TreatmentTreatment ofof thromboembolicthromboembolic diseasedisease Milan Juhas, PharmD.,1,2,3 1Department of pharmacology, Masaryk University School of medicine 2Ist. Internal Cardioangiology clinic, St. Anne`s University Hospital Brno 3Hospital Pharmacy, St.Anne`s University Hospital Brno TENTEN –– ThromboembolicThromboembolic diseasedisease • Presence of thrombus within venous system causing obstruction – Complication - pulmonary embolism potentially fatalfatal • Risk of thrombus leads – Posttrombotického syndrómu – Thromboembolic pulmonary hypertension TENTEN –– ThromboembolicThromboembolic diseasedisease ((2)2) • Clinical pathology layout – flebothrombosis – Pulmonary embolism (50 % patients with flebothrombosis)flebothrombosis) – Statistically 3rd most common cause of death – Superficial phlebitis • NSAID • heparinoids Source of embolismSource of embolism • Secondary with known cause of origin • Primary idiopathic – 30 – 50 % of cases– 30 – 50 % of cases – Oncology screening with detection of possible malignancy – Hereditary thrombophillic status Incidence of thrombosisIncidence of thrombosis PATIENTS IN RISK GROUP INCIDENCE (%) Long time immobility in bed 10 – 20 Abdominal surgery 15 – 40 Stroke 20 – 50 Neurosurgery 15 – 40 Fractures of limbs 20 – 70 Large orthopedic surgery (hip, knee replacement) 40 – 80 Trauma 40 – 70 Critically ill patients on ICU 10 – 80 Spinal cord injury 60 - 80 ThromboembolicThromboembolic diseasedisease andand VirchowVirchow triastrias • Change in laminar blood flow – turbulence – Blood stasis • Change in coagulation blood properties – Shift of ballance towards hypercoagulation • Damaged vessel wall WhatWhat isis thethe goalgoal ofof thethe treatmenttreatment ofof thromboembolicthromboembolic diseasedisease ?? RiskRisk factorsfactors Congenital thrombofilia Insufficiency of anticoagulation factors (AT-III, protein C, proteín S), presence of antiphospholipid antibodies (L.antikoagulans). F-V Leiden mutation, Prothrombin mutation (20210 G-A), hyperhomocysteinemia, Thrombophilia – acquired Malignancy, sepsis, Myeloproliferative diseases, nefrotick syndrom, IBD,acquired Myeloproliferative diseases, nefrotick syndrom, IBD, age (40 years), positive anamnesis, immobility and trauma, serious internal condition (CHF, stroke), autoimmune diseases (lupus a nd „lupus-like“), gravidity, anatomic abnormalities in venous system, obesity Circumstances contributing on thromboembolic disease Travelling and dehydration, trauma coupled with fixation, pharmacotherapy (staroids, HRT, birth-control pills), smoking TherapeuticTherapeutic groupsgroups •• „„indirectindirect““ anticoagulantsanticoagulants – heparin, LMWH a pentasacharides – Vitamin K antagonists (coumarines) •• „„directdirect““ anticoagulantsanticoagulants – NOACs, hirudin • thrombolysis HeparinHeparin structurestructure • mukopolysacharide with variable chain leght (55--30 00030 000 DaDa) • Anticoagulant and pleiotropic activity – Antiinflamnatory– Antiinflamnatory – Cytostatic – immunomodulatory HeparinHeparin –– mechanismmechanism ofof actionaction Quaranta et al. (2015), The physiologic and therapeutic role of heparin in implantation and placentation. PeerJ 3:e691; DOI 10.7717/peerj.691 HeparinHeparin –– mechanismmechanism ofof actionaction (2(2)) –– variablevariable accordingaccording mixturemixture ofof chainschains Unfractioned heparin Short chains (minori fraction) – anti-Xa Long chains (majority) – anti-IIa Quaranta et al. (2015), The physiologic and therapeutic role of heparin in implantation and placentation. PeerJ 3:e691; DOI 10.7717/peerj.691 HeparinHeparin -- advantages • Rapid onset of action (i.v. administration) • Relativelly cheap • Available in patiens with severe kidney insufficiencyinsufficiency • Antidote available – Protamine suplhate 1mg: 100 IU Heparin HeparinHeparin -- cons • Non-linear pharmacokinetics (distribution and elimination) – narrow therapeutic range • Daily monitoring of anticoagulation activity• Daily monitoring of anticoagulation activity (aPTT) • Heparin resistance (acute phase proteins) • Only in i.v. infusion (!!! i.m. and s.c. !!!!) HeparinHeparin –– conscons (2(2)) • Riziko hyperkoagulácie po vysadení – Neschopnosť väzby heparinu na trombin viazaný fibrínom • Aktivita priamo viazaná na prítomnosť AT-III – Deficiencia AT-III (1-5 %) – Substutúcia rekombinantného AT-III a monitorácia MonitoringMonitoring ofof anticoagulationanticoagulation activityactivity • aPTT – activated partial tromboplastin time – Interval 1,5 – 2,5x against control specimen – First value 12 hrs after i.v. heparin – Extracorporeal methods, cathetrisation methods,– Extracorporeal methods, cathetrisation methods, dialysis (ACT-activated coagulation time) •• dosingdosing – Bolus 5000 – 10000 IU – i.v. continual infusion 400 IU/kg HeparinHeparin -- aadversedverse effectseffects • Bleeding • Thrombocytopenia • Osteopenia and osteoporosis• Osteopenia and osteoporosis • allergy HeparinHeparin inducedinduced thrombocytopeniathrombocytopenia (HIT)(HIT) • HIT-1 – Manifestation 1st -2nd day of treatment in 10 % of patients – Mild thrombocyte decrease • HIT-2 – Manifestation 4th–5th day of treatment in 0,5-5 % liečených – Immunologically mediated (IgG AB agains heparin-decrease – Relativelly benign and temporary –– HeparinHeparin treatmenttreatment terminationtermination notnot necessarynecessary (IgG AB agains heparin- PF4) – Endotel and Thrombocytes activation – Life-threatening thrombosis and DIC –– ImmediateImmediate heparinheparin discontinuationdiscontinuation HeparinHeparin--inducedinduced thrombocytopeniathrombocytopenia ((HIT)HIT) • Check platelet count before heparin starts • Monitoring of platelet count dynamics •• HeparinHeparin stopstop indicated with platelet count•• HeparinHeparin stopstop indicated with platelet count below 50 % of initial value (HIT-2) • Fondaparinux, lepirudin, LMWH, warfarin HeparinHeparin neutralisationneutralisation withwith protaminprotamin--sulphatesulphate • Protamin dose calculation – Heparin halflife 1-2 hrs – Heparin dose estimation to neutralize – (cumulative dose in past 3-6 hrs)– (cumulative dose in past 3-6 hrs) • i.v. protaminprotamin--sulphatesulphate (non-registered) •• 11 mg = 100 IUmg = 100 IU heparinheparin LowLow molecularmolecular weightweight heparinheparin BasicBasic differencesdifferences betweenbetween UFUF--heparinheparin and LMWHand LMWH • Native heparin chain depolymerisation – 15 sacharide units •• ImprovedImproved parametersparameters – ↓ plasma protein binding– ↓ plasma protein binding – ↓ thrombocyte and endotel binding – Predictable anticoagulant activity – Possible s.c. administration (1-2x/day) – Dosing according patients weight –– SelfSelf--administrationadministration injectorsinjectors StructureStructure ofof LMWH andLMWH and itit``ss impactimpact on FDon FD • Mixture of various chain leght heparins (average n=15) • ↓ molecular weight (5000 Da) • Anti-Xa activity – Most common chain leght (n=5) • Anti-IIa activity – Most common chain leght (n=18) AnticoagulationAnticoagulation activityactivity monitoringmonitoring viavia AntiAnti--XaXa methodmethod • MAJOR ELIMINATION ORGAN - KIDNEYS – Anti-Xa not necessary if no kidney damage present • Anti-Xa control indicated – gravidity– gravidity – Renal insufficicency – Obese and asthenic patients • anti-Xa control after 3 days of treatment • 2-4 hrs after s.c. dose LMWH PKLMWH PK parametersparameters LMWH weight (Da) ANTI-Xa /ANTI-IIa ratio F (s.c.) (%) HALFLIFE (hod) Enoxaparine 4200 10:1 100 7 Bemiparine 3600 8:1 96 6 Nadroparine 4600 4:1 88 4 Dalteparine 5000 3:1 90 5 ADVANTAGE IN FK PARAMETERS, BUT ABSENT ANTIDOTE .ADVANTAGE IN FK PARAMETERS, BUT ABSENT ANTIDOTE . FONDAPARINUXFONDAPARINUX • PENTASACHARIDE with predictable anticoagulant activity • Complete resorption after s.c. administration 2,5 mg, 7,5 mg • Anti-Xa activity mediated via high AT-III selectivity (300:1) • Prolonged effect • AC activity monitoring not necessary • Absent risk of HIT, absent antidote OralOral anticoagulantsanticoagulants •• WarfarinWarfarin ((antivitaminantivitamin K)K) •• DabigatranDabigatran ((inhibitorinhibitor IIaIIa)) •• RivaroxabanRivaroxaban ((inhibitorinhibitor XaXa))•• RivaroxabanRivaroxaban ((inhibitorinhibitor XaXa)) •• ApixabanApixaban ((InhibitorInhibitor XaXa)) •• EdoxabanEdoxaban ((inhibitorinhibitor XaXa)) VITAMIN KVITAMIN K • SOURCE – Food (20 %) – Intestinal flora (80 %) • insufficiency – Cholestasis – Treatment of broad-spectre ATB • (β-lactam 2nd and higher generation) WARFARINWARFARIN –– FEATURES (1FEATURES (1)) • Coagulation factors systhesis inhibitor – ANTIVITAMIN K ? – VITAMIN K ANTAGONIST– VITAMIN K ANTAGONIST – No effect on blood viscosity S-warfarin 4x more potent than R-warfarin – PK interactions WARFARINWARFARIN –– FEATURES (2FEATURES (2)) •• GoodGood p.op.o.. bioavailabilitybioavailability • High plasma protein binding (albumin) (99 % resorbed fraction) • Extensive liver metabolism• Extensive liver metabolism • Enterohepatal recirculation •• DelayedDelayed onsetonset ofof actionaction (heparin(heparin necessarynecessary)) TreatmentTreatment initiantioninitiantion andand monitorationmonitoration • 5-10 mg in single dose • When ? (morning, noon ?) • Risk of paradox hypercoagulation WARFARINWARFARIN AND POSSIBLEAND POSSIBLE COMPLICATIONSCOMPLICATIONS •• bleedingbleeding – Rectum, GIT (stomach, bowel) – Intracranial bleeding • Skin coumarine necrosis • Blood panel abnormalities • hepatotoxicity • Increased fracture risk WARFARINWARFARIN AND DRUGAND DRUG INTERACTIONSINTERACTIONS NONENONE ...... CLINICALLY RELEVANT INR PARAMETERCLINICALLY RELEVANT INR PARAMETER EXERTIONEXERTION – Slow-down coumarine metabolism in liver – Speed-up coumarine liver metabolism – Enterohepatal recirculation block – FC drug interactions at distribution level –– FDFD drugdrug interactioninteraction NOACsNOACs •• advantagesadvantages – Linear FC and FD parameters – Predictable anticoagulant activity – Monitoration not necessary– Monitoration not necessary – Absent clinically relevant drug interactions – Low risk of genetic resistance – Safe and more effective NOACsNOACs • disadvantages – Antidote absent (except dabigatran) – Higher rate of GIT bleeding*– Higher rate of GIT bleeding* – expensive DABIGATRAN (PRADAXA)DABIGATRAN (PRADAXA) – ester dabigatran etexilat (substrate p-gp) – Hydrolysis via plasma esterase enzymes without P450 CYP effect – DVT treatment: – 5 days LMWH + dabigatran – Profylaktic dose 220 mg , 150 mg once a day DABIGATRAN (PRADAXA) –– DirectDirect thrombinthrombin inhibitorinhibitor ((IIaIIa)) •Free fraction •Fibrin coupled • Inhibition of secondary thrombin-mediated• Inhibition of secondary thrombin-mediated thrombocyte aggregation • DABIGATRAN ETEXILATE (PRADAXA) – Bioavailability 3-7 % – Clinically relevant drug interactions on absorption levelon absorption level – P-GP inhibition – Amiodarone cardioversion RERE--COVER účinnosť a bezpečnosťCOVER účinnosť a bezpečnosť RERE--COVERCOVER efficacyefficacy –– DVT riskDVT risk in 6in 6 monthsmonths RERE--COVERCOVER bleedingbleeding RIVAROXABAN (XARELTO)RIVAROXABAN (XARELTO) • Direct fXa inhibitor • Predictable anticoagulation activity • Prevention and treatment of DVT a PE – 15 mg 2x day (3 weeks) – 20 mg 1x day maintenance dose EINSTEIN TRIALEINSTEIN TRIAL rivaroxabanrivaroxaban vsvs enoxaparinenoxaparin ((warfarinwarfarin)) EINSTEIN TRIALEINSTEIN TRIAL rivaroxabanrivaroxaban vsvs enoxaparinenoxaparin ((warfarinwarfarin)) -- safetysafety APIXABAN (ELIQUIS)APIXABAN (ELIQUIS) • Direct fXa inhibitor – Free and bound fraction – Loading 10 mg 2x day (7 days) – Maintenance dose 5 mg 2x day – *age, body weight, serum creatinine level above 133 umol/L AMPLIFYAMPLIFY apixabanapixaban –– efficacyefficacy APMLIFYAPMLIFY apixabanapixaban –– safetysafety PK FEATURESPK FEATURES dabigatran rivaroxaban apixaban Cieľová štruktúra IIa(trombin) Xa Xa Cmax 0,5-2,0 2,0-4,0 3,0-4,0Cmax 0,5-2,0 2,0-4,0 3,0-4,0 Interakčný potenciál P-gp P-gp a CYP3A4 P-gp a CYP3A4 Polčas 14-17 9-13 12-15 Podiel renálnej eliminácie [%] 80 33 27 Thank you milan.juhas@fnusa.cz