Novel Oral An,coagulants: Prac,cal Aspects Caroline Berube, MD Clinical Associate Professor Division of Hematology November 2015
The New Oral An,coagulants (NOACs) The Non VKA Oral An,coagulants (NOACs) Direct Oral An,coagulants (DOACs) Target-Specific Oral An,coagulants (TSOACs)
Target-Specific Oral An,coagulants (TSOACs) Direct Thrombin inhibitors Dabigatran Direct Xa inhibitors Rivaroxaban Apixaban Edoxaban
Advantages of new oral an,coagulants compared to warfarin Advantage Rapid onset of ac,on Predictable an,coagulant effect Low poten,al for food interac,ons Low poten,al for drug interac,ons No need for bridging Clinical implica8ons No need for rou,ne coagula,on monitoring, fixed dose No dietary restric,on Few drug interac,on
Betrixaban Argatroban Bivalirudin FDA-approved
Betrixaban Argatroban Lepirudin Bivalirudin FDA-approved
Betrixaban Argatroban Lepirudin Bivalirudin FDA-approved
Dabigatran New Oral An,coagulants large phase III studies Drug Stroke Preven8on VTE treatment Orthopedic Prophylaxis RE-LY RECOVER, RECOVER II REMEDY-EXT RESOLVE-EXT RE-MOBILIZE RE-MODEL RE-NOVATE Rivaroxaban ROCKET AF EINSTEIN PE EINSTEIN DVT EINSTEIN-EXT Apixaban AVERROES (ASA) ARISTOTLE (W) AMPLIFY AMPLIFY-EXT RECORD 1 RECORD 2 RECORD 3 RECORD 4 ADVANCE 1 ADVANCE 2 ADVANCE 3 Edoxaban ENGAGE AF-TIMI HOKUSAI-VTE STARS
Current Status on Oral An,coagulant Approval in the United States Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) Edoxaban (Savaysa) Atrial Fibrilla,on VTE Treatment VTE preven,on Ortho surgery Approved Approved Approved Approved Approved Approved Approved Approved Not is US Approved Approved Not is US
Comparison of New Oral An,coagulants Dabigatran etexilate Rivaroxaban Apixaban Edoxaban Target Thrombin FXa FXa FXa Clo^ng,me prolonga,on PTT, TCT, ECT PT, An,-Xa An,-Xa An,-Xa Time to peak (h) 2h 2.5-4 h 3h 1-2h Half-life (h) 14-17 5-9 healthy 9-13 elderly 8-15 9-11 Metabolism/ Elimina,on Renal 80% Bile 20% Renal 35% Renal 25% Bile 75% Renal 35% Bile 65 % An,dote Yes None None None Administra,on bid daily bid daily
Comparison of New Oral An,coagulants Dabigatran etexilate Rivaroxaban Apixaban Edoxaban Target Thrombin FXa FXa FXa Clo^ng,me prolonga,on Time to peak effect (h) PTT, TCT, ECT PT, An,-Xa An,-Xa An,-Xa 2h 2-3h 1-2h 1-2h Half-life (h) 14-17 5-9 healthy 9-13 elderly 8-15 9-11 Metabolism/ Elimina,on Renal 80% Bile 20% Renal 35% Renal 25% Bile 75% Renal 35% Bile 65 % An,dote Yes None None None Administra,on bid daily bid daily
Comparison of New Oral An,coagulants Dabigatran etexilate Rivaroxaban Apixaban Edoxaban Target Thrombin FXa FXa FXa Clo^ng,me prolonga,on Time to peak effect (h) PTT, TCT, ECT PT, An,-Xa An,-Xa An,-Xa 2h 2-3h 1-2h 1-2h Half-life (h) 14-17 5-9 healthy 9-13 elderly 8-15 9-11 Metabolism/ Elimina,on Renal 80% Bile 20% Renal 35% Renal 25% Bile 75% Renal 35% Bile 65 % An,dote Yes None None None Administra,on bid daily bid daily
Stroke Preven,on in Atrial Fibrilla,on
Atrial Fibrilla,on Studies (> 70,000 pts, median age 70-73) Design RE-LY ROCKET-AF ARISTOTLE ENGAGE AF- TIMI Randomized Blinded for dabi dose Open-label for warfarin Randomized Double blind & double dummy Randomized Randomized N 18,113 14,264 18, 202 21,105 Treatment Dabigatran 150 mg BID 110 mg BID Comparator Warfarin 2-3 (67% in-range) Mean CHADS₂ Rivaroxaban 20 mg daily Warfarin 2-3 (57% in-range) Apixaban 5 mg BID Warfarin 2-3 (66% in-range) 2.1 3.5 2.1 2.8 Connolly, SJ. N Engl J Med 2009; 361:1139-1151 Patel et al. N Engl J Med 2011; 365:883 Granger CB et al. N Engl J Med 2011;365:981-992 Giugliano, RP. N Engl J Med 2013; 369:2093. Edoxaban 60 mg daily 30 mg daily in selected pts (25%) Warfarin 2-3
Efficacity of NOACs with warfarin in pa,ents with AF Meta-analysis Stroke or systemic embolic events Ruff, C. Lancet 2014; 383:955
Safety of NOACs with warfarin in pa,ents with AF Meta-analysis Major Bleeding Ruff, C. Lancet 2014; 383:955
Meta-Analysis of Safety of New Oral Anticoagulants (Dabigatran, Rivaroxaban, Apixaban) Versus Warfarin in Patients With Atrial Fibrillation Major bleeding Intracranial bleed GI bleed NOAC warfarin Corey S. Miller, Am J Cardiol 2012; 110:453
Preven,on of Stroke in Atrial Fibrilla,on Summary The new oral an,coagulants are more effec,ve than vit. K antagonists in the preven,on of stroke All new an,coagulants result in a 50% decrease in intracranial bleeding complica,ons compared with warfarin. Dabigatran and rivaroxaban are associated with increased extracranial bleeding risk (GI) in the elderly popula,on
Acute Treatment of Venous Thromboembolism
VTE Treatment VKA VTE treatment RE-COVER I and II LMWH * Bridging LMWH * Switching Day 1 Day 6-11 VKA Dabigatran 150 mg BID At least 6 months Hokusai - VTE LMWH * Day 1 Switching Day 6-11 Edoxaban 60 mg QD At least 3 months EINSTEIN-DVT/PE Day 1 Rivaroxaban 15 mg BID X 3 weeks, then 20 mg QD Single drug approach At least 3 months AMPLIFY *Or UFH or fondaparinux Day 1 Apixaban 10 mg BID X 7 days; then 5 mg BID Single drug approach At least 6 months
Summary phase III trials of NOACs for the acute treatment of VTE Drug Apixaban Dabigatran Edoxaban Rivaroxaban Rivaroxaban Study AMPLIFY RE-COVER I & II Hokusai-VTE EINSTEIN-PE EINSTEIN-DVT Recurrent VTE or VTE-related death* NOAC 2.3 2.4 3.2 2.1 2.1 VKA 2.7 2.2 3.5 1.8 3.0 HR (95%CI) 0.84 (0.60 1.18) 1.08 (0.76 1.57) 0.82 (0.60 1.14) 1.12 (0.75 1.68) 0.68 (0.44 1.04) Major or clinically relevant non-major bleeding NOAC *Primary endpoint varied in some studies. Data are presented for recurrent VTE only. HR, hazard ratio. 95%CI, 95% confidence interval. 4.3 5.3 8.5 10.3 8.1 VKA 9.7 8.5 10.3 11.4 8.1 HR (95%CI) 0.44 (0.36 0.55) 0.62 (0.50 0.76) 0.81 (0.71 0.94) 0.90 (0.76 1.07) Black, SA Thromb.Haemost. 2015; 114:660
NOACs in the Treatment of acute VTE Summary Ini,a,on immediately aler diagnosis Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) No* Yes Yes No* Edoxaban Dosing Bid Once daily Bid Once daily Efficacy compared to warfarin (recurrent VTE) Safety compared to warfarin (bleeding) Same Same Same Same Same/bener Same/bener Bener Bener * Does not eliminate the need for initial UFH/LMWH
Bleeding Risk
Fatal bleeding events comparing TSOACs with VKAss Meta-analysis (> 100,000 patients with AF + VTE) Chatree Chai-Adisaksopha et al. Blood 2014;124:2450-2458
Mortality outcomes in pa8ents receiving direct oral an8coagulants: a systema8c review and metaanalysis of randomized controlled trials Mortality Outcomes Chai-Adisaksopha C. JTH Nov 2015 Journal of Thrombosis and Haemostasis Volume 13, Issue 11, pages 2012-2020, 5 OCT 2015 DOI: 10.1111/jth.13139 http://onlinelibrary.wiley.com/doi/10.1111/jth.13139/full#jth13139-fig-0002
Total bleeding events comparing TSOACs with VAKs Combining indications of AF + VTE Chai-Adisaksopha C et al. Blood 2014;124:2450-2458
Management of Pa,ents who Require Urgent Surgery It is es,mated that urgent surgeries are necessary in 1-2% of an,coagulated pa,ents per year The risk of major bleed is 7 fold higher in the periopera,ve period for urgent surgery/procedure when compared to elec,ve procedure (RE-LY*) New an,coagulants have short half-lives of 9-15h In most cases, surgery can be deferred for approximately 24h, allowing elimina,on of most an,coagulant effect * Douketis NEJM June 2015
Effect of NOAC on Coagula,on Tes,ng Test Dabigatran Rivaroxaban Apixaban PTT* /no effect PT/INR* /no effect TCT No effect No effect ECT No effect No effect An,-Xa** No effect Quan,ta,ve assay At SHC yes yes no *Variability by reagent/lab TCT: Thrombin time ECT: Ecarin clotting time ** Drug specific
URGENT REVERSAL Emerging An,dotes
Emerging An,dotes Idarucizumab à dabigatran specific an,dote (approved October 2015) Monoclonal humanized an,body specific to dabigatran Andexanet à Factor Xa inhibitors universal an,dote PER977 (Aripazine) Has the poten,al to neutralize all an,coagulant (an,thrombin, an,-xa, heparin) Schiele, F. Blood 2013; 121: 3554 Lu, G. et al. Nat. Med 2013; 19, 446 Ansell, J. NEJM 2014; 371: 2141
Idarucizumab (Praxbind) for Dabigatran Reversal approved Oct. 2015 Monoclonal humanized an,body with high binding affinity to dabigatran No procoagulant effect Short half-life Immediate onset of ac,on Low risk of adverse event, no Fc binding Fully humanized antibody fragment (Fab) Schiele, F. Blood 2013; 121: 3554 Douketis, J. NEJM 2015 Pollack, C. Thromb Haemost 2015 Pollack, C. NEJM 2015
Healthy volunteer study: immediate, complete, and sustained reversal of dabigatran an,coagula,on with idarucizumab dtt (s) 70 65 60 55 50 45 End of idarucizumab injec8on (5 min infusion) Dabigatran plus: Placebo (n=9) 2 g idarucizumab (day 4) (n=9) 4 g idarucizumab (day 4) (n=8) Normal upper reference limit (n=86) Dabigatran + placebo Mean baseline (n=86) 40 35 30 2 Antidote Dabigatran 0 2 4 6 8 10 12 24 36 48 60 72 Time awer end of infusion (hours) Glund S. Lancet 2015; 386: 680
RE-VERSE AD Global Trial dabigatran Interim Results Idarucizumab 2.5 g i.v. bolus twice (5g total) within 15 min. 90 days follow- up Pollack C. NEJM 2015; 114: 198 target enrollment n=300
Time Courses of Plasma Concentrations of Unbound Dabigatran and Idarucizumab before and after the Administration of Idarucizumab. Pollack CV Jr et al. N Engl J Med 2015;373:511-520 Pollack C. NEJM 2015; 114: 198
RE-VERSE-AD trial Conclusions Idarucizumab completely reversed the an,coagulant effect of dabigatran within minutes. No safety concerns (interim analysis) Dabigatran-specific FDA approved 10/15/15
Emerging an,dotes Andexanet alfa Injectable recombinant protein Modified factor Xa, no procoagulant ac,vity Acts as decoy for Xa inhibitor Minimal adverse events Short-term and long-term reversal Trials ongoing with all Xa inhibitors Enriquez, A Europace 2015 Siegal DM, NEJM 2015
Time Courses of Anti Factor Xa Activity before and after Administration of Andexanet alfa in healthy subjects 50-75 y.o. Siegal DM et al. N Engl J Med 2015. DOI: 10.1056/NEJMoa1510991
Emerging an,dotes Andexanet alfa Ongoing confirmatory phase 3b/4 study (ANNEXA-4) in pa,ents with acute major bleed is ongoing
Suggested strategy for management of TSOAC-associated bleeding. Siegal D M et al. Blood 2014;123:1152-1158 2014 by American Society of Hematology
Periopera,ve Management
Warfarin interrup,on and Heparin/LMWH Bridging warfarin warfarin Hep/LMWH Hep/LMWH Surgery NOAC NOAC Low dose DVT prophylaxis NOAC
Guide to the Discon,nua,on of Xa inhibitors prior to elec,ve procedure or surgery Renal func,on ClCr (ml/min) Half life Standard risk of bleeding (2-3 half-lives) Timing of last dose Type of procedures High risk of bleeding (4-5 half-lives) > 50 12h 24h** 2 days 30-50 2 days 2 days < 30 unknown 2 days 2-4 days ** last dose Day -2 Schulman S., Crowther M. Blood 2012 Schulman S. J Intern Med 2104; 275:1
Reversal of Dabigatran An,coagulant Effect Guide to the discon,nua,on of dabigatran prior to elec,ve surgery Renal func,on ClCr (ml/min) Half life (hours) Timing of discon8nua8on of dabigatran BEFORE surgery Standard risk of bleeding (2-3 half-lives) High risk of bleeding (4-5 drug half-lives) > 80 13 (11-22) 1-1.5 days 2-3 days > 50 to < 80 15 (12-34) 1-2 days 2-3 days 30 to < 50 18 (13-23) 2 days 3-4 days < 30 27 (22-35) 2-3 days 4-6 days Weitz, J. Circulation 2012; 126:2428. Thromb Haemostasis 2010; 103: 1116
Educa,on Resources
ical Services harmacy
Is there any Future for Warfarin? Special Pa,ent Popula,ons Pa,ents with mechanical heart valves will remain on warfarin Pa,ents with valvular AF (mitral disease) Pa,ents who fail therapy on a new AC Efficacy/safety of an,-xa or direct thrombin inhibitors not established Extreme weight pa,ents Pa,ent with cancer (vs. LMWH) Pa,ents with APS Pa,ents with significant renal insufficiency Pa,ent with gastric bypass surgery Pa,ents with compliance issues Warfarin will not disappear!
One size does not fit all-1 Pa8ent characteris8c Drug of Choice Ra8onale New comers NOAC At least as effec,ve and safe as VKAs, more convenient, less ICH Pt stable INR on warfarin Pt on warfarin, poor INR control CrCl 30-50 ml/min warfarin or switch to NOAC Any NOAC Apixaban, Rivaroxaban, or edoxaban Depends on pa,ent and physician preference More predictable and stable an,coagulant effect and no monitoring Less affected by renal impairment than dabigatran CrCl < 15 ml/min VKA NOACs not recommended Ischemic stroke on warfarin or an,-xa Dabigatran Lowest risk of ischemic stroke with dabigatran (150mg)
One size does not fit all-2 Pa8ent characteris8c Drug of Choice Ra8onale Dyspepsia An,-Xa Dyspepsia with dabigatran in 10% of pts. Recent GI bleed apixaban Dabigatran, rivaroxaban, and edoxaban produce more GI bleeding than warfarin Poor compliance with twice-daily dosing Rivaroxaban or edoxaban Only agents given once daily