Rivaroxaban or Aspirin for Extended Treatment of Venous

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism (EINSTEIN CHOICE) Ryan Sparks, Pharm. D, BCPS PGY 2 Cardiology Resident Wake. Med Health & Hosptials Raleigh, NC

Dr. Ryan Sparks (presenter) Current PGY 2 Cardiology Resident at Wake. Med Health & Hospitals in Raleigh, North Carolina. He completed the doctor of pharmacy program at the UNC Eshelman School of Pharmacy in 2015. After completing residency, he will be taking a position at New Hanover Regional Medical Center in Wilmington, North Carolina

Dr. Paul Dobesh (Mentor) Dr. Dobesh received his Bachelor of Science in Pharmacy and his Pharm. D Degree from South Dakota State University in Brookings, SD. He completed an Internal Medicine Specialty Residency at the University of Texas at Austin at Brackenridge Hospital in Austin, TX. He is currently as Associate Professor of Pharmacy Practice with the University of Nebraska Medical Center in Omaha, NE. He lectures in the area of ischemic heart disease, antithrombotic therapy, and other cardiology and critical care topics. He has conducted research on antiplatelet and antithrombotic therapy, focusing on real-world utilization and health economics. Dr. Dobesh has published book chapters and several manuscripts in this area.

Disclosure Statement I have no financial relationships with commercial interests that pertain to the content presented in this program.

Background • Cumulative incidence of VTE is ~11% within 1 year after stopping VKA • VTE has associated long term sequelae – Post-thrombotic syndrome – Chronic thromboembolic pulmonary hypertension – Recurrent VTE • Guidelines support long-term anticoagulation Haematologica 2007; 92: 199 -205 Chest 2016; 149: 315 -352

Background • Warfarin is effective for prevention of recurrent VTE but has significant limitations – INR monitoring – Drug and food interactions – Variability in response • Lower intensity warfarin strategies are less effective and do not decrease bleeding risk – Kearon, et al. (ELATE): Increase in VTE recurrence with similar bleeding rates when lower INR target was utilized N Engl J Med 2003; 348: 1425 -34 N Engl J Med 2003; 349: 631 -639

Background EINSTEIN-EXTENSION • Double blind, placebo controlled, RCT • 1197 patients who had completed treatment for confirmed symptomatic VTE • Rivaroxaban 20 mg PO daily vs placebo • Significant reduction in recurrent VTE with rivaroxaban • No difference in major bleeding events N Engl J Med 2013; 368: 699 -708 N Engl J Med 2010; 363: 2499 -510 AMPLIFY-EXTENSION • Double blind, placebo controlled, RCT • 2482 patients who had completed treatment for confirmed symptomatic VTE • Apixaban 2. 5 mg PO BID vs apixaban 5 mg PO BID vs placebo • Significant reduction in recurrent VTE or death with both apixaban arms • No difference in major bleeding events

Background • • ASPIRE Double blind, placebo controlled RCT 822 patients who had completed treatment for first unprovoked VTE ASA 100 mg/d vs placebo Composite of VTE, MI, stroke, CV death: 8. 0% with placebo vs 5. 2% with aspirin (p=0. 01) N Engl J Med 2012; 367; 1979 -87 N Engl J Med 2012; 366: 1959 -67 • • WARFASA Double blind, placebo controlled RCT 403 patients who had completed treatment for first unprovoked VTE ASA 100 mg/d vs placebo Recurrent VTE occurred in 6. 6% of aspirin and 11. 2% of placebo patients per year (p=0. 02)

EINSTEIN CHOICE - Objective To compare the safety and efficacy of rivaroxaban to aspirin in patients with venous thromboembolism who had completed 6 to 12 months of therapy and for whom there was clinical uncertainty over the need for continued anticoagulation

Methods Design Treatment • Randomized, double-blind, double dummy, active control trial • Stratified by index diagnosis – DVT vs PE • Index event treated for 6 to 12 months • 1: 1: 1 randomization • Rivaroxaban 20 mg PO daily • Rivaroxaban 10 mg PO daily • Aspirin 100 mg PO daily

Methods Inclusion • • 18 years of age or older Confirmed symptomatic proximal DVT or PE – Treated for 6 to 12 months with anticoagulant – Had not interrupted anticoagulant therapy for more than 7 days before randomization Exclusion • • Contraindication to anticoagulant therapy Requirement of extended anticoagulant or antiplatelet therapy Cr. Cl less than 30 ml/min Hepatic disease with associated coagulopathy Concomitant strong CYP 3 A 4 and P-gp inhibitor/inducers Life expectancy less than 6 months Child bearing potential without proper contraception, pregnancy or breast feeding Participation in another study within 30 days prior to randomization

Efficacy Outcomes Primary Efficacy Secondary Efficacy • Composite of fatal and non-fatal symptomatic recurrent VTE • Composite of primary endpoint plus MI, ischemic stroke, systemic VTE • All-cause mortality

Safety Outcomes Primary Safety Secondary Safety • Major bleeding (ISTH definition) • Clinically relevant non-major bleeding • Composite of major and clinically relevant non-major bleeding

Statistical Analysis • 80 primary efficacy outcomes needed to provide 90% power for superiority • Needed to enroll 3300 patients to provide power • Analysis included all patients who received at least one dose of study medication

Baseline Demographics N = 3365 Median age 58 years 55% male 34% with BMI>30 kg/m 2 51% index DVT, 34% index PE, 15% index DVT+PE 59% with provoked event 17% prior VTE

Primary Efficacy Results % of patients with recurrent VTE 5 4 3. 5 3 2. 5 2 1. 5 1 0. 5 0 Rivaroxaban 20 Rivaroxaban 10 Aspirin 100 mg mg daily • P-value < 0. 001 for rivaroxaban 20 mg vs aspirin • P-value < 0. 001 for rivaroxaban 10 mg vs aspirin • P-value = 0. 42 for rivaroxaban 20 mg vs rivaroxaban 10 mg comparison

Efficacy Results Rivaroxaban 20 mg PO daily (n=1107) Rivaroxaban 10 mg PO daily (n=1127) Aspirin 100 mg (n=1131) p-value 20 mg vs ASA p-value 10 mg vs ASA Primary - Recurrent VTE, n (%) 17 (1. 5) 13 (1. 2) 50 (4. 4) <0. 001 Deep vein thrombosis, n (%) 9 (0. 8) 7 (0. 6) 29 (2. 6) -- -- Pulmonary embolism, n (%) 6 (0. 5) 5 (0. 4) 19 (1. 7) -- -- 2 (0. 2) 0 (0) 2 (0. 2) -- -- 3 (0. 3) 5 (0. 4) 7 (0. 6%) -- -- Outcomes Fatal VTE, n (%) MI, ischemic stroke, systemic embolism; n (%)

Safety Results Outcomes Major bleeding, n (%) Clinically relevant nonmajor bleeding, n (%) Non-major bleeding associated with study drug interruption for more than 14 days, n (%) Rivaroxaban 20 mg PO daily (n=1107) Rivaroxaban 10 mg PO daily (n=1127) Aspirin 100 mg (n=1131) p-value 20 mg vs ASA p-value 10 mg vs ASA 6 (0. 5) 5 (0. 4) 3 (0. 3) 0. 32 0. 50 30 (2. 7) 22 (2. 0) 20 (1. 8) 0. 14 0. 78 17 (1. 5) 12 (1. 1) 0. 33 0. 96

Author’s Conclusions • Rivaroxaban was more effective than aspirin for prevention of recurrent VTE without increased bleeding risk in patients with VTE in equipoise for continued anticoagulation – With either 20 mg or 10 mg rivaroxaban dosing • Benefit was demonstrated in patients with provoked and non-provoked VTE

Critique Strengths • Large randomized controlled trial • Tested full dose and prophylactic dose rivaroxaban • Active control – aspirin • Inclusion of patients with weight > 90 kg Weaknesses • Excluded patients who required long term anticoagulation • Not powered to detect difference between rivaroxaban doses • Limited data for patients with renal dysfunction

Conclusions • Aspirin is inferior to rivaroxaban for the prevention of recurrent VTE • Rivaroxaban 10 mg PO daily may be considered for secondary prevention in patients who do not require extended anticoagulation • Full dose anticoagulation should still be utilized in patients who require anticoagulation • Risk of low dose rivaroxaban strategy is still unknown for many patients

Practice Implications • Rivaroxaban should be used preferentially over aspirin for recurrent VTE prevention • Anticoagulation clinics and services will need to modify practice to accommodate new strategies • No direct DOAC comparisons • Long term safety of extended rivaroxaban remains unclear • More patients may receive extended DOAC therapy

Acknowledgements • Paul Dobesh, Pharm. D, FCCP, BCPS-AQ Cardiology • J. Erin (Allender) Ledford, Pharm. D, BCPS-AQ Cardiology, BCCCP • Janna Beavers, Pharm. D, BCPS

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism (EINSTEIN CHOICE) Ryan Sparks, Pharm. D, BCPS PGY 2 Cardiology Resident Wake. Med Health & Hosptials Raleigh, NC

Announcements • Please join us June 27 th as Dr. Taylor Church (Vanderbilt) presents the Ticagrelor versus Clopidogrel in Symptomatic Peripheral Artery Disease (EUCLID) trial. Her mentor will be Dr. Kelly Rogers (University of Tennessee).