1. New Oral AnticoagulantsWho Gets What for Atrial Fibrillation andVenous Thromboembolism?Kathryn Hassell, MDProfessor of Medicine, Division of HematologyUniversity of Colorado Denver

2. Disclosures No financial or commercial conflicts of interest No intended off-label discussion 3. Objectives Describe the basic characteristics of new oralanticoagulants (OACs) Recognize potential candidates for newanticoagulants for atrial fibrillation and treatmentof venous thrombosis 4. Outline of Presentation Discuss the properties of new oral anticoagulants(new OACs) Compare/contrast with older anticoagulants Mechanisms and reversibility Review the pivotal trials for atrial fibrillation andvenous thromboembolism Glean important and pertinent clinical lessons Consider ways to decide who gets what 5. Anticoagulant Mechanisms of ActionAdapted from Eriksson, Ann Rev Med 62:41, 2011RivaroxabanApixabanDabigatranWarfarinFondaparinuxHeparin LWMHVII 6. Another way to look at it Heparin blocks most activated factors Low molecular weight heparin blocks twoactivated factors: Xa and thrombin (IIa) Newer agents block only one factor: Anti-Xa agents Fondaparinux (Arixtra) s.q. daily Rivaroxaban (Xarelto) p.o. every 24 hrs Apixaban (Eliquis) p.o. every 12 hrs Anti-IIa agents Argatroban i.v. Bivalirudin i.v, Dabigatran (Pradaxa) p.o. every 12 hrs Warfarin doesnt block ANY activated factors 7. Yet another way to look at itCOOHCOOH = carboxyl groupsplaced by vitamin KFactors II, VII, IX, XProtein unfolds withactivation, revealingCOOH, used to adhereFactors circulate folded until they are to build a clotactivated during a prothrombotic stress 8. Warfarin: Fewer Sticky FactorsProthromboticstimulusNo COOH COOH 9. Heparins/New Oral Anticoagulants:Inhibition of Activated FactorsCOOHProthromboticstimulus 10. New OACs: Like drinking your LMWHLMWH Inhibit activated factors No vitamin K impact Weight-adjusted dose Dependent on renalclearance No medication interactions No monitoring needed Irreversible Injections (ouch) Very expensiveNEW ORAL AGENTS Inhibit activated factors No vitamin K impact Fixed dose Dependent on renalclearance (not apixaban) Few medication interactions No monitoring needed (cant) Irreversible Oral 5-10x cheaper than LMWH 11. Potential Drug Interactions Dabigatran: affected by pGP inhibitors or inducers Not excluded from clinical trials PI notes quinidine contraindicated; use caution with: strong inhibitors like verapamil, clarithomycin and others strong inducers (rifampin, St. Johns wort) reduced effect May be impacted by degree of renal insufficiency 12. Potential Drug Interactions Rivaroxaban: affected by combined pGP and CYP3A4 Studies excluded subjects on strong inhibitors (e.g. HIVmeds), strong inducers (e.g. rifampin, phenytoin) Package insert (PI) advises avoiding or increasingrivaroxaban dose if using carbamazepine, phenytoin,rifampin, St. Johns wort May be impacted by degree of renal insufficiency 13. Potential Drug Interactions Apixaban: affected by combined pGP and CYP3A4;per package insert: For patients receiving >2.5 mg twice daily, decreasedose of by 50% when coadministered with strong dualinhibitors of CYP3A4 and P-gp (e.g., ketoconazole,itraconazole, ritonavir, clarithromycin) For patients receiving 2.5 mg twice daily, avoidcoadministration with strong dual inhibitors Avoid concomitant use of strong dual inducers ofCYP3A4 and P-gp (e.g., rifampin, carbamazepine,phenytoin, St. Johns wort) May be impacted by degree of renal insufficiency 14. Potential Drug Interactions pGP + CYP3A inhibitors: itraconazole, ketoconzole, clarithromycin, azithromycin cyclosporin, dronedarone verapamil, diltiazem, dronedarone lopinavir/ritonavir, conivaptan amiodarone, captopril, carvedilol, felodipine, quinidine pGP inducers: carbamazepine, phenytoin, rifampin, tipranavir/ritonavir, St. Johns wort CYP3A inhibitors: voriconazole (strong), cimetidine(weak) 15. New Oral Anticoagulants:Measurement Monitoring Common assays (aPTT, prothombin time)insensitive and inconsistently affected INR is a lab parameter created ONLY for warfarin Other measures may better reflect drugs Ecarin clotting time (ECT): dabigatran Chromogenic factor Xa actvity level (as done forpeople with a lupus anticoagulant): rivaroxaban,apixaban Even if drug effect can be measured, not thesame as what results correlated with outcomes inthe studies 16. New Oral Anticoagulants:Effect on INR Dabigatran: therapeutic concentration (NOT clinicaloutcomes) correlates with INR range of 1.3-1.7Stangier, Clin Pharmacokinet 47:285, 2008 17. New Oral Anticoagulants:Effect on Protime Itself Rivaroxaban: therapeutic concentrations (NOTclinical outcomes) associated with PT 13-23 secondsKubitza D, et al. Clin Pharmacol Ther 2005;78:412-421 18. New Oral Anticoagulants:Effect on aPTT Dabigatran: therapeutic concentrations (NOT clinicaloutcomes) associated with aPTT 45-55 secondsEriksson BI, et al. J Thromb Haemost 2004;2:1573-1580.Liesenfeld L-H, et al. Br J Clin Pharmacol 2006;62:527-537. 19. New Oral Anticoagulants:Effect on Coagulation Assays Rivaroxaban, Apixaban: anti-Xa, so how about ananti-Xa (heparin) assay? Relatively linear, with some scatter Expected range unknown, no clinical correlationsBarrett Thromb Haemost 104:1263, 2010 20. New Oral Anticoagulants:Pharmacological PropertiesAttributeDabigatranEtexilateRivaroxaban ApixabanAbsorption 6.5%Better in acidicenvironment(tartaric acid added)Sl delayed high-fat diet66-80%Slightly delayed byfood66%Not affected byfoodTmax 1.25-3 h 0.5-4 h 0.5-3 hHalf-Life 7-17 h 3.2-11 h 8-15 hMetabolism Converted to activedrug by esterases inplasma or liverMetabolized byCYP3A4 (18%) andCYP212 (14%)Metabolized byCYP3A4,1A 1/2Elimination 80% renal 66% renal 30% renalReversibility ?Factor VIIa concMay be dialyzed?aPCC conc ?aPCC concGiorgi. Expert Opin Pharmacother 12:567, 2011 21. Renal Clearance Warfarin: not impacted by renal function Dabigatran, rivaroxaban: GFR 60 ml/min best Mean GFR in studies 60-100 ml/min Very few subjects had lower GFR Will not detect drug accumulation no monitoring Apixaban: only 25% cleared really Likely to be better tolerated with lower GFR Subgroups defined in pivotal trial for reduceddose (2.5 mg bid instead of 5 mg bid) 80 yrs, Cr 1.5, wt 60 kgBauersachs, Thromb Res 129:107, 2012 22. Drug Clearance in the Elderly Dabigatran (150 mg bid dosing) Healthy elderly ( 75 yrs): up to 2x exposure after 6dys Risk of major bleeding higher in subjects 75 yrs Doubled risk if >80 yrs and CrCl 50-80 ml/min Recommended dose of 75 mg bid based on modeling Rivaroxaban (20 mg/day dosing) Healthy elderly (>75 yrs): AUC but not max level Similar safety & efficacy in subjects >75 yrs No differences with mild-moderate renal impairment 15 mg/day (instead of 20) used for CrCl 30-49 ml/minBauersachs, Thromb Res 129:107, 2012 23. Principles Regarding Bleeding Anticoagulation doesnt cause bleeding Bleeding occurs when a vessel ruptures Anticoagulation doesnt weaken vessels Most people who bleed to death arent onanticoagulation Risk of major bleeding, including intracranial,does not correlate with history of fallsDonze, Am J Med 125:773, 2012Outcome PlaceboApixaban2.5 mg po bidApixaban5.0 mg po bidBleeding 22 (2.7%) 27 (3.5%) 35 (4.3%)Major 4 (0.5%) 2 (0.2%) 1 (0.1%) 24. Anticoagulants and Bleeding Risk of major bleeding 0.7-1.2%/year Warfarin: the most reversible form of oralanticoagulation Fresh frozen plasma immediate repletion offactors, temporary effect Vitamin K p.o. or i.v. production of functionalfactors within 6-12 hrs New agents: active anticoagulation (e.g. bindsactivated factors) no benefit with FFP/Vit K No proven way to reverse anticoagulation Twice-daily (e.g. dabigatran or apixaban) may bepreferred with shorter effective half-life 25. Vitamin K and Warfarin With excessive anticoagulation, can use vitaminK to drop INRs:INR Drop By Time Interval1 mg i.v. 4-5 6-8 hrs1 mg s.q. 2-4 24-48 hrs2.5-5 mg p.o. 4-5 12-24 hrs Guidelines (and experience) advise AGAINSTsubcutaneous vitamin K for patients on oralanticoagulation 26. Reversal of New OACs FIX THE HOLE thats bleeding Decrease quantity of drug Activated charcoal if thought to still be in stomach Dabigatran may be dialyzed Bypass the drug effect Prothrombin complex (PCC), factor VIIa concentratesanecdotally successful Recent study suggested aPCC may work best for anti-Xa (rivaroxaban) but not anti-thrombin (dabigatran) No increased risk of mortality or morbidity (evenin >75 y.o.) related to bleeding with new agentsDeLoughery, Am J Hem 86:586, 2011Eerenberg, Circulation 124:1508, 2011Sardar, J Am Geriat Soc 62:857, 2014 27. New OACs: Interruption of Therapy Dabigatran (per package insert) If CrCl>50 ml/min, hold 1-2 days If CrCl