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 Clinical implica ons Rapid onset of ac on No need for bridging Predictable an coagulant effect No need for rou ne coagula on monitoring, fixed dose Low poten al for food interac ons No dietary restric on Low poten al for drug interac ons Few drug interac on Betrixaban
Argatroban Bivalirudin
FDA-approved Betrixaban
Argatroban Lepirudin Bivalirudin
FDA-approved Betrixaban
Argatroban Lepirudin Bivalirudin
FDA-approved New Oral An coagulants large phase III studies Drug Stroke Preven on VTE treatment Orthopedic Prophylaxis RE-LY RECOVER, RECOVER II RE-MOBILIZE Dabigatran REMEDY-EXT RE-MODEL RESOLVE-EXT RE-NOVATE
Rivaroxaban ROCKET AF EINSTEIN PE RECORD 1 EINSTEIN DVT RECORD 2 EINSTEIN-EXT RECORD 3 RECORD 4 Apixaban AVERROES (ASA) AMPLIFY ADVANCE 1 ARISTOTLE (W) AMPLIFY-EXT ADVANCE 2 ADVANCE 3
Edoxaban ENGAGE AF-TIMI HOKUSAI-VTE STARS Current Status on Oral An coagulant Approval in the United States
Dabigatran Rivaroxaban Apixaban Edoxaban (Pradaxa) (Xarelto) (Eliquis) (Savaysa) Atrial Approved Approved Approved Approved Fibrilla on VTE Approved Approved Approved Approved Treatment VTE preven on Not is US Approved Approved Not is US Ortho surgery Comparison of New Oral An coagulants
Dabigatran Rivaroxaban Apixaban Edoxaban etexilate Target Thrombin FXa FXa FXa
Clo ng me PTT, TCT, ECT PT, An -Xa An -Xa An -Xa prolonga on Time to peak (h) 2h 2.5- 4 h 3h 1-2h
Half-life (h) 14-17 5-9 healthy 8-15 9-11 9-13 elderly
Metabolism/ Renal 80% Renal 35% Renal 25% Renal 35% Elimina on Bile 20% Bile 75% Bile 65 %
An dote Yes None None None
Administra on bid daily bid daily Comparison of New Oral An coagulants
Dabigatran Rivaroxaban Apixaban Edoxaban etexilate Target Thrombin FXa FXa FXa
Clo ng me PTT, TCT, ECT PT, An -Xa An -Xa An -Xa prolonga on Time to peak 2h 2-3h 1-2h 1-2h effect (h) Half-life (h) 14-17 5-9 healthy 8-15 9-11 9-13 elderly
Metabolism/ Renal 80% Renal 35% Renal 25% Renal 35% Elimina on Bile 20% Bile 75% Bile 65 %
An dote Yes None None None
Administra on bid daily bid daily Comparison of New Oral An coagulants
Dabigatran Rivaroxaban Apixaban Edoxaban etexilate Target Thrombin FXa FXa FXa
Clo ng me PTT, TCT, ECT PT, An -Xa An -Xa An -Xa prolonga on Time to peak 2h 2-3h 1-2h 1-2h effect (h) Half-life (h) 14-17 5-9 healthy 8-15 9-11 9-13 elderly
Metabolism/ Renal 80% Renal 35% Renal 25% Renal 35% Elimina on Bile 20% Bile 75% 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)
RE-LY ROCKET-AF ARISTOTLE ENGAGE AF- TIMI
Design Randomized Randomized Randomized Randomized Blinded for dabi dose Double blind & Open-label for warfarin double dummy N 18,113 14,264 18, 202 21,105 Treatment Dabigatran Rivaroxaban Apixaban Edoxaban 150 mg BID 20 mg daily 5 mg BID 60 mg daily 110 mg BID 30 mg daily in selected pts (25%) Comparator Warfarin 2-3 Warfarin 2-3 Warfarin 2-3 Warfarin 2-3 (67% in-range) (57% in-range) (66% in-range) Mean 2.1 3.5 2.1 2.8 CHADS₂
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. 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 LMWH * VKA Bridging
RE-COVER I and II LMWH * Dabigatran 150 mg BID Switching Day 1 Day 6 -11 At least 6 months Hokusai - VTE LMWH * Edoxaban 60 mg QD Day 1 Switching Day 6 -11 At least 3 months
EINSTEIN-DVT/PE Rivaroxaban 15 mg BID X 3 weeks, then 20 mg QD
Day 1 Single drug approach At least 3 months
AMPLIFY Apixaban 10 mg BID X 7 days; then 5 mg BID
Day 1 Single drug approach At least 6 months
*Or UFH or fondaparinux Black, Cohen: Tailoring NOAC therapy for VTE 662 period of 15 mg twice daily, against standard therapy with rhage) was reported with any of the NOACs, supporting the safety LMWH followed by dose-adjusted VKAs. The primary efficacy of these drugs. endpoint of symptomatic recurrent VTE was reported in 2.1 % of the rivaroxaban group vs 3.0 % of the warfarin group (HR 0.68, 95 % CI 0.44–1.04) and 2.1 % of the rivaroxaban group and 1.8 % Pulmonary embolism in the warfarin group (HR 1.12, 95 % CI 0.75–1.68), for the DVT and PE trials, respectively. Major or clinically relevant non-major Silent pulmonary embolism (PE) is present in 32 % of patients with bleeding (the principal safety outcome) occurred in 8.1 % of each symptomatic deep-vein thrombosis (DVT) (28). Given that 10 % of group in the EINSTEIN-DVT trial, and a non-significant reduc- patients with acute PE die within 1 hour and 30 % within one week tion in events was observed with rivaroxaban in the EINSTEIN- (29), time is critical to instigate effective treatment. For these rea- PE study (10.3 % vs 11.4 %, HR 0.90, 95 % CI 0.76–1.07). Finally, sons, empirical administration of therapeutic doses of LMWH is in the AMPLIFY study of apixaban monotherapy given at 10 mg indicated prior to CT confirmation where there is a reasonable twice daily for seven days and 5 mg twice daily for six months, clinical suspicion. Of the active control trials reporting on PE sub- the primary efficacy endpoint was recurrent symptomatic VTE groups, the AMPLIFY and Hokusai-VTE trials for apixaban and recurrence or related deaths. Recurrent VTE or related deaths edoxaban, respectively, were unique in reporting a risk reduction, occurred in 2.3 % of the apixaban group compared with 2.7 % in albeit non-significant, with NOAC therapy relative to standard the standard therapy group (relative risk [RR] 0.84, 95 % treatment (▶ Table 3). The EINSTEIN-PE study, which compared 0.60–1.18). The composite safety endpoint of major plus clini- rivaroxaban monotherapy with standard treatment involving initial cally relevant non-major bleeding occurred in 4.3 % of the apixa- heparin therapy demonstrated non-inferiority with respect to the ban group vs 9.7 % of those receiving standard therapy (RR 0.44, primary efficacy endpoint. The safety endpoints were reported 95 % 0.36–0.55). The risk of major bleeding alone was also re- among some subgroups with PE and those available show a reduc- duced in the apixaban group where it occurred in 0.6 % of pa- tion in risk of bleeding associated with NOAC therapy relative to tients compared to 1.8 % in the conventional therapy group (RR active controls. In the AMPLIFY study, the primary safety endpoint 0.31; 95 % CI 0.17–0.55). of major bleeding occurred in 0.4 % of patients with PE assigned to In summary, all NOAC trials in the acute setting met non-in- apixaban and 2.8 % of those on conventional therapy. Similar bene- feriority for the primary efficacy endpoint. Furthermore, there was fits in the primary safety measure for those with PE were observed no clear disparity in efficacy endpoints between trials adopting a in Hokusai-VTE where clinically relevant minor or major bleeding heparin lead in and those with monotherapy of the trial drug. A occurred in 10.1 % and 11.2 % of the edoxaban and conventional comparison of outcomes with differing duration of intensive arms, respectively. In the EINSTEIN-PE study, major or clinically monotherapy in the EINSTEIN (3 weeks) and AMPLIFY (1 week) relevant non-major bleeding occurred in 10.3 and 11.4 % of the studies does not support one approach over the other, particularly rivaroxaban and conventional therapy groups, respectively. with respect to efficacy. All NOACs discussed above appear to be Heparin therapy is thought to have beneficial effects above and at least as efficacious as the conventional regimen of parenteral he- beyond its anticoagulant properties (30), particularly in the pul- parin with bridging to warfarin. In RE-COVER I, RE-COVER II, monary circulation where it exerts pleiotropic effects including Hokusai-VTE,Summary phase III trials of NOACs for the and AMPLIFY trials, significant reductions in the anti-inflammatory and vasodilatory effects. Consistent with the composite safety endpoint of major or clinically relevant non- factor Xa inhibitors, the onset of action of heparin is fast. In com- major bleeding were observed. In the AMPLIFY and EINSTEIN bination with its early time to peak effect, these benefits may ex- pooled analyses, the NOACsacute treatment of VTE were associated with a significant re- plain why trials using an initial heparin strategy were able to re- duction in major bleeding. Importantly, no increased risk estimate cruit more patients with large PEs. Of the enrolled patients with for any subcategory of bleeding (including intracranial haemor- PE in the Hokusai-VTE trial, more than 45.8 % had an extensive
Drug Study Recurrent VTE or HR (95%CI) Major or clinically HR (95%CI) Table 2: Results from VTE-related death* relevant non-major phase III trials of non- bleeding VKA oral anticoagu- lants for the acute NOAC VKA NOAC VKA treatment of VTE. Apixaban AMPLIFY 2.3 2.7 0.84 (0.60–1.18) 4.3 9.7 0.44 (0.36–0.55) Dabigatran RE-COVER I & II 2.4 2.2 1.08 (0.76–1.57) 5.3 8.5 0.62 (0.50–0.76) Edoxaban† Hokusai-VTE 3.2 3.5 0.82 (0.60–1.14) 8.5 10.3 0.81 (0.71–0.94) Rivaroxaban† EINSTEIN-PE 2.1 1.8 1.12 (0.75–1.68) 10.3 11.4 0.90 (0.76–1.07) Rivaroxaban† EINSTEIN-DVT 2.1 3.0 0.68 (0.44–1.04) 8.1 8.1 … *Primary endpoint varied in some studies. †Data are presented for recurrent VTE only. HR, hazard ratio. 95%CI, 95% confidence in- terval.
© Schattauer 2015 Thrombosis and Haemostasis 114.4/2015
Black, SA Thromb.HaemostDownloaded. 2015; from 114:660 www.thrombosis-online.com on 2015-11-19 | ID: 1000490262 | IP: 171.65.65.46 For personal or educational use only. No other uses without permission. All rights reserved. NOACs in the Treatment of acute VTE Summary
Dabigatran Rivaroxaban Apixaban Edoxaban (Pradaxa) (Xarelto) (Eliquis) Ini a on immediately No* Yes Yes No* a er diagnosis Dosing Bid Once daily Bid Once daily Efficacy compared to Same Same Same Same warfarin (recurrent VTE) Safety compared to Same/be er Same/be er Be er Be er warfarin (bleeding)
* 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 pa ents receiving direct oral an coagulants: a systema c review and meta- analysis 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 yes yes no At SHC
*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
Fully humanized antibody • Monoclonal humanized fragment (Fab) 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
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
End of idarucizumab injec on (5 min infusion) 70 Dabigatran plus: 65 Placebo (n=9) 60 2 g idarucizumab (day 4) (n=9) 4 g idarucizumab (day 4) (n=8) 55 Normal upper reference limit (n=86) Dabigatran + placebo 50 Mean baseline (n=86) dTT (s) 45
40
35
30
–2 0 2 4 6 8 10 12 24 36 48 60 72 Time a er end of infusion (hours) Antidote Dabigatran
Glund S. Lancet 2015; 386: 680 RE-VERSE AD Global Trial dabigatran Interim Results
Idarucizumab 2.5 g i.v. bolus twice (5g total) 90 days follow- up within 15 min.
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
Timing of last dose Type of procedures Renal func on Half life Standard risk of bleeding High risk of bleeding ClCr (ml/min) (2-3 half-lives) (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
Timing of discon nua on of dabigatran BEFORE surgery Renal func on Half life (hours) Standard risk of bleeding High risk of bleeding ClCr (ml/min) (2-3 half-lives) (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
Clinical Services
Pharmacy 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
Pa ent characteris c Drug of Choice Ra onale “New comers” NOAC At least as effec ve and safe as VKAs, more convenient, less ICH Pt stable INR on warfarin warfarin or switch to Depends on pa ent and NOAC physician preference Pt on warfarin, poor INR Any NOAC More predictable and stable control an coagulant effect and no monitoring CrCl 30-50 ml/min Apixaban, Less affected by renal Rivaroxaban, or impairment than dabigatran edoxaban CrCl < 15 ml/min VKA NOACs not recommended Ischemic stroke on Dabigatran Lowest risk of ischemic stroke warfarin or an -Xa with dabigatran (150mg) One size does not fit all-2
Pa ent characteris c Drug of Choice Ra onale 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 Rivaroxaban or Only agents given once daily twice-daily dosing edoxaban