazzano LA, Thompson AM, Tees MT, Nguyen CH, Winham DM. Non-soy legume
consumption lowers cholesterol levels: a meta-analysis of randomized controlled
trials. Nutr Metab Cardiovasc Dis 2011;21:94–103.
180. Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA,
Fruchart JC, James WP, Loria CM, Smith SC Jr. Harmonizing the metabolic syndrome:
a joint interim statement of the International Diabetes Federation Task
Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute;
American Heart Association; World Heart Federation; International Atherosclerosis
Society; and International Association for the Study of Obesity. Circulation
2009;120:1640–1645.
181. Puzziferri N, Roshek TB 3rd, Mayo HG, Gallagher R, Belle SH, Livingston EH.
Long-term follow-up after bariatric surgery: a systematic review. JAMA 2014;
312:934–942.
182. Harris WS, Mozaffarian D, Rimm E, Kris-Etherton P, Rudel LL, Appel LJ,
Engler MM, Engler MB, Sacks F. Omega-6 fatty acids and risk for cardiovascular
disease: a science advisory from the American Heart Association Nutrition Subcommittee
of the Council on Nutrition, Physical Activity, and Metabolism; Council
on Cardiovascular Nursing; and Council on Epidemiology and Prevention.
Circulation 2009;119:902–907.
183. Mozaffarian D, Lemaitre RN, King IB, Song X, Huang H, Sacks FM, Rimm EB,
Wang M, Siscovick DS. Plasma phospholipid long-chain omega-3 fatty acids and
total and cause-speciﬁc mortality in older adults: a cohort study. Ann Intern Med
2013;158:515–525.
184. Sirtori CR, Galli C, Anderson JW, Arnoldi A. Nutritional and nutraceutical approaches
to dyslipidemia and atherosclerosis prevention: focus on dietary proteins.
Atherosclerosis 2009;203:8–17.
185. Lea LJ, Hepburn PA. Safety evaluation of phytosterol-esters. Part 9: results of a
European post-launch monitoring programme. Food Chem Toxicol 2006;44:
1213–1222.
186. AbuMweis SS, Jew S, Ames NP. b-glucan from barley and its lipid-lowering capacity:
a meta-analysis of randomized, controlled trials. Eur J Clin Nutr 2010;64:
1472–1480.
187. Wolever TM, Tosh SM, Gibbs AL, Brand-Miller J, Duncan AM, Hart V,
Lamarche B, Thomson BA, Duss R, Wood PJ. Physicochemical properties of
oat beta-glucan inﬂuence its ability to reduce serum LDL cholesterol in humans:
a randomized clinical trial. Am J Clin Nutr 2010;92:723–732.
188. Ma´s R, Castan˜o G, Illnait J, Ferna´ndez L, Ferna´ndez J, Alema´n C, Pontigas V,
Lescay M. Effects of policosanol in patients with type II hypercholesterolemia
and additional coronary risk factors. Clin Pharmacol Ther 1999;65:439–447.
189. Reiner Z, Tedeschi-Reiner E, Romic Z. Effects of rice policosanol on serum lipoproteins,
homocysteine, ﬁbrinogen and C-reactive protein in hypercholesterolaemic
patients. Clin Drug Investig 2005;25:701–707.
190. Lan J, Zhao Y, Dong F, Yan Z, Zheng W, Fan J, Sun G. Meta-analysis of the effect
and safety of berberine in the treatment of type 2 diabetes mellitus, hyperlipemia
and hypertension. J Ethnopharmacol 2015;161:69–81.
191. Weng TC, Yang YH, Lin SJ, Tai SH. A systematic review and meta-analysis on the
therapeutic equivalence of statins. J Clin Pharm Ther 2010;35:139–151.
192. Chasman DI, Giulianini F, MacFadyen J, Barratt BJ, Nyberg F, Ridker PM. Genetic
determinants of statin-induced low-density lipoprotein cholesterol reduction: the
Justiﬁcation for the Use of Statins in Prevention: an Intervention Trial Evaluating
Rosuvastatin (JUPITER) trial. Circ Cardiovasc Genet 2012;5:257–264.
193. Reiner Z. Resistance and intolerance to statins. Nutr Metab Cardiovasc Dis 2014;24:
1057–1066.
194. Gould AL, Rossouw JE, Santanello NC, Heyse JF, Furberg CD. Cholesterol reduction
yields clinical beneﬁt. A new look at old data. Circulation 1995;91:2274–2282.
195. Gould AL, Rossouw JE, Santanello NC, Heyse JF, Furberg CD. Cholesterol reduction
yields clinical beneﬁt: impact of statin trials. Circulation 1998;97:946–952.
196. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A,
Sourjina T, Peto R, Collins R, Simes R. Efﬁcacy and safety of cholesterol-lowering
treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised
trials of statins. Lancet 2005;366:1267–1278.
197. Genser B, Marz W. Low density lipoprotein cholesterol, statins and cardiovascular
events: a meta-analysis. Clin Res Cardiol 2006;95:393–404.
198. Mills EJ, Wu P, Chong G, Ghement I, Singh S, Akl EA, Eyawo O, Guyatt G,
Berwanger O, Briel M. Efﬁcacy and safety of statin treatment for cardiovascular
disease: a network meta-analysis of 170,255 patients from 76 randomized trials.
QJM 2011;104:109–124.
199. Ray KK, Seshasai SR, Erqou S, Sever P, Jukema JW, Ford I, Sattar N. Statins and
all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized
controlled trials involving 65,229 participants. Arch Intern Med 2010;170:
1024–1031.
200. Taylor F, Huffman MD, Macedo AF, Moore TH, Burke M, Davey Smith G, Ward K,
Ebrahim S. Statins for the primary prevention of cardiovascular disease. Cochrane
Database Syst Rev 2013;1:CD004816.
201. Davignon J. Beneﬁcial cardiovascular pleiotropic effects of statins. Circulation 2004;
109(23 Suppl 1):III-39–III-43.
202. Zhou Q, Liao JK. Pleiotropic effects of statins. Basic research and clinical perspectives.
Circulation J 2010;74:818–826.
203. Pedersen TR. Pleiotropic effects of statins: evidence against beneﬁts beyond
LDL-cholesterol lowering. Am J Cardiovasc Drugs 2010;10(Suppl 1):10–17.
204. McGuinness B, Craig D, Bullock R, Malouf R, Passmore P. Statins for the treatment
of dementia. Cochrane Database Syst Rev 2014;7:CD007514.
205. Eslami L, Merat S, Malekzadeh R, Nasseri-Moghaddam S, Aramin H. Statins for
non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Cochrane Database
Syst Rev 2013;12:CD008623.
ESC/EAS Guidelines3058d
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
206. Cholesterol Treatment Trialists’ (CTT) Collaboration, Emberson JR, Kearney PM,
Blackwell L, Newman C, Reith C, Bhala N, Holland L, Peto R, Keech A, Collins R,
Simes J, Baigent C. Lack of effect of lowering LDL cholesterol on cancer:
meta-analysis of individual data from 175,000 people in 27 randomised trials of
statin therapy. PLoS One 2012;7:e29849.
207. Nielsen SF, Nordestgaard BG, Bojesen SE. Statin use and reduced cancer-related
mortality. N Engl J Med 2012;367:1792–1802.
208. Li L, Sun T, Zhang P, Tian J, Yang K. Statins for primary prevention of venous
thromboembolism. Cochrane Database Syst Rev 2011;12:CD008203.
209. Raval AD, Hunter T, Stuckey B, Hart RJ. Statins for women with polycystic ovary
syndrome not actively trying to conceive. Cochrane Database Syst Rev 2011;10:
CD008565.
210. Gauthier JM, Massicotte A. Statins and their effect on cognition: let’s clear up the
confusion. Can Pharm J (Ott) 2015;148:150–155.
211. Stroes ES, Thompson PD, Corsini A, Vladutiu GD, Raal FJ, Ray KK, Roden M,
Stein E, Tokgo¨zog˘lu L, Nordestgaard BG, Bruckert E, De Backer G, Krauss RM,
Laufs U, Santos RD, Hegele RA, Hovingh GK, Leiter LA, Mach F, Ma¨rz W,
Newman CB, Wiklund O, Jacobson TA, Catapano AL, Chapman MJ,
Ginsberg HN; European Atherosclerosis Society Consensus Panel.
Statin-associated muscle symptoms: impact on statin therapy—European Atherosclerosis
Society Consensus Panel Statement on Assessment, Aetiology and Management.
Eur Heart J 2015;36:1012–1022.
212. Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol 2006;97(8A):
52C–60C.
213. Finegold JA, Francis DP. What proportion of symptomatic side-effects in patients
taking statins are genuinely caused by the drug? A response to letters. Eur J Prev
Cardiol 2015;22:1328–1330.
214. Naci H, Brugts J, Ades T. Comparative tolerability and harms of individual statins: a
study-level network meta-analysis of 246 955 participants from 135 randomized,
controlled trials. Circ Cardiovasc Qual Outcomes 2013;6:390–399.
215. Bruckert E, Hayem G, Dejager S, Yau C, Be´gaud B. Mild to moderate muscular
symptoms with high-dosage statin therapy in hyperlipidemic patients—the
PRIMO study. Cardiovasc Drugs Ther 2005;19:403–414.
216. Davidson MH, Clark JA, Glass LM, Kanumalla A. Statin safety: an appraisal from the
adverse event reporting system. Am J Cardiol 2006;97(8A):32C–43C.
217. Parker BA, Capizzi JA, Grimaldi AS, Clarkson PM, Cole SM, Keadle J, Chipkin S,
Pescatello LS, Simpson K, White CM, Thompson PD. Effect of statins on skeletal
muscle function. Circulation 2013;127:96–103.
218. Moriarty PM, Jacobson TA, Bruckert E, Thompson PD, Guyton JR,
Baccara-Dinet MT, Gipe D. Efﬁcacy and safety of alirocumab, a monoclonal antibody
to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY
ALTERNATIVE, a randomized phase 3 trial. J Clin Lipidol 2014;8:554–561.
219. Stroes E, Colquhoun D, Sullivan D, Civeira F, Rosenson RS, Watts GF, Bruckert E,
Cho L, Dent R, Knusel B, Xue A, Scott R, Wasserman SM, Rocco M. Anti-PCSK9
antibody effectively lowers cholesterol in patients with statin intolerance: the
GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab.
J Am Coll Cardiol 2014;63:2541–2548.
220. Keating AJ, Campbell KB, Guyton JR. Intermittent nondaily dosing strategies in patients
with previous statin-induced myopathy. Ann Pharmacother 2013;47:
398–404.
221. Marcum ZA, Vande Griend JP, Linnebur SA. FDA drug safety communications: a
narrative review and clinical considerations for older adults. Am J Geriatr Pharmacother
2012;10:264–271.
222. Chalasani N, Aljadhey H, Kesterson J, Murray MD, Hall SD. Patients with elevated
liver enzymes are not at higher risk for statin hepatotoxicity. Gastroenterology
2004;126:1287–1292.
223. Vuppalanchi R, Teal E, Chalasani N. Patients with elevated baseline liver enzymes
do not have higher frequency of hepatotoxicity from lovastatin than those with
normal baseline liver enzymes. Am J Med Sci 2005;329:62–65.
224. Dongiovanni P, Petta S, Mannisto V, Mancina RM, Pipitone R, Karja V, Maggioni M,
Kakela P, Wiklund O, Mozzi E, Grimaudo S, Kaminska D, Rametta R, Craxi A,
Fargion S, Nobili V, Romeo S, Pihlajamaki J, Valenti L. Statin use and non-alcoholic
steatohepatitis in at risk individuals. J Hepatol 2015;63:705–712.
225. Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, Seshasai SR,
McMurray JJ, Freeman DJ, Jukema JW, Macfarlane PW, Packard CJ, Stott DJ,
Westendorp RG, Shepherd J, Davis BR, Pressel SL, Marchioli R, Marﬁsi RM,
Maggioni AP, Tavazzi L, Tognoni G, Kjekshus J, Pedersen TR, Cook TJ,
Gotto AM, Clearﬁeld MB, Downs JR, Nakamura H, Ohashi Y, Mizuno K,
Ray KK, Ford I. Statins and risk of incident diabetes: a collaborative meta-analysis
of randomised statin trials. Lancet 2010;375:735–742.
226. Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters DD, DeMicco DA,
Barter P, Cannon CP, Sabatine MS, Braunwald E, Kastelein JJ, de Lemos JA,
Blazing MA, Pedersen TR, Tikkanen MJ, Sattar N, Ray KK. Risk of incident diabetes
with intensive-dose compared with moderate-dose statin therapy: a
meta-analysis. JAMA 2011;305:2556–2564.
227. Waters DD, Ho JE, Boekholdt SM, DeMicco DA, Kastelein JJ, Messig M, Breazna A,
Pedersen TR. Cardiovascular event reduction versus new-onset diabetes during
atorvastatin therapy: effect of baseline risk factors for diabetes. J Am Coll Cardiol
2013;61:148–152.
228. Palmer SC, Navaneethan SD, Craig JC, Perkovic V, Johnson DW, Nigwekar SU,
Hegbrant J, Strippoli GF. HMG CoA reductase inhibitors (statins) for kidney transplant
recipients. Cochrane Database Syst Rev 2014;1:CD005019.
229. Vidt DG. Statins and proteinuria. Curr Atheroscler Rep 2005;7:351–357.
230. Sidaway JE, Davidson RG, McTaggart F, Orton TC, Scott RC, Smith GJ,
Brunskill NJ. Inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase reduce
receptor-mediated endocytosis in opossum kidney cells. J Am Soc Nephrol 2004;
15:2258–2265.
231. Davidson MH. Rosuvastatin safety: lessons from the FDA review and postapproval
surveillance. Expert Opin Drug Saf 2004;3:547–557.
232. Egan A, Colman E. Weighing the beneﬁts of high-dose simvastatin against the risk
of myopathy. N Engl J Med 2011;365:285–287.
233. Wiklund O, Pirazzi C, Romeo S. Monitoring of lipids, enzymes, and creatine kinase
in patients on lipid-lowering drug therapy. Curr Cardiol Rep 2013;15:397.
234. Holoshitz N, Alsheikh-Ali AA, Karas RH. Relative safety of gemﬁbrozil and fenoﬁbrate
in the absence of concomitant cerivastatin use. Am J Cardiol 2008;101:
95–97.
235. Franssen R, Vergeer M, Stroes ES, Kastelein JJ. Combination statin-ﬁbrate therapy:
safety aspects. Diabetes Obes Metab 2009;11:89–94.
236. Guyton JR, Bays HE. Safety considerations with niacin therapy. Am J Cardiol 2007;
99(6A):22C–31C.
237. Cziraky MJ, Willey VJ, McKenney JM, Kamat SA, Fisher MD, Guyton JR,
Jacobson TA, Davidson MH. Statin safety: an assessment using an administrative
claims database. Am J Cardiol 2006;97(8A):61C–68C.
238. Ooi CP, Loke SC. Colesevelam for type 2 diabetes mellitus: an abridged Cochrane
review. Diabet Med 2014;31:2–14.
239. The Lipid Research Clinics Coronary Primary Prevention Trial
results. I. Reduction in incidence of coronary heart disease. JAMA 1984;251:
351–364.
240. Pre-entry characteristics of participants in the Lipid Research Clinics’ Coronary
Primary Prevention Trial. J Chronic Dis 1983;36:467–479.
241. The Lipid Research Clinics Coronary Primary Prevention Trial. Results of 6 years
of post-trial follow-up. The Lipid Research Clinics Investigators. Arch Intern Med
1992;152:1399–1410.
242. He L, Wickremasingha P, Lee J, Tao B, Mendell-Harary J, Walker J, Wight D. Lack
of effect of colesevelam HCl on the single-dose pharmacokinetics of aspirin, atenolol,
enalapril, phenytoin, rosiglitazone, and sitagliptin. Diabetes Res Clin Pract 2014;
104:401–409.
243. Rossebø AB, Pedersen TR, Boman K, Brudi P, Chambers JB, Egstrup K, Gerdts E,
Gohlke-Ba¨rwolf C, Holme I, Kesa¨niemi YA, Malbecq W, Nienaber CA, Ray S,
Skjaerpe T, Wachtell K, Willenheimer R. Intensive lipid lowering with simvastatin
and ezetimibe in aortic stenosis. N Engl J Med 2008;359:1343–1356.
244. Sharp Collaborative Group. Study of Heart and Renal Protection (SHARP): randomized
trial to assess the effects of lowering low-density lipoprotein cholesterol
among 9,438 patients with chronic kidney disease. Am Heart J 2010;160:785–794
e10.
245. Myocardial Infarction Genetics Consortium Investigators, Stitziel NO, Won HH,
Morrison AC, Peloso GM, Do R, Lange LA, Fontanillas P, Gupta N, Duga S,
Goel A, Farrall M, Saleheen D, Ferrario P, Ko¨nig I, Asselta R, Merlini PA,
Marziliano N, Notarangelo MF, Schick U, Auer P, Assimes TL, Reilly M,
Wilensky R, Rader DJ, Hovingh GK, Meitinger T, Kessler T, Kastrati A,
Laugwitz KL, Siscovick D, Rotter JI, Hazen SL, Tracy R, Cresci S, Spertus J,
Jackson R, Schwartz SM, Natarajan P, Crosby J, Muzny D, Ballantyne C, Rich SS,
O’Donnell CJ, Abecasis G, Sunyaev S, Nickerson DA, Buring JE, Ridker PM,
Chasman DI, Austin E, Ye Z, Kullo IJ, Weeke PE, Shaffer CM, Bastarache LA,
Denny JC, Roden DM, Palmer C, Deloukas P, Lin DY, Tang ZZ, Erdmann J,
Schunkert H, Danesh J, Marrugat J, Elosua R, Ardissino D, McPherson R,
Watkins H, Reiner AP, Wilson JG, Altshuler D, Gibbs RA, Lander ES,
Boerwinkle E, Gabriel S, Kathiresan S. Inactivating mutations in NPC1L1 and protection
from coronary heart disease. N Engl J Med 2014;371:2072–2082.
246. Tsujita K, Sugiyama S, Sumida H, Shimomura H, Yamashita T, Yamanaga K,
Komura N, Sakamoto K, Oka H, Nakao K, Nakamura S, Ishihara M, Matsui K,
Sakaino N, Nakamura N, Yamamoto N, Koide S, Matsumura T, Fujimoto K,
Tsunoda R, Morikami Y, Matsuyama K, Oshima S, Kaikita K, Hokimoto S,
Ogawa H. Impact of dual lipid-lowering strategy with ezetimibe and atorvastatin
on coronary plaque regression in patients with percutaneous coronary intervention:
the multicenter randomized controlled PRECISE-IVUS trial. J Am Coll Cardiol
2015;66:495–507.
247. Abifadel M, Varret M, Rabe`s JP, Allard D, Ouguerram K, Devillers M, Cruaud C,
Benjannet S, Wickham L, Erlich D, Derre´ A, Ville´ger L, Farnier M, Beucler I,
Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J,
ESC/EAS Guidelines 3058e
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
Prat A, Krempf M, Junien C, Seidah NG, Boileau C. Mutations in PCSK9 cause
autosomal dominant hypercholesterolemia. Nat Genet 2003;34:154–156.
248. Norata GD, Tibolla G, Catapano AL. Targeting PCSK9 for hypercholesterolemia.
Annu Rev Pharmacol Toxicol 2014;54:273–293.
249. Navarese EP, Kolodziejczak M, Kereiakes DJ, Tantry US, O’Connor C, Gurbel PA.
Proprotein convertase subtilisin/kexin type 9 monoclonal antibodies for acute
coronary syndrome: a narrative review. Ann Intern Med 2016;164:600–607.
250. Zhang XL, Zhu L, Wei ZH, Zhu QQ, Qiao JZ, Dai Q, Huang W, Li XH, Xie J,
Kang LN, Wang L, Xu B. Comparative efﬁcacy and safety of everolimus-eluting
bioresorbable scaffold versus everolimus-eluting metallic stents: a systematic review
and meta-analysis. Ann Intern Med 2016;164:752–763.
251. AIM-HIGH Investigators, Boden WE, Probstﬁeld JL, Anderson T, Chaitman BR,
Desvignes-Nickens P, Koprowicz K, McBride R, Teo K, Weintraub W. Niacin in
patients with low HDL cholesterol levels receiving intensive statin therapy. N
Engl J Med 2011;365:2255–2267.
252. HPS2-THRIVE Collaborative Group, Landray MJ, Haynes R, Hopewell JC, Parish S,
Aung T, Tomson J, Wallendszus K, Craig M, Jiang L, Collins R, Armitage J. Effects of
extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014;
371:203–212.
253. Zhao XQ, Krasuski RA, Baer J, Whitney EJ, Neradilek B, Chait A, Marcovina S,
Albers JJ, Brown BG. Effects of combination lipid therapy on coronary stenosis
progression and clinical cardiovascular events in coronary disease patients with
metabolic syndrome: a combined analysis of the Familial Atherosclerosis Treatment
Study (FATS), the HDL-Atherosclerosis Treatment Study (HATS), and
the Armed Forces Regression Study (AFREGS). Am J Cardiol 2009;104:
1457–1464.
254. Jones MR, Nwose OM. Role of colesevelam in combination lipid-lowering therapy.
Am J Cardiovasc Drugs 2013;13:315–323.
255. Abumweis SS, Barake R, Jones PJ. Plant sterols/stanols as cholesterol lowering
agents: a meta-analysis of randomized controlled trials. Food Nutr Res 2008;52.
ISSN 1654-661X. Available at http://www.foodandnutritionresearch.net/index
.php/fnr/article/view/1811.
256. Tyroler HA. Cholesterol and cardiovascular disease. An overview of Lipid Research
Clinics (LRC) epidemiologic studies as background for the LRC Coronary
Primary Prevention Trial. Am J Cardiol 1984;54:14C–19C.
257. Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, Prineas RJ,
Friedewald W. Fifteen year mortality in Coronary Drug Project patients: longterm
beneﬁt with niacin. J Am Coll Cardiol 1986;8:1245–1255.
258. Kotseva K, Wood D, De Backer G, De Bacquer D, Pyo¨ra¨la¨ K, Keil U. EUROASPIRE
III: a survey on the lifestyle, risk factors and use of cardioprotective drug therapies
in coronary patients from 22 European countries. Eur J Cardiovasc Prev
Rehabil 2009;16:121–137.
259. Berglund L, Brunzell JD, Goldberg AC, Goldberg IJ, Sacks F, Murad MH,
Stalenhoef AF. Evaluation and treatment of hypertriglyceridemia: an Endocrine
Society clinical practice guideline. J Clin Endocrinol Metab 2012;97:2969–2989.
260. Chapman MJ, Ginsberg HN, Amarenco P, Andreotti F, Bore´n J, Catapano AL,
Descamps OS, Fisher E, Kovanen PT, Kuivenhoven JA, Lesnik P, Masana L,
Nordestgaard BG, Ray KK, Reiner Z, Taskinen MR, Tokgo¨zoglu L,
Tybjærg-Hansen A, Watts GF. Triglyceride-rich lipoproteins and high-density
lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence
and guidance for management. Eur Heart J 2011;32:1345–1361.
261. Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder P, Pillai A,
Davis T, Glasziou P, Drury P, Kesa¨niemi YA, Sullivan D, Hunt D, Colman P,
d’Emden M, Whiting M, Ehnholm C, Laakso M. Effects of long-term fenoﬁbrate
therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus
(the FIELD study): randomised controlled trial. Lancet 2005;366:1849–1861.
262. ACCORD Study Group, Ginsberg HN, Elam MB, Lovato LC, Crouse JR 3rd,
Leiter LA, Linz P, Friedewald WT, Buse JB, Gerstein HC, Probstﬁeld J,
Grimm RH, Ismail-Beigi F, Bigger JT, Goff DC Jr, Cushman WC,
Simons-Morton DG, Byington RP. Effects of combination lipid therapy in type 2
diabetes mellitus. N Engl J Med 2010;362:1563–1574.
263. Chapman MJ, Redfern JS, McGovern ME, Giral P. Niacin and ﬁbrates in atherogenic
dyslipidemia: pharmacotherapy to reduce cardiovascular risk. Pharmacol Ther
2010;126:314–345.
264. Catapano AL, Farnier M, Foody JM, Toth PP, Tomassini JE, Brudi P,
Tershakovec AM. Combination therapy in dyslipidemia: where are we now?
Atherosclerosis 2014;237:319–335.
265. Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK,
Kaitaniemi P, Koskinen P, Manninen V et al. Helsinki Heart Study: primaryprevention
trial with gemﬁbrozil in middle-aged men with dyslipidemia. Safety
of treatment, changes in risk factors, and incidence of coronary heart disease.
N Engl J Med 1987;317:1237–1245.
266. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH,
Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J. Gemﬁbrozil for the secondary
prevention of coronary heart disease in men with low levels of high-density
lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol
Intervention Trial Study Group. N Engl J Med 1999;341:410–418.
267. Lipids and lipoproteins in symptomatic coronary heart disease. Distribution, intercorrelations,
and signiﬁcance for risk classiﬁcation in 6,700 men and 1,500 women.
The Bezaﬁbrate Infarction Prevention (BIP) Study Group, Israel. Circulation 1992;
86:839–848.
268. Keene D, Price C, Shun-Shin MJ, Francis DP. Effect on cardiovascular risk of high
density lipoprotein targeted drug treatments niacin, ﬁbrates, and CETP inhibitors:
meta-analysis of randomised controlled trials including 117,411 patients. BMJ
2014;349:g4379.
269. Ip CK, Jin DM, Gao JJ, Meng Z, Meng J, Tan Z, Wang JF, Geng DF. Effects of add-on
lipid-modifying therapy on top of background statin treatment on major cardiovascular
events: a meta-analysis of randomized controlled trials. Int J Cardiol
2015;191:138–148.
270. Jun M, Foote C, Lv J, Neal B, Patel A, Nicholls SJ, Grobbee DE, Cass A, Chalmers J,
Perkovic V. Effects of ﬁbrates on cardiovascular outcomes: a systematic review
and meta-analysis. Lancet 2010;375:1875–1884.
271. Lee M, Saver JL, Towﬁghi A, Chow J, Ovbiagele B. Efﬁcacy of ﬁbrates for cardiovascular
risk reduction in persons with atherogenic dyslipidemia: a meta-analysis.
Atherosclerosis 2011;217:492–498.
272. Bruckert E, Labreuche J, Deplanque D, Touboul PJ, Amarenco P. Fibrates effect on
cardiovascular risk is greater in patients with high triglyceride levels or atherogenic
dyslipidemia proﬁle: a systematic review and meta-analysis. J Cardiovasc Pharmacol
2011;57:267–272.
273. Davidson MH, Armani A, McKenney JM, Jacobson TA. Safety considerations with
ﬁbrate therapy. Am J Cardiol 2007;99(6A):3C–18C.
274. Jun M, Zhu B, Tonelli M, Jardine MJ, Patel A, Neal B, Liyanage T, Keech A, Cass A,
Perkovic V. Effects of ﬁbrates in kidney disease: a systematic review and
meta-analysis. J Am Coll Cardiol 2012;60:2061–2071.
275. Taskinen MR, Sullivan DR, Ehnholm C, Whiting M, Zannino D, Simes RJ,
Keech AC, Barter PJ. Relationships of HDL cholesterol, ApoA-I, and ApoA-II
with homocysteine and creatinine in patients with type 2 diabetes treated with
fenoﬁbrate. Arterioscler Thromb Vasc Biol 2009;29:950–955.
276. Herrmann M, Whiting MJ, Veillard AS, Ehnholm C, Sullivan DR, Keech AC. Plasma
homocysteine and the risk of venous thromboembolism: insights from the FIELD
study. Clin Chem Lab Med 2012;50:2213–2219.
277. Kamanna VS, Kashyap ML. Mechanism of action of niacin. Am J Cardiol 2008;
101(8A):20B–26B.
278. Bruckert E, Labreuche J, Amarenco P. Meta-analysis of the effect of nicotinic acid
alone or in combination on cardiovascular events and atherosclerosis. Atherosclerosis
2010;210:353–361.
279. Brown BG, Zhao XQ. Nicotinic acid, alone and in combinations, for reduction of
cardiovascular risk. Am J Cardiol 2008;101(8A):58B–62B.
280. Balk EM, Lichtenstein AH, Chung M, Kupelnick B, Chew P, Lau J. Effects of
omega-3 fatty acids on serum markers of cardiovascular disease risk: a systematic
review. Atherosclerosis 2006;189:19–30.
281. Ballantyne CM, Bays HE, Kastelein JJ, Stein E, Isaacsohn JL, Braeckman RA,
Soni PN. Efﬁcacy and safety of eicosapentaenoic acid ethyl ester (AMR101)
therapy in statin-treated patients with persistent high triglycerides (from the
ANCHOR study). Am J Cardiol 2012;110:984–992.
282. Bays HE, Ballantyne CM, Kastelein JJ, Isaacsohn JL, Braeckman RA, Soni PN. Eicosapentaenoic
acid ethyl ester (AMR101) therapy in patients with very high triglyceride
levels (from the Multi-center, plAcebo-controlled, Randomized,
double-blINd, 12-week study with an open-label Extension [MARINE] trial).
Am J Cardiol 2011;108:682–690.
283. Kastelein JJ, Maki KC, Susekov A, Ezhov M, Nordestgaard BG, Machielse BN,
Kling D, Davidson MH. Omega-3 free fatty acids for the treatment of severe hypertriglyceridemia:
the EpanoVa fOr Lowering Very high triglyceridEs (EVOLVE)
trial. J Clin Lipidol 2014;8:94–106.
284. Wei MY, Jacobson TA. Effects of eicosapentaenoic acid versus docosahexaenoic
acid on serum lipids: a systematic review and meta-analysis. Curr Atheroscler Rep
2011;13:474–483.
285. Kotwal S, Jun M, Sullivan D, Perkovic V, Neal B. Omega 3 fatty acids and cardiovascular
outcomes: systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes
2012;5:808–818.
286. Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y,
Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N,
Sakata T, Shimada K, Shirato K. Effects of eicosapentaenoic acid on major coronary
events in hypercholesterolaemic patients (JELIS): a randomised open-label,
blinded endpoint analysis. Lancet 2007;369:1090–1098.
287. Hooper L, Thompson RL, Harrison RA, Summerbell CD, Ness AR, Moore HJ,
Worthington HV, Durrington PN, Higgins JP, Capps NE, Riemersma RA,
Ebrahim SB, Davey Smith G. Risks and beneﬁts of omega 3 fats for mortality, cardiovascular
disease, and cancer: systematic review. BMJ 2006;332:752–760.
ESC/EAS Guidelines3058f
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
288. Marchioli R, Barzi F, Bomba E, Chieffo C, Di Gregorio D, Di Mascio R,
Franzosi MG, Geraci E, Levantesi G, Maggioni AP, Mantini L, Marﬁsi RM,
Mastrogiuseppe G, Mininni N, Nicolosi GL, Santini M, Schweiger C, Tavazzi L,
Tognoni G, Tucci C, Valagussa F. Early protection against sudden death by n-3
polyunsaturated fatty acids after myocardial infarction: time-course analysis of
the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto
Miocardico (GISSI)-Prevenzione. Circulation 2002;105:1897–1903.
289. Brasky TM, Darke AK, Song X, Tangen CM, Goodman PJ, Thompson IM,
Meyskens FL Jr, Goodman GE, Minasian LM, Parnes HL, Klein EA, Kristal AR. Plasma
phospholipid fatty acids and prostate cancer risk in the SELECT trial. J Natl
Cancer Inst 2013;105:1132–1141.
290. Nicholls SJ, Tuzcu EM, Sipahi I, Grasso AW, Schoenhagen P, Hu T, Wolski K,
Crowe T, Desai MY, Hazen SL, Kapadia SR, Nissen SE. Statins, high-density lipoprotein
cholesterol, and regression of coronary atherosclerosis. JAMA 2007;297:
499–508.
291. Barter PJ, Brandrup-Wognsen G, Palmer MK, Nicholls SJ. Effect of statins
on HDL-C: a complex process unrelated to changes in LDL-C: analysis of the
VOYAGER Database. J Lipid Res 2010;51:1546–1553.
292. Barter P, Gotto AM, LaRosa JC, Maroni J, Szarek M, Grundy SM, Kastelein JJ,
Bittner V, Fruchart JC. HDL cholesterol, very low levels of LDL cholesterol,
and cardiovascular events. N Engl J Med 2007;357:1301–1310.
293. Fruchart JC, Sacks FM, Hermans MP, Assmann G, Brown WV, Ceska R,
Chapman MJ, Dodson PM, Fioretto P, Ginsberg HN, Kadowaki T,
Lablanche JM, Marx N, Plutzky J, Reiner Z, Rosenson RS, Staels B, Stock JK,
Sy R, Wanner C, Zambon A, Zimmet P. The Residual Risk Reduction Initiative:
a call to action to reduce residual vascular risk in dyslipidaemic patient. Diab
Vasc Dis Res 2008;5:319–335.
294. Barter PJ, Caulﬁeld M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M,
Lopez-Sendon J, Mosca L, Tardif JC, Waters DD, Shear CL, Revkin JH,
Buhr KA, Fisher MR, Tall AR, Brewer B. Effects of torcetrapib in patients at
high risk for coronary events. N Engl J Med 2007;357:2109–2122.
295. Global Lipids Genetics Consortium, Willer CJ, Schmidt EM, Sengupta S,
Peloso GM, Gustafsson S, Kanoni S, Ganna A, Chen J, Buchkovich ML, Mora S,
Beckmann JS, Bragg-Gresham JL, Chang HY, Demirkan A, Den Hertog HM,
Do R, Donnelly LA, Ehret GB, Esko T, Feitosa MF, Ferreira T, Fischer K,
Fontanillas P, Fraser RM, Freitag DF, Gurdasani D, Heikkila¨ K, Hyppo¨nen E,
Isaacs A, Jackson AU, Johansson A, Johnson T, Kaakinen M, Kettunen J,
Kleber ME, Li X, Luan J, Lyytika¨inen LP, Magnusson PK, Mangino M, Mihailov E,
Montasser ME, Mu¨ller-Nurasyid M, Nolte IM, O’Connell JR, Palmer CD,
Perola M, Petersen AK, Sanna S, Saxena R, Service SK, Shah S, Shungin D,
Sidore C, Song C, Strawbridge RJ, Surakka I, Tanaka T, Teslovich TM,
Thorleifsson G, Van den Herik EG, Voight BF, Volcik KA, Waite LL, Wong A,
Wu Y, Zhang W, Absher D, Asiki G, Barroso I, Been LF, Bolton JL,
Bonnycastle LL, Brambilla P, Burnett MS, Cesana G, Dimitriou M, Doney AS,
Do¨ring A, Elliott P, Epstein SE, Eyjolfsson GI, Gigante B, Goodarzi MO,
Grallert H, Gravito ML, Groves CJ, Hallmans G, Hartikainen AL, Hayward C,
Hernandez D, Hicks AA, Holm H, Hung YJ, Illig T, Jones MR, Kaleebu P,
Kastelein JJ, Khaw KT, Kim E, Klopp N, Komulainen P, Kumari M, Langenberg C,
Lehtima¨ki T, Lin SY, Lindstro¨m J, Loos RJ, Mach F, McArdle WL, Meisinger C,
Mitchell BD, Mu¨ller G, Nagaraja R, Narisu N, Nieminen TV, Nsubuga RN,
Olafsson I, Ong KK, Palotie A, Papamarkou T, Pomilla C, Pouta A, Rader DJ,
Reilly MP, Ridker PM, Rivadeneira F, Rudan I, Ruokonen A, Samani N,
Scharnagl H, Seeley J, Silander K, Stanca´kova´ A, Stirrups K, Swift AJ, Tiret L,
Uitterlinden AG, van Pelt LJ, Vedantam S, Wainwright N, Wijmenga C,
Wild SH, Willemsen G, Wilsgaard T, Wilson JF, Young EH, Zhao JH, Adair LS,
Arveiler D, Assimes TL, Bandinelli S, Bennett F, Bochud M, Boehm BO,
Boomsma DI, Borecki IB, Bornstein SR, Bovet P, Burnier M, Campbell H,
Chakravarti A, Chambers JC, Chen YD, Collins FS, Cooper RS, Danesh J,
Dedoussis G, de Faire U, Feranil AB, Ferrie`res J, Ferrucci L, Freimer NB,
Gieger C, Groop LC, Gudnason V, Gyllensten U, Hamsten A, Harris TB,
Hingorani A, Hirschhorn JN, Hofman A, Hovingh GK, Hsiung CA,
Humphries SE, Hunt SC, Hveem K, Iribarren C, Ja¨rvelin MR, Jula A, Ka¨ho¨nen M,
Kaprio J, Kesa¨niemi A, Kivimaki M, Kooner JS, Koudstaal PJ, Krauss RM, Kuh D,
Kuusisto J, Kyvik KO, Laakso M, Lakka TA, Lind L, Lindgren CM, Martin NG,
Ma¨rz W, McCarthy MI, McKenzie CA, Meneton P, Metspalu A, Moilanen L,
Morris AD, Munroe PB, Njølstad I, Pedersen NL, Power C, Pramstaller PP,
Price JF, Psaty BM, Quertermous T, Rauramaa R, Saleheen D, Salomaa V,
Sanghera DK, Saramies J, Schwarz PE, Sheu WH, Shuldiner AR, Siegbahn A,
Spector TD, Stefansson K, Strachan DP, Tayo BO, Tremoli E, Tuomilehto J,
Uusitupa M, van Duijn CM, Vollenweider P, Wallentin L, Wareham NJ,
Whitﬁeld JB, Wolffenbuttel BH, Ordovas JM, Boerwinkle E, Palmer CN,
Thorsteinsdottir U, Chasman DI, Rotter JI, Franks PW, Ripatti S, Cupples LA,
Sandhu MS, Rich SS, Boehnke M, Deloukas P, Kathiresan S, Mohlke KL,
Ingelsson E, Abecasis GR. Discovery and reﬁnement of loci associated with lipid
levels. Nat Genet 2013;45:1274–1283.
296. Veerkamp MJ, de Graaf J, Bredie SJ, Hendriks JC, Demacker PN, Stalenhoef AF.
Diagnosis of familial combined hyperlipidemia based on lipid phenotype expression
in 32 families: results of a 5-year follow-up study. Arterioscler Thromb Vasc Biol
2002;22:274–282.
297. Benn M, Watts GF, Tybjaerg-Hansen A, Nordestgaard BG. Familial hypercholesterolemia
in the Danish general population: prevalence, coronary artery disease,
and cholesterol-lowering medication. J Clin Endocrinol Metab 2012;97:3956–3964.
298. de Ferranti SD, Rodday AM, Mendelson MM, Wong JB, Leslie LK, Sheldrick RC.
Prevalence of familial hypercholesterolemia in the 1999 to 2012 United States
National Health and Nutrition Examination Surveys (NHANES). Circulation
2016;133:1067–1072.
299. Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientiﬁc
Steering Committee on behalf of the Simon Broome Register Group. BMJ
1991;303:893–896.
300. World Health Organization. Human Genetics Programme. Familial hypercholesterolemia:
report of a second WHO consultation. WHO/HGN/FH/Cons/992.
Geneva: World Health Organization, 1999.
301. Defesche JC, Lansberg PJ, Umans-Eckenhausen MA, Kastelein JJ. Advanced method
for the identiﬁcation of patients with inherited hypercholesterolemia. Semin
Vasc Med 2004;4:59–65.
302. Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA,
Kuivenhoven JA, Nordestgaard BG, Descamps OS, Steinhagen-Thiessen E,
Tybjærg-Hansen A, Watts GF, Averna M, Boileau C, Bore´n J, Catapano AL,
Defesche JC, Hovingh GK, Humphries SE, Kovanen PT, Masana L, Pajukanta P,
Parhofer KG, Ray KK, Stalenhoef AF, Stroes E, Taskinen MR, Wiegman A,
Wiklund O, Chapman MJ. Homozygous familial hypercholesterolaemia: new insights
and guidance for clinicians to improve detection and clinical management.
A position paper from the Consensus Panel on Familial Hypercholesterolaemia of
the European Atherosclerosis Society. Eur Heart J 2014:35:2146–2157.
303. Wiegman A, Gidding SS, Watts GF, Chapman MJ, Ginsberg HN, Cuchel M, Ose L,
Averna M, Boileau C, Bore´n J, Bruckert E, Catapano AL, Defesche JC,
Descamps OS, Hegele RA, Hovingh GK, Humphries SE, Kovanen PT,
Kuivenhoven JA, Masana L, Nordestgaard BG, Pajukanta P, Parhofer KG, Raal FJ,
Ray KK, Santos RD, Stalenhoef AF, Steinhagen-Thiessen E, Stroes ES,
Taskinen MR, Tybjærg-Hansen A, Wiklund O. Familial hypercholesterolaemia in
children and adolescents: gaining decades of life by optimizing detection and treatment.
Eur Heart J 2015;36:2425–2437.
304. Johansen CT, Wang J, Lanktree MB, McIntyre AD, Ban MR, Martins RA,
Kennedy BA, Hassell RG, Visser ME, Schwartz SM, Voight BF, Elosua R,
Salomaa V, O’Donnell CJ, Dallinga-Thie GM, Anand SS, Yusuf S, Huff MW,
Kathiresan S, Cao H, Hegele RA. An increased burden of common and rare
lipid-associated risk alleles contributes to the phenotypic spectrum of hypertriglyceridemia.
Arterioscler Thromb Vasc Biol 2011;31:1916–1926.
305. Gaudet D, Me´thot J, De´ry S, Brisson D, Essiembre C, Tremblay G, Tremblay K, de
Wal J, Twisk J, van den Bulk N, Sier-Ferreira V, van Deventer S. Efﬁcacy and longterm
safety of alipogene tiparvovec (AAV1-LPLS447X) gene therapy for lipoprotein
lipase deﬁciency: an open-label trial. Gene Ther 2013;20:361–369.
306. Huff MW, Hegele RA. Apolipoprotein C-III: going back to the future for a lipid
drug target. Circ Res 2013;112:1405–1408.
307. Lindkvist B, Appelros S, Regner S, Manjer J. A prospective cohort study on risk of
acute pancreatitis related to serum triglycerides, cholesterol and fasting glucose.
Pancreatology 2012;12:317–324.
308. Ewald N, Hardt PD, Kloer HU. Severe hypertriglyceridemia and pancreatitis: presentation
and management. Curr Opin Lipidol 2009;20:497–504.
309. Reiner Z, Guardamagna O, Nair D, Soran H, Hovingh K, Bertolini S, Jones S,
C´ oric´ M, Calandra S, Hamilton J, Eagleton T, Ros E. Lysosomal acid lipase deﬁciency—an
under-recognized cause of dyslipidaemia and liver dysfunction. Atherosclerosis
2014;235:21–30.
310. National Heart, Lung, and Blood Institute. Expert panel on integrated guidelines
for cardiovascular health and risk reduction in children and adolescents: summary
report. Pediatrics 2011;128(Suppl 5):S213–S256.
311. Reiner Z. Impact of early evidence of atherosclerotic changes on early treatment
in children with familial hypercholesterolemia. Circ Res 2014;114:233–235.
312. Jonsdottir LS, Sigfu´sson N, Gudnason V, Sigvaldason H, Thorgeirsson G. Do lipids,
blood pressure, diabetes, and smoking confer equal risk of myocardial infarction in
women as in men? The Reykjavik Study. J Cardiovasc Risk 2002;9:67–76.
313. Falk E, Nakano M, Bentzon JF, Finn AV, Virmani R. Update on acute coronary syndromes:
the pathologists’ view. Eur Heart J 2013;34:719–728.
314. Walsh JM, Pignone M. Drug treatment of hyperlipidemia in women. JAMA 2004;
291:2243–2252.
315. d’Emden MC, Jenkins AJ, Li L, Zannino D, Mann KP, Best JD, Stuckey BG, Park K,
Saltevo J, Keech AC. Favourable effects of fenoﬁbrate on lipids and cardiovascular
disease in women with type 2 diabetes: results from the Fenoﬁbrate Intervention
and Event Lowering in Diabetes (FIELD) study. Diabetologia 2014;57:2296–2303.
ESC/EAS Guidelines 3058g
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
316. Spitzer WO, Faith JM, MacRae KD. Myocardial infarction and third generation oral
contraceptives: aggregation of recent studies. Human Reprod 2002;17:
2307–2314.
317. Shufelt CL, Bairey Merz CN. Contraceptive hormone use and cardiovascular disease.
J Am Coll Cardiol 2009;53:221–231.
318. Manson JE, Hsia J, Johnson KC, Rossouw JE, Assaf AR, Lasser NL, Trevisan M,
Black HR, Heckbert SR, Detrano R, Strickland OL, Wong ND, Crouse JR,
Stein E, Cushman M. Estrogen plus progestin and the risk of coronary heart disease.
N Engl J Med 2003;349:523–534.
319. Rosengren A. Better treatment and improved prognosis in elderly patients with
AMI: but do registers tell the whole truth? Eur Heart J 2012;33:562–563.
320. Gale CP, Cattle BA, Woolston A, Baxter PD, West TH, Simms AD, Blaxill J,
Greenwood DC, Fox KA, West RM. Resolving inequalities in care? Reduced mortality
in the elderly after acute coronary syndromes. The Myocardial Ischaemia
National Audit Project 2003–2010. Eur Heart J 2012;33:630–639.
321. Prospective Studies Collaboration, Lewington S, Whitlock G, Clarke R,
Sherliker P, Emberson J, Halsey J, Qizilibash N, Peto R, Collins R. Blood cholesterol
and vascular mortality by age, sex, and blood pressure: a meta-analysis of
individual data from 61 prospective studies with 55,000 vascular deaths. Lancet
2007;370:1829–1839.
322. Prevention of coronary heart disease in clinical practice. Recommendations of the
Second Joint Task Force of European and other societies on coronary prevention.
Eur Heart J 1998;19:1434–1503.
323. Berry JD, Dyer A, Cai X, Garside DB, Ning H, Thomas A, Greenland P, Van
Horn L, Tracy RP, Lloyd-Jones DM. Lifetime risks of cardiovascular disease. N
Engl J Med 2012;366:321–329.
324. Giang KW, Bjo¨rck L, Novak M, Lappas G, Wilhelmsen L, Tore´n K, Rosengren A.
Stroke and coronary heart disease: predictive power of standard risk factors into
old age—long-term cumulative risk study among men in Gothenburg, Sweden.
Eur Heart J 2013;34:1068–1074.
325. Wilhelmsen L, Sva¨rdsudd K, Eriksson H, Rosengren A, Hansson PO, Welin C,
Ode´n A, Welin L. Factors associated with reaching 90 years of age: a study of
men born in 1913 in Gothenburg, Sweden. J Intern Med 2011;269:441–451.
326. Reiner Z. Primary prevention of cardiovascular disease with statins in the elderly.
Curr Atheroscler Rep 2014;16:420.
327. Savarese G, Gotto AM Jr, Paolillo S, D’Amore C, Losco T, Musella F, Scala O,
Marciano C, Ruggiero D, Marsico F, De Luca G, Trimarco B, Perrone-Filardi P.
Beneﬁts of statins in elderly subjects without established cardiovascular disease:
a meta-analysis. J Am Coll Cardiol 2013;62:2090–2099.
328. Downs JR, Clearﬁeld M, Weis S, Whitney E, Shapiro DR, Beere PA,
Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr. Primary prevention of acute
coronary events with lovastatin in men and women with average cholesterol levels:
results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis
Prevention Study. JAMA 1998;279:1615–1622.
329. Glynn RJ, Koenig W, Nordestgaard BG, Shepherd J, Ridker PM. Rosuvastatin for
primary prevention in older persons with elevated C-reactive protein and low to
average low-density lipoprotein cholesterol levels: exploratory analysis of a randomized
trial. Ann Intern Med 2010;152:488–496, W174.
330. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, Ford I,
Gaw A, Hyland M, Jukema JW, Kamper AM, Macfarlane PW, Meinders AE,
Norrie J, Packard CJ, Perry IJ, Stott DJ, Sweeney BJ, Twomey C,
Westendorp RG. Pravastatin in elderly individuals at risk of vascular disease
(PROSPER): a randomised controlled trial. Lancet 2002;360:1623–1630.
331. Deedwania P, Stone PH, Bairey Merz CN, Cosin-Aguilar J, Koylan N, Luo D,
Ouyang P, Piotrowicz R, Schenck-Gustafsson K, Sellier P, Stein JH,
Thompson PL, Tzivoni D. Effects of intensive versus moderate lipid-lowering
therapy on myocardial ischemia in older patients with coronary heart disease: results
of the Study Assessing Goals in the Elderly (SAGE). Circulation 2007;115:
700–707.
332. Miettinen TA, Pyo¨ra¨la¨ K, Olsson AG, Musliner TA, Cook TJ, Faergeman O, Berg K,
Pedersen T, Kjekshus J. Cholesterol-lowering therapy in women and elderly patients
with myocardial infarction or angina pectoris: ﬁndings from the Scandinavian
Simvastatin Survival Study (4S). Circulation 1997;96:4211–4218.
333. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study
of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised
placebo-controlled trial. Lancet 2002;360:7–22.
334. Hunt D, Young P, Simes J, Hague W, Mann S, Owensby D, Lane G, Tonkin A. Beneﬁts
of pravastatin on cardiovascular events and mortality in older patients with
coronary heart disease are equal to or exceed those seen in younger patients: results
from the LIPID trial. Ann Intern Med 2001;134:931–940.
335. Lewis SJ, Moye LA, Sacks FM, Johnstone DE, Timmis G, Mitchell J, Limacher M,
Kell S, Glasser SP, Grant J, Davis BR, Pfeffer MA, Braunwald E. Effect of pravastatin
on cardiovascular events in older patients with myocardial infarction and cholesterol
levels in the average range. Results of the Cholesterol and Recurrent Events
(CARE) trial. Ann Intern Med 1998;129:681–689.
336. Wenger NK, Lewis SJ, Herrington DM, Bittner V, Welty FK. Outcomes of using
high- or low-dose atorvastatin in patients 65 years of age or older with stable coronary
heart disease. Ann Intern Med 2007;147:1–9.
337. Gra¨nsbo K, Melander O, Wallentin L, Lindba¨ck J, Stenestrand U, Carlsson J,
Nilsson J. Cardiovascular and cancer mortality in very elderly post-myocardial infarction
patients receiving statin treatment. J Am Coll Cardiol 2010;55:1362–1369.
338. Zimmet PZ, Magliano DJ, Herman WH, Shaw JE. Diabetes: a 21st century challenge.
Lancet Diabetes Endocrinol 2014;2:56–64.
339. Emerging Risk Factors Collaboration, Seshasai SR, Kaptoge S, Thompson A, Di
Angelantonio E, Gao P, Sarwar N, Whincup PH, Mukamal KJ, Gillum RF,
Holme I, Njølstad I, Fletcher A, Nilsson P, Lewington S, Collins R, Gudnason V,
Thompson SG, Sattar N, Selvin E, Hu FB, Danesh J. Diabetes mellitus, fasting glucose,
and risk of cause-speciﬁc death. N Engl J Med 2011;364:829–841.
340. Gregg EW, Li Y, Wang J, Burrows NR, Ali MK, Rolka D, Williams DE, Geiss L.
Changes in diabetes-related complications in the United States, 1990–2010. N
Engl J Med 2014;370:1514–1523.
341. Emerging Risk Factors Collaboration, Sarwar N, Gao P, Seshasai SR, Gobin R,
Kaptoge S, Di Angelantonio E, Ingelsson E, Lawlor DA, Selvin E, Stampfer M,
Stehouwer CD, Lewington S, Pennells L, Thompson A, Sattar N, White IR,
Ray KK, Danesh J. Diabetes mellitus, fasting blood glucose concentration, and
risk of vascular disease: a collaborative meta-analysis of 102 prospective studies.
Lancet 2010;375:2215–2222.
342. Sattar N. Revisiting the links between glycaemia, diabetes and cardiovascular disease.
Diabetologia 2013;56:686–695.
343. Liu J, Grundy SM, Wang W, Smith SC Jr, Vega GL, Wu Z, Zeng Z, Wang W,
Zhao D. Ten-year risk of cardiovascular incidence related to diabetes, prediabetes,
and the metabolic syndrome. Am Heart J 2007;153:552–558.
344. Despres JP. Body fat distribution and risk of cardiovascular disease: an update.
Circulation 2012;126:1301–1313.
345. Donahoe SM, Stewart GC, McCabe CH, Mohanavelu S, Murphy SA, Cannon CP,
Antman EM. Diabetes and mortality following acute coronary syndromes. JAMA
2007; 298:765–775.
346. Tchernof A, Despres JP. Pathophysiology of human visceral obesity: an update.
Physiol Rev 2013;93:359–404.
347. van Vliet-Ostaptchouk JV, Nuotio ML, Slagter SN, Doiron D, Fischer K, Foco L,
Gaye A, Go¨gele M, Heier M, Hiekkalinna T, Joensuu A, Newby C, Pang C,
Partinen E, Reischl E, Schwienbacher C, Tammesoo ML, Swertz MA, Burton P,
Ferretti V, Fortier I, Giepmans L, Harris JR, Hillege HL, Holmen J, Jula A,
Kootstra-Ros JE, Kvaløy K, Holmen TL, Ma¨nnisto¨ S, Metspalu A, Midthjell K,
Murtagh MJ, Peters A, Pramstaller PP, Saaristo T, Salomaa V, Stolk RP,
Uusitupa M, van der Harst P, van der Klauw MM, Waldenberger M, Perola M,
Wolffenbuttel BH. The prevalence of metabolic syndrome and metabolically
healthy obesity in Europe: a collaborative analysis of ten large cohort studies.
BMC Endocr Disord 2014;14:9.
348. Mottillo S, Filion KB, Genest J, Joseph L, Pilote L, Poirier P, Rinfret S, Schiffrin EL,
Eisenberg MJ. The metabolic syndrome and cardiovascular risk a systematic review
and meta-analysis. J Am Coll Cardiol 2010;56:1113–1132.
349. Adiels M, Olofsson SO, Taskinen MR, Bore´n J. Overproduction of very lowdensity
lipoproteins is the hallmark of the dyslipidemia in the metabolic syndrome.
Arterioscler Thromb Vasc Biol 2008;28:1225–1236.
350. Taskinen MR, Boren J. New insights into the pathophysiology of dyslipidemia in
type 2 diabetes. Atherosclerosis 2015;239:483–495.
351. Scott R, O’Brien R, Fulcher G, Pardy C, D’Emden M, Tse D, Taskinen MR,
Ehnholm C, Keech A. Effects of fenoﬁbrate treatment on cardiovascular disease
risk in 9,795 individuals with type 2 diabetes and various components of the metabolic
syndrome: the Fenoﬁbrate Intervention and Event Lowering in Diabetes
(FIELD) study. Diabetes Care 2009;32:493–498.
352. Ballantyne CM, Olsson AG, Cook TJ, Mercuri MF, Pedersen TR, Kjekshus J. Inﬂuence
of low high-density lipoprotein cholesterol and elevated triglyceride on coronary
heart disease events and response to simvastatin therapy in 4S. Circulation
2001;104:3046–3051.
353. Saha SA, Arora RR. Fibrates in the prevention of cardiovascular disease in patients
with type 2 diabetes mellitus—a pooled meta-analysis of randomized placebocontrolled
clinical trials. Int J Cardiol 2010;141:157–166.
354. Ilanne-Parikka P, Eriksson JG, Lindstrom J, Peltonen M, Aunola S, Ha¨ma¨la¨inen H,
Keina¨nen-Kiukaanniemi S, Laakso M, Valle TT, Lahtela J, Uusitupa M, Tuomilehto J;
Finnish Diabetes Prevention Study Group. Effect of lifestyle intervention on the
occurrence of metabolic syndrome and its components in the Finnish Diabetes
Prevention Study. Diabetes Care 2008;31:805–807.
355. Laing SP, Swerdlow AJ, Slater SD, Burden AC, Morris A, Waugh NR, Gatling W,
Bingley PJ, Patterson CC. Mortality from heart disease in a cohort of 23,000 patients
with insulin-treated diabetes. Diabetologia 2003;46:760–765.
356. Chillaron JJ, Flores Le-Roux JA, Benaiges D, Pedro-Botet J. Type 1 diabetes, metabolic
syndrome and cardiovascular risk. Metabolism 2014;63:181–187.
ESC/EAS Guidelines3058h
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
357. Collins R, Armitage J, Parish S, Sleigh P, Peto R; Heart Protection Study Collaborative
Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin
in 5963 people with diabetes: a randomised placebo-controlled trial.
Lancet 2003;361:2005–2016.
358. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D,
Zeiher A, Chaitman BR, Leslie S, Stern T. Effects of atorvastatin on early recurrent
ischemic events in acute coronary syndromes: the MIRACL study: a randomized
controlled trial. JAMA 2001;285:1711–1718.
359. de Lemos JA, Blazing MA, Wiviott SD, Lewis EF, Fox KA, White HD, Rouleau JL,
Pedersen TR, Gardner LH, Mukherjee R, Ramsey KE, Palmisano J, Bilheimer DW,
Pfeffer MA, Califf RM, Braunwald E. Early intensive vs a delayed conservative simvastatin
strategy in patients with acute coronary syndromes: phase Z of the A to Z
trial. JAMA 2004;292:1307–1316.
360. Ray KK, Cannon CP, McCabe CH, Cairns R, Tonkin AM, Sacks FM, Jackson G,
Braunwald E. Early and late beneﬁts of high-dose atorvastatin in patients with
acute coronary syndromes: results from the PROVE IT-TIMI 22 trial. J Am Coll Cardiol
2005;46:1405–1410.
361. Rizos EC, Ntzani EE, Bika E, Kostapanos MS, Elisaf MS. Association between
omega-3 fatty acid supplementation and risk of major cardiovascular disease
events: a systematic review and meta-analysis. JAMA 2012;308:1024–1033.
362. Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J,
Chaitman BR, Holme IM, Kallend D, Leiter LA, Leitersdorf E, McMurray JJ,
Mundl H, Nicholls SJ, Shah PK, Tardif JC, Wright RS. Effects of dalcetrapib in patients
with a recent acute coronary syndrome. N Engl J Med 2012;367:
2089–2099.
363. Di Sciascio G, Patti G, Pasceri V, Gaspardone A, Colonna G, Montinaro A. Efﬁcacy
of atorvastatin reload in patients on chronic statin therapy undergoing percutaneous
coronary intervention: results of the ARMYDA-RECAPTURE (Atorvastatin
for Reduction of Myocardial Damage During Angioplasty) Randomized Trial. J Am
Coll Cardiol 2009;54:558–565.
364. Patti G, Cannon CP, Murphy SA, Mega S, Pasceri V, Briguori C, Colombo A,
Yun KH, Jeong MH, Kim JS, Choi D, Bozbas H, Kinoshita M, Fukuda K, Jia XW,
Hara H, Cay S, Di Sciascio G. Clinical beneﬁt of statin pretreatment in patients
undergoing percutaneous coronary intervention: a collaborative patient-level
meta-analysis of 13 randomized studies. Circulation 2011;123:1622–1632.
365. Briguori C, Visconti G, Focaccio A, Golia B, Chieffo A, Castelli A, Mussardo M,
Montorfano M, Ricciardelli B, Colombo A. Novel approaches for preventing or
limiting events (Naples) II trial: impact of a single high loading dose of atorvastatin
on periprocedural myocardial infarction. J Am Coll Cardiol 2009;54:2157–2163.
366. Kim JS, Kim J, Choi D, Lee CJ, Lee SH, Ko YG, Hong MK, Kim BK, Oh SJ, Jeon DW,
Yang JY, Cho JR, Lee NH, Cho YH, Cho DK, Jang Y. Efﬁcacy of high-dose atorvastatin
loading before primary percutaneous coronary intervention in ST-segment
elevation myocardial infarction: the STATIN STEMI trial. JACC Cardiovasc Interv
2010;3:332–339.
367. Gandhi S, Mosleh W, Abdel-Qadir H, Farkouh ME. Statins and contrast-induced
acute kidney injury with coronary angiography. Am J Med 2014;127:987–1000.
368. Kjekshus J, Pedersen TR, Olsson AG, Faergeman O, Pyo¨ra¨la¨ K. The effects of simvastatin
on the incidence of heart failure in patients with coronary heart disease.
J Card Fail 1997;3:249–254.
369. Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study
Group. Prevention of cardiovascular events and death with pravastatin in patients
with coronary heart disease and a broad range of initial cholesterol levels. N Engl J
Med 1998;339:1349–1357.
370. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L,
Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E. The effect of pravastatin
on coronary events after myocardial infarction in patients with average cholesterol
levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med
1996;335:1001–1009.
371. Scirica BM, Morrow DA, Cannon CP, Ray KK, Sabatine MS, Jarolim P, Shui A,
McCabe CH, Braunwald E. Intensive statin therapy and the risk of hospitalization
for heart failure after an acute coronary syndrome in the PROVE IT-TIMI 22 study.
J Am Coll Cardiol 2006;47:2326–2331.
372. Khush KK, Waters DD, Bittner V, Deedwania PC, Kastelein JJ, Lewis SJ,
Wenger NK. Effect of high-dose atorvastatin on hospitalizations for heart failure:
subgroup analysis of the Treating to New Targets (TNT) study. Circulation 2007;
115:576–583.
373. Kjekshus J, Apetrei E, Barrios V, Bo¨hm M, Cleland JG, Cornel JH, Dunselman P,
Fonseca C, Goudev A, Grande P, Gullestad L, Hjalmarson A, Hradec J, Ja´nosi A,
Kamensky´ G, Komajda M, Korewicki J, Kuusi T, Mach F, Mareev V, McMurray JJ,
Ranjith N, Schaufelberger M, Vanhaecke J, van Veldhuisen DJ, Waagstein F,
Wedel H, Wikstrand J. Rosuvastatin in older patients with systolic heart failure.
N Engl J Med 2007;357:2248–2261.
374. GISSI-HF Investigators, Tavazzi L, Maggioni AP, Marchioli R, Barlera S,
Franzosi MG, Latini R, Lucci D, Nicolosi GL, Porcu M, Tognoni G. Effect of
rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised,
double-blind, placebo-controlled trial. Lancet 2008;372:1231–1239.
375. Rogers JK, Jhund PS, Perez AC, Bo¨hm M, Cleland JG, Gullestad L, Kjekshus J, van
Veldhuisen DJ, Wikstrand J, Wedel H, McMurray JJ, Pocock SJ. Effect of rosuvastatin
on repeat heart failure hospitalizations: the CORONA Trial (Controlled Rosuvastatin
Multinational Trial in Heart Failure). JACC Heart Fail 2014;2:289–297.
376. GISSI-HF Investigators, Tavazzi L, Maggioni AP, Marchioli R, Barlera S,
Franzosi MG, Latini R, Lucci D, Nicolosi GL, Porcu M, Tognoni G. Effect of n-3
polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF
trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008;372:
1223–1230.
377. Cowell SJ, Newby DE, Prescott RJ, Bloomﬁeld P, Reid J, Northridge DB, Boon NA.
A randomized trial of intensive lipid-lowering therapy in calciﬁc aortic stenosis. N
Engl J Med 2005;352:2389–2397.
378. Chan KL, Teo K, Dumesnil JG, Ni A, Tam J. Effect of lipid lowering with rosuvastatin
on progression of aortic stenosis: results of the aortic stenosis progression
observation: measuring effects of rosuvastatin (ASTRONOMER) trial. Circulation
2010;121:306–314.
379. Arsenault BJ, Boekholdt SM, Mora S, DeMicco DA, Bao W, Tardif JC, Amarenco P,
Pedersen T, Barter P, Waters DD. Impact of high-dose atorvastatin therapy and
clinical risk factors on incident aortic valve stenosis in patients with cardiovascular
disease (from TNT, IDEAL, and SPARCL). Am J Cardiol 2014;113:1378–1382.
380. Milin AC, Vorobiof G, Aksoy O, Ardehali R. Insights into aortic sclerosis and its
relationship with coronary artery disease. J Am Heart Assoc 2014;3:e001111.
381. Antonini-Canterin F, Moura LM, Enache R, Leiballi E, Pavan D, Piazza R,
Popescu BA, Ginghina C, Nicolosi GL, Rajamannan NM. Effect of hydroxymethylglutaryl
coenzyme-a reductase inhibitors on the long-term progression of rheumatic
mitral valve disease. Circulation 2010;121:2130–2136.
382. Antonini-Canterin F, Zuppiroli A, Popescu BA, Granata G, Cervesato E, Piazza R,
Pavan D, Nicolosi GL. Effect of statins on the progression of bioprosthetic aortic
valve degeneration. Am J Cardiol 2003;92:1479–1482.
383. Goldberg RJ, Urowitz MB, Iban˜ez D, Nikpour M, Gladman DD. Risk factors for
development of coronary artery disease in women with systemic lupus erythematosus.
J Rheumatol 2009;36:2454–2461.
384. Ogdie A, Yu Y, Haynes K, Love TJ, Maliha S, Jiang Y, Troxel AB, Hennessy S,
Kimmel SE, Margolis DJ, Choi H, Mehta NN, Gelfand JM. Risk of major cardiovascular
events in patients with psoriatic arthritis, psoriasis and rheumatoid arthritis:
a population-based cohort study. Ann Rheum Dis 2015;74:326–332.
385. Peters MJ, Symmons DP, McCarey D, Dijkmans BA, Nicola P, Kvien TK,
McInnes IB, Haentzschel H, Gonzalez-Gay MA, Provan S, Semb A,
Sidiropoulos P, Kitas G, Smulders YM, Soubrier M, Szekanecz Z, Sattar N,
Nurmohamed MT. EULAR evidence-based recommendations for cardiovascular
risk management in patients with rheumatoid arthritis and other forms of inﬂammatory
arthritis. Ann Rheum Dis 2010;69:325–331.
386. De Vera MA, Choi H, Abrahamowicz M, Kopec J, Goycochea-Robles MV,
Lacaille D. Statin discontinuation and risk of acute myocardial infarction in patients
with rheumatoid arthritis: a population-based cohort study. Ann Rheum
Dis 2011;70:1020–1024.
387. Barry R, James MT. Guidelines for classiﬁcation of acute kidney diseases and disorders.
Nephron 2015;131:221–226.
388. Olechnowicz-Tietz S, Gluba A, Paradowska A, Banach M, Rysz J. The risk of atherosclerosis
in patients with chronic kidney disease. Int Urol Nephrol 2013;45:
1605–1612.
389. Franczyk-Sko´ra B, Gluba A, Banach M, Rozentryt P, Polon´ski L, Rysz J. Acute coronary
syndromes in patients with chronic kidney disease. Curr Vasc Pharmacol
2013;11:758–767.
390. Gansevoort RT, Correa-Rotter R, Hemmelgarn BR, Jafar TH, Heerspink HJ,
Mann JF, Matsushita K, Wen CP. Chronic kidney disease and cardiovascular
risk: epidemiology, mechanisms, and prevention. Lancet 2013;382:339–352.
391. Chronic Kidney Disease Prognosis Consortium, Matsushita K, van der Velde M,
Astor BC, Woodward M, Levey AS, de Jong PE, Coresh J, Gansevoort RT. Association
of estimated glomerular ﬁltration rate and albuminuria with all-cause and
cardiovascular mortality in general population cohorts: a collaborative
meta-analysis. Lancet 2010;375:2073–2081.
392. Loncar G, Barthelemy O, Berman E, Kerneis M, Petroni T, Payot L, Choussat R,
Silvain J, Collet JP, Helft G, Montalescot G, Le Feuvre C. Impact of renal failure
on all-cause mortality and other outcomes in patients treated by percutaneous
coronary intervention. Arch Cardiovasc Dis 2015;108:554–562.
393. Palmer SC, Navaneethan SD, Craig JC, Johnson DW, Perkovic V, Hegbrant J,
Strippoli GF. HMG CoA reductase inhibitors (statins) for people with chronic kidney
disease not requiring dialysis. Cochrane Database Syst Rev 2014;5:CD007784.
394. Barylski M, Nikfar S, Mikhailidis DP, Toth PP, Salari P, Ray KK, Pencina MJ, Rizzo M,
Rysz J, Abdollahi M, Nicholls SJ, Banach M. Statins decrease all-cause mortality
only in CKD patients not requiring dialysis therapy--a meta-analysis of 11
ESC/EAS Guidelines 3058i
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
randomized controlled trials involving 21,295 participants. Pharmacol Res 2013;72:
35–44.
395. Wanner C, Krane V, Ma¨rz W, Olschewski M, Mann JF, Ruf G, Ritz E. Atorvastatin in
patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005;
353:238–248.
396. Fellstro¨m BC, Jardine AG, Schmieder RE, Holdaas H, Bannister K, Beutler J,
Chae DW, Chevaile A, Cobbe SM, Gro¨nhagen-Riska C, De Lima JJ, Lins R,
Mayer G, McMahon AW, Parving HH, Remuzzi G, Samuelsson O, Sonkodi S,
Sci D, Su¨leymanlar G, Tsakiris D, Tesar V, Todorov V, Wiecek A, Wu¨thrich RP,
Gottlow M, Johnsson E, Zannad F. Rosuvastatin and cardiovascular events in patients
undergoing hemodialysis. N Engl J Med 2009;360:1395–1407.
397. Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, Wanner C,
Krane V, Cass A, Craig J, Neal B, Jiang L, Hooi LS, Levin A, Agodoa L, Gaziano M,
Kasiske B, Walker R, Massy ZA, Feldt-Rasmussen B, Krairittichai U,
Ophascharoensuk V, Fellstro¨m B, Holdaas H, Tesar V, Wiecek A, Grobbee D,
de Zeeuw D, Gro¨nhagen-Riska C, Dasgupta T, Lewis D, Herrington W,
Mafham M, Majoni W, Wallendszus K, Grimm R, Pedersen T, Tobert J,
Armitage J, Baxter A, Bray C, Chen Y, Chen Z, Hill M, Knott C, Parish S,
Simpson D, Sleight P, Young A, Collins R. The effects of lowering LDL cholesterol
with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of
Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 2011;
377:2181–2192.
398. Erickson KF, Japa S, Owens DK, Chertow GM, Garber AM, Goldhaber-Fiebert JD.
Cost-effectiveness of statins for primary cardiovascular prevention in chronic kidney
disease. J Am Coll Cardiol 2013;61:1250–1258.
399. Tonelli M, Wanner C, Kidney Disease: Improving Global Outcomes Lipid Guideline
Development Work Group Members. Lipid management in chronic kidney
disease: synopsis of the Kidney Disease: Improving Global Outcomes 2013 clinical
practice guideline. Ann Intern Med 2014;160:182.
400. Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman L, Wang XM, Chia D,
Terasaki PI, Sabad A, Cogert GA. Effect of pravastatin on outcomes after cardiac
transplantation. N Engl J Med 1995;333:621–627.
401. Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Steinbeck G, Seidel D,
Reichart B. Simvastatin reduces graft vessel disease and mortality after heart transplantation:
a four-year randomized trial. Circulation 1997;96:1398–1402.
402. Page RL 2nd, Miller GG, Lindenfeld J. Drug therapy in the heart transplant recipient:
part IV: drug-drug interactions. Circulation 2005;111:230–229.
403. Navaneethan SD, Perkovic V, Johnson DW, Nigwekar SU, Craig JC, Strippoli GF.
HMG CoA reductase inhibitors (statins) for kidney transplant recipients. Cochrane
Database Syst Rev 2009;2:CD005019.
404. Shaw SM, Chaggar P, Ritchie J, Shah MK, Baynes AC, O’Neill N, Fildes JE, Yonan N,
Williams SG. The efﬁcacy and tolerability of ezetimibe in cardiac transplant recipients
taking cyclosporin. Transplantation 2009;87:771–775.
405. European Stroke Organisation, Tendera M, Aboyans V, Bartelink ML,
Baumgartner I, Cle´ment D, Collet JP, Cremonesi A, De Carlo M, Erbel R,
Fowkes FG, Heras M, Kownator S, Minar E, Ostergren J, Poldermans D,
Riambau V, Rofﬁ M, Ro¨ther J, Sievert H, van Sambeek M, Zeller T. ESC Guidelines
on the diagnosis and treatment of peripheral artery diseases: document covering
atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal,
upper and lower extremity arteries: the Task Force on the Diagnosis and Treatment
of Peripheral Artery Diseases of the European Society of Cardiology (ESC).
Eur Heart J 2011;32:2851–2906.
406. McDermott MM, Mandapat AL, Moates A, Albay M, Chiou E, Celic L, Greenland P.
Knowledge and attitudes regarding cardiovascular disease risk and prevention in
patients with coronary or peripheral arterial disease. Arch Intern Med 2003;163:
2157–2162.
407. Aung PP, Maxwell HG, Jepson RG, Price JF, Leng GC. Lipid-lowering for
peripheral arterial disease of the lower limb. Cochrane Database Syst Rev 2007;4:
CD000123.
408. Kumbhani DJ, Steg PG, Cannon CP, Eagle KA, Smith SC Jr, Goto S, Ohman EM,
Elbez Y, Sritara P, Baumgartner I, Banerjee S, Creager MA, Bhatt DL. Statin therapy
and long-term adverse limb outcomes in patients with peripheral artery disease:
insights from the REACH registry. Eur Heart J 2014;35:2864–2872.
409. Westin GG, Armstrong EJ, Bang H, Yeo KK, Anderson D, Dawson DL, Pevec WC,
Amsterdam EA, Laird JR. Association between statin medications and mortality,
major adverse cardiovascular event, and amputation-free survival in patients
with critical limb ischemia. J Am Coll Cardiol 2014;63:682–690.
410. Amarenco P, Labreuche J, Lavallee P, Touboul PJ. Statins in stroke prevention and
carotid atherosclerosis: systematic review and up-to-date meta-analysis. Stroke
2004;35:2902–2909.
411. Huang Y, Li W, Dong L, Li R, Wu Y. Effect of statin therapy on the progression of
common carotid artery intima-media thickness: an updated systematic review and
meta-analysis of randomized controlled trials. J Atheroscler Thromb 2013;20:
108–121.
412. Tedeschi-Reiner E, Strozzi M, Skoric B, Reiner Z. Relation of atherosclerotic
changes in retinal arteries to the extent of coronary artery disease. Am J Cardiol
2005;96:1107–1109.
413. Keech AC, Mitchell P, Summanen PA, O’Day J, Davis TM, Mofﬁtt MS,
Taskinen MR, Simes RJ, Tse D, Williamson E, Merriﬁeld A, Laatikainen LT,
d’Emden MC, Crimet DC, O’Connell RL, Colman PG. Effect of fenoﬁbrate on
the need for laser treatment for diabetic retinopathy (FIELD study): a randomised
controlled trial. Lancet 2007;370:1687–1697.
414. ACCORD Study Group; ACCORD Eye Study Group, Chew EY, Ambrosius WT,
Davis MD, Danis RP, Gangaputra S, Greven CM, Hubbard L, Esser BA, Lovato JF,
Perdue LH, Goff DC Jr, Cushman WC, Ginsberg HN, Elam MB, Genuth S,
Gerstein HC, Schubart U, Fine LJ. Effects of medical therapies on retinopathy progression
in type 2 diabetes. N Engl J Med 2010;363:233–244.
415. Golledge J, Muller J, Daugherty A, Norman P. Abdominal aortic aneurysm: pathogenesis
and implications for management. Arterioscler Thromb Vasc Biol 2006;26:
2605–2613.
416. Paraskevas KI, Liapis CD, Hamilton G, Mikhailidis DP. Can statins reduce perioperative
morbidity and mortality in patients undergoing non-cardiac vascular
surgery? Eur J Vasc Endovasc Surg 2006;32:286–293.
417. Durazzo AE, Machado FS, Ikeoka DT, De Bernoche C, Monachini MC,
Puech-Lea˜o P, Caramelli B. Reduction in cardiovascular events after vascular surgery
with atorvastatin: a randomized trial. J Vasc Surg 2004;39:967–975; discussion
975–976.
418. Schouten O, Boersma E, Hoeks SE, Benner R, van Urk H, van Sambeek MR,
Verhagen HJ, Khan NA, Dunkelgrun M, Bax JJ, Poldermans D. Fluvastatin and perioperative
events in patients undergoing vascular surgery. N Engl J Med 2009;361:
980–989.
419. Takagi H, Yamamoto H, Iwata K, Goto S, Umemoto T, Group A. Effects of statin
therapy on abdominal aortic aneurysm growth: a meta-analysis and
meta-regression of observational comparative studies. Eur J Vasc Endovasc Surg
2012;44:287–292.
420. Hackam DG, Wu F, Li P, Austin PC, Tobe SW, Mamdani MM, Garg AX. Statins and
renovascular disease in the elderly: a population-based cohort study. Eur Heart J
2011;32:598–610.
421. Subherwal S, Patel MR, Kober L, Peterson ED, Bhatt DL, Gislason GH, Olsen AM,
Jones WS, Torp-Pedersen C, Fosbol EL. Peripheral artery disease is a coronary
heart disease risk equivalent among both men and women: results from a nationwide
study. Eur J Prev Cardiol 2015;22:317–325.
422. Amarenco P, Labreuche J. Lipid management in the prevention of stroke: review
and updated meta-analysis of statins for stroke prevention. Lancet Neurol 2009;8:
453–463.
423. McKinney JS, Kostis WJ. Statin therapy and the risk of intracerebral hemorrhage: a
meta-analysis of 31 randomized controlled trials. Stroke 2012;43:2149–2156.
424. Sever PS, Dahlo¨f B, Poulter NR, Wedel H, Beevers G, Caulﬁeld M, Collins R,
Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O’Brien E,
Ostergren J. Prevention of coronary and stroke events with atorvastatin in hypertensive
patients who have average or lower-than-average cholesterol concentrations,
in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm
(ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003;361:
1149–1158.
425. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ,
Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J,
Willerson JT, Glynn RJ. Rosuvastatin to prevent vascular events in men and women
with elevated C-reactive protein. N Engl J Med 2008;359:2195–2207.
426. Byington RP, Davis BR, Plehn JF, White HD, Baker J, Cobbe SM, Shepherd J. Reduction
of stroke events with pravastatin: the Prospective Pravastatin Pooling
(PPP) Project. Circulation 2001;103:387–392.
427. Heart Protection Study Collaborative Group, Bulbulia R, Bowman L,
Wallendszus K, Parish S, Armitage J, Peto R, Collins R. Effects on 11-year mortality
and morbidity of lowering LDL cholesterol with simvastatin for about 5 years in
20,536 high-risk individuals: a randomised controlled trial. Lancet 2011;378:
2013–2020.
428. Amarenco P, Bogousslavsky J, Callahan A 3rd, Goldstein LB, Hennerici M,
Rudolph AE, Sillesen H, Simunovic L, Szarek M, Welch KM, Zivin JA. High-dose
atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006;355:
549–559.
429. Merwick A´ , Albers GW, Arsava EM, Ay H, Calvet D, Coutts SB, Cucchiara BL,
Demchuk AM, Giles MF, Mas JL, Olivot JM, Purroy F, Rothwell PM, Saver JL,
Sharma VK, Tsivgoulis G, Kelly PJ. Reduction in early stroke risk in carotid stenosis
with transient ischemic attack associated with statin treatment. Stroke 2013;44:
2814–2820.
430. Riddler SA, Smit E, Cole SR, Li R, Chmiel JS, Dobs A, Palella F, Visscher B, Evans R,
Kingsley LA. Impact of HIV infection and HAART on serum lipids in men. JAMA
2003;289:2978–2982.
ESC/EAS Guidelines3058j
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
431. Hemkens LG, Bucher HC. HIV infection and cardiovascular disease. Eur Heart J
2014;35:1373–1381.
432. Islam FM, Wu J, Jansson J, Wilson DP. Relative risk of cardiovascular disease among
people living with HIV: a systematic review and meta-analysis. HIV Med 2012;13:
453–468.
433. Bavinger C, Bendavid E, Niehaus K, Olshen RA, Olkin I, Sundaram V, Wein N,
Holodniy M, Hou N, Owens DK, Desai M. Risk of cardiovascular disease from
antiretroviral therapy for HIV: a systematic review. PLoS One 2013;8:e59551.
434. Triant VA, Lee H, Hadigan C, Grinspoon SK. Increased acute myocardial infarction
rates and cardiovascular risk factors among patients with human immunodeﬁciency
virus disease. J Clin Endocrinol Metab 2007;92:2506–2512.
435. Wohl DA, Waters D, Simpson RJ Jr, Richard S, Schnell A, Napravnik S, Keys J,
Eron JJ Jr, Hsue P. Ezetimibe alone reduces low-density lipoprotein cholesterol
in HIV-infected patients receiving combination antiretroviral therapy. Clin Infect
Dis 2008;47:1105–1108.
436. Calza L, Manfredi R, Chiodo F. Statins and ﬁbrates for the treatment of
hyperlipidaemia in HIV-infected patients receiving HAART. AIDS 2003;17:
851–859.
437. Correll CU, Robinson DG, Schooler NR, Brunette MF, Mueser KT,
Rosenheck RA, Marcy P, Addington J, Estroff SE, Robinson J, Penn DL, Azrin S,
Goldstein A, Severe J, Heinssen R, Kane JM. Cardiometabolic risk in patients
with ﬁrst-episode schizophrenia spectrum disorders: baseline results from the
RAISE-ETP study. JAMA Psychiatry 2014;71:1350–1363.
438. Andrade C. Primary prevention of cardiovascular events in patients with major
mental illness: a possible role for statins. Bipolar Disord 2013;15:813–823.
439. Tiihonen J, Lo¨nnqvist J, Wahlbeck K, Klaukka T, Niskanen L, Tanskanen A,
Haukka J. 11-year follow-up of mortality in patients with schizophrenia: a
population-based cohort study (FIN11 study). Lancet 2009;374:620–627.
440. Laursen TM. Life expectancy among persons with schizophrenia or bipolar affective
disorder. Schizophr Res 2011;131:101–104.
441. Godin O, Etain B, Henry C, Bougerol T, Courtet P, Mayliss L, Passerieux C,
Azorin JM, Kahn JP, Gard S, Costagliola D, Leboyer M. Metabolic syndrome in a
French cohort of patients with bipolar disorder: results from the FACE-BD cohort.
J Clin Psychiatry 2014;75:1078–1085; quiz 1085.
442. Lawrence D, Kisely S, Pais J. The epidemiology of excess mortality in people with
mental illness. Can J Psychiatry 2010;55:752–760.
443. Goldstein BI, Fagiolini A, Houck P, Kupfer DJ. Cardiovascular disease and hypertension
among adults with bipolar I disorder in the United States. Bipolar Disord
2009;11:657–662.
444. De Hert M, Dekker JM, Wood D, Kahl KG, Holt RI, Mo¨ller HJ. Cardiovascular disease
and diabetes in people with severe mental illness position statement from the
European Psychiatric Association (EPA), supported by the European Association
for the Study of Diabetes (EASD) and the European Society of Cardiology (ESC).
Eur Psychiatry 2009;24:412–424.
445. Ojala K, Repo-Tiihonen E, Tiihonen J, Niskanen L. Statins are effective in treating
dyslipidemia among psychiatric patients using second-generation antipsychotic
agents. J Psychopharmacol 2008;22:33–38.
446. Mitchell AJ, Lord O. Do deﬁcits in cardiac care inﬂuence high mortality rates in
schizophrenia? A systematic review and pooled analysis. J Psychopharmacol 2010;
24(4 Suppl):69–80.
447. Wood D, Kotseva K, Connolly S, Jennings C, Mead A, Jones J, Holden A, De
Bacquer D, Collier T, De Backer G, Faergeman O. Nurse-coordinated multidisciplinary,
family-based cardiovascular disease prevention programme (EUROACTION)
for patients with coronary heart disease and asymptomatic individuals at
high risk of cardiovascular disease: a paired, cluster-randomised controlled trial.
Lancet 2008;371:1999–2012.
448. Michie S, Richardson M, Johnston M, Abraham C, Francis J, Hardeman W,
Eccles MP, Cane J, Wood CE. The behavior change technique taxonomy (v1)
of 93 hierarchically clustered techniques: building an international consensus
for the reporting of behavior change interventions. Ann Behav Med 2013;46:
81–95.
449. Craig P, Dieppe P, Macintyre S, Michie S, Nazareth I, Petticrew M. Developing and
evaluating complex interventions: the new Medical Research Council guidance. Int
J Nurs Stud 2013;50:587–592.
450. Benner JS, Glynn RJ, Mogun H, Neumann PJ, Weinstein MC, Avorn J.
Long-term persistence in use of statin therapy in elderly patients. JAMA 2002;
288:455–461.
451. Chodick G, Shalev V, Gerber Y, Heymann AD, Silber H, Simah V, Kokia E. Longterm
persistence with statin treatment in a not-for-proﬁt health maintenance organization:
a population-based retrospective cohort study in Israel. Clin Ther 2008;
30:2167–2179.
452. Jackevicius CA, Mamdani M, Tu JV. Adherence with statin therapy in elderly
patients with and without acute coronary syndromes. JAMA 2002;288:
462–467.
453. McGinnis BD, Olson KL, Delate TM, Stolcpart RS. Statin adherence and mortality
in patients enrolled in a secondary prevention program. Am J Manag Care 2009;15:
689–695.
454. Huser MA, Evans TS, Berger V. Medication adherence trends with statins. Adv Ther
2005;22:163–171.
455. Bosworth HB, Granger BB, Mendys P, Brindis R, Burkholder R, Czajkowski SM,
Daniel JG, Ekman I, Ho M, Johnson M, Kimmel SE, Liu LZ, Musaus J,
Shrank WH, Whalley Buono E, Weiss K, Granger CB. Medication adherence: a
call for action. Am Heart J 2011;162:412–424.
456. Hinchcliffe A. Patient Adherence to Treatment with Statins for the Prevention of Cardiovascular
Disease. Cardiff: Public Health Wales NHS Trust, 2011.
457. Blackburn DF, Dobson RT, Blackburn JL, Wilson TW, Stang MR, Semchuk WM.
Adherence to statins, beta-blockers and angiotensin-converting enzyme inhibitors
following a ﬁrst cardiovascular event: a retrospective cohort study. Can J
Cardiol 2005;21:485–488.
458. Wei L, Wang J, Thompson P, Wong S, Struthers AD, MacDonald TM. Adherence
to statin treatment and readmission of patients after myocardial infarction: a six
year follow up study. Heart 2002;88:229–233.
459. Corrao G, Conti V, Merlino L, Catapano AL, Mancia G. Results of a retrospective
database analysis of adherence to statin therapy and risk of nonfatal ischemic heart
disease in daily clinical practice in Italy. Clin Ther 2010;32:300–310.
460. Aubert RE, Yao J, Xia F, Garavaglia SB. Is there a relationship between early statin
compliance and a reduction in healthcare utilization? Am J Manag Care 2010;16:
459–466.
461. Sokol MC, McGuigan KA, Verbrugge RR, Epstein RS. Impact of medication adherence
on hospitalization risk and healthcare cost. Med Care 2005;43:
521–530.
462. Naderi SH, Bestwick JP, Wald DS. Adherence to drugs that prevent cardiovascular
disease: meta-analysis on 376,162 patients. Am J Med 2012;125:882–887.e1.
463. Wise J. Open letter raises concerns about NICE guidance on statins. BMJ 2014;
348:g3937.
464. Abramson JD, Rosenberg HG, Jewell N, Wright JM. Should people at low risk of
cardiovascular disease take a statin? BMJ 2013;347:f6123.
465. Huffman M, Taylor F, Ebrahim S. Huffman and colleagues’ response to Abramson
and colleagues’ article on statins in low risk people. BMJ 2014;348:g1520.
466. Ajzen I. The Theory of Planned Behaviour. Organ Behav Hum Decis Process 1991;
50:179–211.
467. Becker MH. The Health Belief Model and personal health behaviour. Health Educ
Monogr 1974;2:324–508.
468. Rich A, Brandes K, Mullan B, Hagger MS. Theory of planned behavior and adherence
in chronic illness: a meta-analysis. J Behav Med 2015;38:673–688.
469. Kamran A, Sadeghieh Ahari S, Biria M, Malepour A, Heydari H. Determinants of
patient’s adherence to hypertension medications: application of health belief
model among rural patients. Ann Med Health Sci Res 2014;4:922–927.
470. Jackson C, Eliasson L, Barber N, Weinman J. Applying COM-B to medication adherence.
Eur Health Psychol 2014;16:7–17.
471. Michie S, van Stralen MM, West R. The behaviour change wheel: a new method for
characterising and designing behaviour change interventions. Implement Sci 2011;
6:42.
472. Mann DM, Woodward M, Muntner P, Falzon L, Kronish I. Predictors of nonadherence
to statins: a systematic review and meta-analysis. Ann Pharmacother 2010;44:
1410–1421.
473. Latry P, Molimard M, Dedieu B, Coufﬁnhal T, Be´gaud B, Martin-Latry K. Adherence
with statins in a real-life setting is better when associated cardiovascular
risk factors increase: a cohort study. BMC Cardiovascular Disorders 2011;11:46.
474. Lewey J, Shrank WH, Bowry AD, Kilabuk E, Brennan TA, Choudhry NK. Gender
and racial disparities in adherence to statin therapy: a meta-analysis. Am Heart J
2013;165:665–678.e1.
475. Harrison TN, Derose SF, Cheetham TC, Chiu V, Vansomphone SS, Green K,
Tunceli K, Scott RD, Marrett E, Reynolds K. Primary nonadherence to statin therapy:
patients’ perceptions. Am J Manag Care 2013;19:e133–e139.
476. DeWalt DA, Broucksou KA, Hawk V, Brach C, Hink A, Rudd R, Callahan L. Developing
and testing the health literacy universal precautions toolkit. Nurs Outlook
2011;59:85–94.
477. Rubak S, Sandbaek A, Lauritzen T, Christensen B. Motivational interviewing: a systematic
review and meta-analysis. Br J Gen Pract 2005;55:305–312.
478. Bandura A. Self-Efﬁcacy: The Exercise of Control. New York: Freeman, 1997.
479. Schedlbauer A, Davies P, Fahey T. Interventions to improve adherence to lipid
lowering medication. Cochrane Database Syst Rev 2010;3:CD004371.
480. Nieuwlaat R, Wilczynski N, Navarro T, Hobson N, Jeffery R, Keepanasseril A,
Agoritsas T, Mistry N, Iorio A, Jack S, Sivaramalingam B, Iserman E, Mustafa RA,
Jedraszewski D, Cotoi C, Haynes RB. Interventions for enhancing medication adherence.
Cochrane Database Syst Rev 2014;11:CD000011.
481. Martin SS, Sperling LS, Blaha MJ, Wilson PW, Gluckman TJ, Blumenthal RS,
Stone NJ. Clinician-patient risk discussion for atherosclerotic cardiovascular
ESC/EAS Guidelines 3058k
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018
disease prevention: importance to implementation of the 2013 ACC/AHA
Guidelines. J Am Coll Cardiol 2015;65:1361–1368.
482. Thom S, Poulter N, Field J, Patel A, Prabhakaran D, Stanton A, Grobbee DE, Bots ML,
Reddy KS, Cidambi R, Bompoint S, Billot L, Rodgers A. Effects of a ﬁxed-dose
combination strategy on adherence and risk factors in patients with or at high risk
of CVD: the UMPIRE randomized clinical trial. JAMA 2013;310:918–929.
483. Castellano JM, Sanz G, Pen˜alvo JL, Bansilal S, Ferna´ndez-Ortiz A, Alvarez L, Guzma´n L,
Linares JC, Garcı´a F, D’Aniello F, Arna´iz JA, Varea S, Martı´nez F, Lorenzatti A, Imaz I,
Sa´nchez-Go´mez LM, Roncaglioni MC, Baviera M, Smith SC Jr, Taubert K, Pocock S,
Brotons C, Farkouh ME, Fuster V. A polypill strategy to improve adherence: results
from the FOCUS project. J Am Coll Cardiol 2014;64:2071–2082.
484. Ryan R, Santesso N, Lowe D, Hill S, Grimshaw J, Prictor M, Kaufman C, Cowie G,
Taylor M. Interventions to improve safe and effective medicines use by
consumers: an overview of systematic reviews. Cochrane Database Syst Rev
2014;4:CD007768.
485. Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, Cooney MT,
Corra` U, Cosyns B, Deaton C, Graham I, Hall MS, Hobbs FD, Løchen ML,
Lo¨llgen H, Marques-Vidal P, Perk J, Prescott E, Redon J, Richter DJ, Sattar N,
Smulders Y, Tiberi M, van der Worp HB, van Dis I, Verschuren WM; Authors/
Task Force Members. 2016 European Guidelines on cardiovascular disease
prevention in clinical practice: The Sixth Joint Task Force of the European Society
of Cardiology and Other Societies on Cardiovascular Disease Prevention
in Clinical Practice (constituted by representatives of 10 societies and by invited
experts) Developed with the special contribution of the European Association
for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2016;37:
2315–2381.
ESC/EAS Guidelines3058l
Downloaded from https://academic.oup.com/eurheartj/article-abstract/37/39/2999/2414995
by guest
on 23 April 2018