1. Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism (EINSTEIN CHOICE)
Ryan Sparks, PharmD, BCPS
PGY2 Cardiology Resident
WakeMed Health & Hosptials
Raleigh, NC

2. Dr. Ryan Sparks (presenter)
Current PGY2 Cardiology Resident at WakeMed Health & Hospitals in Raleigh, North Carolina. He completed the doctor of pharmacy program at the UNC Eshelman School of Pharmacy in After completing residency, he will be taking a position at New Hanover Regional Medical Center in Wilmington, North Carolina

3. Dr. Paul Dobesh (Mentor)
Dr. Dobesh received his Bachelor of Science in Pharmacy and his PharmD 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.

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

5. 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:
Chest 2016; 149:

6. 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:
N Engl J Med 2003; 349:

7. Background EINSTEIN-EXTENSION AMPLIFY-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
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
N Engl J Med 2013; 368:
N Engl J Med 2010; 363:

8. Background ASPIRE WARFASA 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)
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)
N Engl J Med 2012; 367;
N Engl J Med 2012; 366:

9. 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

10. 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
Design
Rivaroxaban 20 mg PO daily
Rivaroxaban 10 mg PO daily
Aspirin 100 mg PO daily
Treatment

11. Methods Inclusion Exclusion 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
Contraindication to anticoagulant therapy
Requirement of extended anticoagulant or antiplatelet therapy
CrCl less than 30 ml/min
Hepatic disease with associated coagulopathy
Concomitant strong CYP3A4 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

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

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

14. 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

15. Baseline Demographics
Median age 58 years
55% male
34% with BMI>30 kg/m2
51% index DVT, 34% index PE, 15% index DVT+PE
59% with provoked event
17% prior VTE

16. Primary Efficacy Results
P-value < for rivaroxaban 20 mg vs aspirin
P-value < for rivaroxaban 10 mg vs aspirin
P-value = 0.42 for rivaroxaban 20 mg vs rivaroxaban 10 mg comparison

17. Efficacy Results Outcomes Rivaroxaban 20 mg PO daily (n=1107)
Aspirin 100 mg (n=1131)
p-value
20 mg vs ASA
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,
6 (0.5)
5 (0.4)
19 (1.7)
Fatal VTE, n (%)
2 (0.2)
0 (0)
MI, ischemic stroke, systemic embolism;
3 (0.3)
7 (0.6%)

18. Safety Results Outcomes Rivaroxaban 20 mg PO daily (n=1107)
Aspirin 100 mg (n=1131)
p-value
20 mg vs ASA
10 mg vs ASA
Major bleeding, n (%)
6 (0.5)
5 (0.4)
3 (0.3)
0.32
0.50
Clinically relevant nonmajor bleeding, n (%)
30 (2.7)
22 (2.0)
20 (1.8)
0.14
0.78
Non-major bleeding associated with study drug interruption for more than 14 days, n (%)
17 (1.5)
12 (1.1)
0.33
0.96

19. 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

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

21. 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

22. 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

23. Acknowledgements Paul Dobesh, PharmD, FCCP, BCPS-AQ Cardiology
J. Erin (Allender) Ledford, PharmD, BCPS-AQ Cardiology, BCCCP
Janna Beavers, PharmD, BCPS

24. Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism (EINSTEIN CHOICE)
Ryan Sparks, PharmD, BCPS
PGY2 Cardiology Resident
WakeMed Health & Hosptials
Raleigh, NC

25. Announcements
Please join us June 27th 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).