Novel Oral An,coagulants: Prac,cal Aspects. Caroline Berube, MD Clinical Associate Professor Division of Hematology November 2015

Transcription

1 Novel Oral An,coagulants: Prac,cal Aspects Caroline Berube, MD Clinical Associate Professor Division of Hematology November 2015

2 The New Oral An,coagulants (NOACs) The Non VKA Oral An,coagulants (NOACs) Direct Oral An,coagulants (DOACs) Target-Specific Oral An,coagulants (TSOACs)

3 Target-Specific Oral An,coagulants (TSOACs) Direct Thrombin inhibitors Dabigatran Direct Xa inhibitors Rivaroxaban Apixaban Edoxaban

4 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

5 Betrixaban Argatroban Bivalirudin FDA-approved

6 Betrixaban Argatroban Lepirudin Bivalirudin FDA-approved

7 Betrixaban Argatroban Lepirudin Bivalirudin FDA-approved

8 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

9 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

10 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 h 3h 1-2h Half-life (h) healthy 9-13 elderly 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

11 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) healthy 9-13 elderly 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

12 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) healthy 9-13 elderly 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

13 Stroke Preven,on in Atrial Fibrilla,on

14 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, ,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) Connolly, SJ. N Engl J Med 2009; 361: Patel et al. N Engl J Med 2011; 365:883 Granger CB et al. N Engl J Med 2011;365: Giugliano, RP. N Engl J Med 2013; 369:2093. Edoxaban 60 mg daily 30 mg daily in selected pts (25%) Warfarin 2-3

15 Efficacity of NOACs with warfarin in pa,ents with AF Meta-analysis Stroke or systemic embolic events Ruff, C. Lancet 2014; 383:955

16 Safety of NOACs with warfarin in pa,ents with AF Meta-analysis Major Bleeding Ruff, C. Lancet 2014; 383:955

17 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

18 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

19 Acute Treatment of Venous Thromboembolism

20 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

21 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 VKA HR (95%CI) 0.84 ( ) 1.08 ( ) 0.82 ( ) 1.12 ( ) 0.68 ( ) 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 VKA HR (95%CI) 0.44 ( ) 0.62 ( ) 0.81 ( ) 0.90 ( ) Black, SA Thromb.Haemost. 2015; 114:660

22 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

23 Bleeding Risk

24 Fatal bleeding events comparing TSOACs with VKAss Meta-analysis (> 100,000 patients with AF + VTE) Chatree Chai-Adisaksopha et al. Blood 2014;124:

25 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 , 5 OCT 2015 DOI: /jth

26 Total bleeding events comparing TSOACs with VAKs Combining indications of AF + VTE Chai-Adisaksopha C et al. Blood 2014;124:

27 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

28 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

29 URGENT REVERSAL Emerging An,dotes

30 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

31 Idarucizumab (Praxbind) for Dabigatran Reversal approved Oct 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

32 Healthy volunteer study: immediate, complete, and sustained reversal of dabigatran an,coagula,on with idarucizumab dtt (s) 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) Antidote Dabigatran Time awer end of infusion (hours) Glund S. Lancet 2015; 386: 680

33 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

34 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: Pollack C. NEJM 2015; 114: 198

35 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

36 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

37 Time Courses of Anti Factor Xa Activity before and after Administration of Andexanet alfa in healthy subjects y.o. Siegal DM et al. N Engl J Med DOI: /NEJMoa

38 Emerging an,dotes Andexanet alfa Ongoing confirmatory phase 3b/4 study (ANNEXA-4) in pa,ents with acute major bleed is ongoing

39 Suggested strategy for management of TSOAC-associated bleeding. Siegal D M et al. Blood 2014;123: by American Society of Hematology

40 Periopera,ve Management

41 Warfarin interrup,on and Heparin/LMWH Bridging warfarin warfarin Hep/LMWH Hep/LMWH Surgery NOAC NOAC Low dose DVT prophylaxis NOAC

42 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 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

43 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) > (11-22) days 2-3 days > 50 to < (12-34) 1-2 days 2-3 days 30 to < (13-23) 2 days 3-4 days < (22-35) 2-3 days 4-6 days Weitz, J. Circulation 2012; 126:2428. Thromb Haemostasis 2010; 103: 1116

44 Educa,on Resources

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46 ical Services harmacy

47 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!

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49 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 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)

50 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