ACCP Cardiology PRN Journal Club

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Leo Buckley, PharmD, BCPS PGY-2 Cardiovascular Pharmacy Resident Department of Pharmacy Services Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism Cardiology PRN Journal Club April 2, 2015 Mentor: Evan Nix, PharmD Presenter: Leo Buckley, PharmD Disclosures: none

Oral Anticoagulant Properties Fontana P, et al. Eur Heart J. 2014;35(28): WarfarinDabigatranRivaroxabanApixabanEdoxaban Target Vitamin K epoxide Factor IIaFactor Xa OnsetDays2 hr2.5-4 hr3 hr1-5 hr Dosing interval QDBIDBID/QDBIDQD Half-life36-42 hr12-14 hr9-13 hr8-11 hr8-10 hr Interactions CYP 2C9 CYP 3A4 P-gp CYP 3A4 P-gp CYP 3A4 P-gp CYP 3A4 MonitoringRequiredNot required Renal Elimination (%) Hepatic

Oral Anticoagulation for VTE Favors DOACFavors warfarin Dabigatran Rivaroxaban Apixaban Fontana P. Eur Heart J. 2014;35(28): Prins MH, et al. Thrombosis Journal. 2013;11:21-31.

Bleeding Rates in VTE trials Bleeding definition DOACWarfarin ISTH major %1.2-2% ISTH clinically relevant nonmajor %7-8% Major and clinically relevant nonmajor % % *Acute treatment period only Bleeding Rates According to Definition Fontana P. Eur Heart J. 2014;35(28): Drug (primary safety) DOACWarfarin Dabigatran-pooled analysis (ISTH major) 1.4%2% Rivaroxaban-PE (Major and clinically relevant non major) 10.3%11.4% Rivaroxaban-DVT (Major and clinically relevant non major) 8.1% Apixaban (ISTH major) 0.6%1.8% Bleeding Rates According to Drug

Comparison of VTE Study Designs RE-COVER RE-COVER 2 EINSTEIN-DVT EINSTEIN-PE AMPLIFY DrugDabigatranRivaroxabanApixaban DosingFixed DesignDouble-blindOpen-labelDouble-blind Parenteral ACAt least 5 daysNone NI margin Duration6 months 3, 6 12 months (prespecified) 6 months TTR60% 57.7% (DVT); 62.7% (PE) 61% Extension6-36 months12-24 months18-24 months Raskob G, et al. J Thromb Haemost. 2013;11: AC = anticoagulation; DVT = deep vein thrombosis; NI = noninferiority; PE = pulmonary embolism

Study Design  Randomized, double-blind, double dummy, active control  Objective: evaluate whether initial heparin followed by edoxaban is noninferior to heparin, overlapped with and followed by warfarin for the prevention of symptomatic recurrent VTE Buller HR, et al. N Engl J Med. 2013;369(15):

CONSORT Diagram Buller HR, et al. N Engl J Med. 2013;369(15): Randomized N = 8292 patients Heparin-edoxaban Dummy warfarin n = 4143 Deaths = 132 Withdrew constent = 36 LTFU = 7 Other = 6 Heparin-warfarin Dummy edoxaban n = 4149 Deaths = 126 Withdrew constent = 34 LTFU = 4 Other = 3 Screened N = ?? patients  Lost to follow up (< 0.2%)  Withdrew consent (< 0.9%)

Treatment Arms RandomizationDay 5 … Edoxaban* Warfarin placebo Edoxaban placebo Warfarin Heparin/LMWH Month 3-12 Buller HR, et al. N Engl J Med. 2013;369(15): Raskob G, et al. J Thromb Haemost. 2013;11:

Treatment Buller HR, et al. N Engl J Med. 2013;369(15): Raskob G, et al. J Thromb Haemost. 2013;11:  Edoxaban: –60 mg QD –30 mg QD if: weight < 60 kg, CrCl 30-50, P-gp inhibitors (verapamil, quinidine azithromycin, clarithromycin, erythromycin, oral itraconazole or oral ketoconazole)  Warfarin INR 2-3 –TTR calculated by Rosendaal method –Center TTR monitoring, dose adjustment protocol provided

Inclusion/Exclusion Criteria Inclusion  DVT (acute, symptomatic) –Compression ultrasound –Venography with contrast –CT-scan –MR-venography –Popliteal, femoral, iliac vein  PE –Spiral CT –Pulmonary angiogram –Ventilation/perfusion scan Exclusion  Contraindications to warfarin or heparin  > 48 hr therapeutic UFH  > 1 dose VKA  Cancer + long-term LMWH  Other indication for VKA  > 100 mg ASA or DAPT  CrCl < 30 ml/min  Thrombectomy/olysis  Mechanical valve  Recent or current bleeding Buller HR, et al. N Engl J Med. 2013;369(15): Raskob G, et al. J Thromb Haemost. 2013;11:

Endpoints  Primary efficacy: –Symptomatic, objectively verified recurrent DVT or fatal or nonfatal PE  Primary safety: –Clinically relevant bleeding Composite of ISTH major bleeding and clinically relevant nonmajor bleeding  Follow-up: –12 months from randomization, regardless of treatment duration Buller HR, et al. N Engl J Med. 2013;369(15): Raskob G, et al. J Thromb Haemost. 2013;11:

Statistics  Noninferiority, event-driven  220 events or 7500 patients  3% incidence primary outcome  85% power  Two-sided alpha 0.05  mITT (>1 dose study drug)  Preserve > 70% warfarin benefit Buller HR, et al. N Engl J Med. 2013;369(15): Raskob G, et al. J Thromb Haemost. 2013;11: Favors edoxabanFavors warfarin Upper boundary of 95% CI for HR edoxaban v. warfarin

Baseline Characteristics Characteristic, n (%)EdoxabanWarfarin Age, mean years55.7± ±16.2 Weight ≤ 60 kg524 (12.7)519 (12.6) Weight > 100 kg611 (14.8)654 (15.9) CrCl ml/min268 (6.5)273 (6.6) Received edoxaban 30 mg733 (17.8)719 (17.4) Extensive DVT1035/2468 (41.9)1049 (42.8) Extensive PE743/1650 (45)778 (46.6) NT-proBNP ≥ 500 pg/mL*454/1650 (27.5)484/1669 (29) Unprovoked VTE2713 (65.9)2697 (65.4) Temporary risk factor1132 (27.5)1140 (27.7) Prior VTE784 (19)736 (17.9) Buller HR, et al. N Engl J Med. 2013;369(15): *PE only

Efficacy Outcomes Buller HR, et al. N Engl J Med. 2013;369(15): Favors edoxaban Favors warfarin p-value < for noninferiority EdoxabanWarfarinHR (95% CI) Primary130 (3.2)146 (3.5)0.89 ( ) On treatment only66 (1.6)80 (1.9)0.82 ( ) Fatal PE4 (0.1)3 (0.1)-- ?Fatal PE20 (0.5)21 (0.5)-- Nonfatal PE49 (1.2)59 (1.4)-- DVT alone57 (1.4)63 (1.5)-- Duration (months) EdoxabanWarfarin 3485 (11.8)528 (12.8) (26.1)1084 (26.3) (62.1)2510 (60.9)

Durability of Efficacy Outcomes Time (days) Primary event rate (%)

Safety Outcomes EdoxabanWarfarinP Clinically relevant bleeding 349 (8.5)423 (10.3)0.004 Major bleeding 56 (1.4)66 (1.6)0.35 CRNM bleeding 298 (7.2)368 (8.9)0.004 Intracranial hemorrhage 06 (0.1)-- Drug discontinuation 121 (2.9)105 (2.5)-- SAE 503 (12.2)544 (13.2)-- Buller HR, et al. N Engl J Med. 2013;369(15): CRNM = clinically relevant nonmajor; SAE = serious adverse event Event rate (%) Time (days)

Other Outcomes Buller HR, et al. N Engl J Med. 2013;369(15): Edoxaban 30 mg patients onlyEdoxaban (n = 733) Warfarin (n = 719) HR (95% CI) Recurrent VTE 22 (3)30 (4.2) 0.73 ( ) Major + clinically relevant nonmajor bleeding 58 (7.9)92 (12.8) 0.62 ( ) Major bleeding 11 (1.5)22 (3.1) 0.50 ( )  TTR 63.5%  Mortality: 132 (3.2%) vs. 126 (3.1%)  Acute coronary event: 20 (0.5%) vs. 13 (0.3%)  No differences in liver enzyme tests  No treatment effect across age, CrCl, weight, region, ethnicity

Discussion: Patients Baroletti S, Szumita P. Crit Pathways in Cardiol. 2004;3: Buller HR, et al. N Engl J Med. 2013;369(15):  Significant disease burden –~40% per study definitions of extensive DVT and PE –Approximately 1/3 RV dysfunction on CT, elevated BNP  Subgroups addressed: –Advanced age (~13% were ≥75 years) –Renal impairment (~6% had CrCl 30-50) –Weight (~12% were ≤60 kg and ~15% were >100 kg)

Discussion: Intervention Baroletti S, Szumita P. Crit Pathways in Cardiol. 2004;3: Buller HR, et al. N Engl J Med. 2013;369(15):  60 mg dose tested for SPAF and VTE prophylaxis after orthopedic surgery  Dose adjustment for ~16% of patients with similar efficacy/safety as 60 mg dose  Use of parenteral anticoagulation?

Discussion: Intervention  Flexible (ad hoc) treatment duration –Dabigatran = 6 months –Rivaroxaban = prespecified 3, 6 or 12 months –Apixaban = 6 months –Extension studies not available for edoxaban  Center TTR monitoring

Discussion: Endpoints Baroletti S, Szumita P. Crit Pathways in Cardiol. 2004;3: Buller HR, et al. N Engl J Med. 2013;369(15):  Standard definitions with central adjudication  Composite bleeding endpoint  Would ICH and fatal bleeding have been significantly lower if tested? Results summary: Recurrent VTE: edoxaban noninferior Clinically relevant bleeding: edoxaban noninferior Major bleeding: edoxaban noninferior CRNM bleeding: edoxaban superior Results summary: Recurrent VTE: edoxaban noninferior Clinically relevant bleeding: edoxaban noninferior Major bleeding: edoxaban noninferior CRNM bleeding: edoxaban superior

Discussion: Statistics Baroletti S, Szumita P. Crit Pathways in Cardiol. 2004;3: Buller HR, et al. N Engl J Med. 2013;369(15):  Stricter noninferiority margin than prior studies  Double blind design to reduce suspicion bias  Met power requirements (276 events vs. 220 events)

Conclusions  Edoxaban provides a convenient, safe and effective alternative to warfarin.  Edoxaban adds valuable experience on the use of FXa inhibitors in patients with: –Submassive PE and extensive DVT –Weight extremes –Advanced age –Renal impairment  Additional data is required for direct comparisons of DOACs, DAPT, ASA > 100 mg, reversal, treatment beyond 12 months, cancer, systemic thrombolysis…

References Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26): Buller HR, Decousus H, Grosso MA, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15): Buller HR, Prins MH, Lensing AWA, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14): Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12): Fontana P, Goldhaber SZ, Bounameaux H. Direct oral anticoagulants in the treatment and long-term prevention of venous thrombo-embolism. Eur Heart J. 2014;35(28): Labropoulos N, Spentzouris G, Gasparis AP, Meissner M. Impact and clinical significance of recurrent venous thromboembolism. Br J Surg. 2010;97: Mahmoodi BK, Gansevoort RT, Naess IA, et al. Association of mild to moderate chronic kidney disease with venous thromboembolism: pooled analysis of five prospective general population cohorts. Circulation. 2012;126(16): Martinez C, Cohen AT, Rietbrock S. Epidemiology of first and recurrent venous thromboembolism: a population-based cohort study in patients without active cancer. Thromb Haemost. 2014;112:[epub ahead of print].

References Prins MH, Lensing AWA, Bauersachs R, et al. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thrombosis Journal. 2013;11: Raskob G, Buller H, Prins M, et al. Edoxaban for the long-term treatment of venous thromboembolism: rationale and design of the Hokusai-venous thromboembolism study – methodological implications for clinical trials. J Thromb Haemost. 2013;11: Ridout G, de la Motte S, Niemczyk S, et al. Effect of renal function on edoxaban pharmacokinetics (PK) and on population PK/PK-PD model. J Clin Pharmacol. 2009;49:1124. Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous thromboembolism with dabigatran or wafarin and pooled analysis. Circulation. 2014;129: Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3: Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24): Schulman S, Kearon C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368(8): Weitz JI, Connolly SJ, Patel I, et al. Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation. Thromb Haemost. 2010;104:

Questions? Thank you to Dr. Evan Nix, PharmD and Dr. Craig Beavers, PharmD, from ACCP Cardiology PRN. Special acknowledgement for Ahmed Aldemerdash, PharmD.

Thank you for attending!  If you would like to have your resident present, would like to be a mentor, or have questions or comments please the journal club at or  Our next Journal Club will be in late April –Laura Halder from Abbott Northwestern will be presenting on OSLER Trial from ACC.15