Rivaroxaban real world evidence

1. The Power of Real World
Evidence
Rivaroxaban Real World Evidence

2. Real world evidence (RWE) - Are we (RWE) ready?
Real-world
evidence, or RWE, is
fundamentally
changing the future
of healthcare.
Here’s how it
happens:
● Real-world data (RWD) is aggregated and transformed into RWE
through robust analytics.
● Real-world evidence (RWE) provides clinically-rich insights into
what actually happens in everyday practice and why.
● Stakeholders across the healthcare ecosystem use this new
knowledge to support decision-making and improve safety and
effectiveness, and ultimately, patient outcomes.
RWE: Real World Evidence
Real-World Evidence [Internet]. U.S. Food and Drug Administration. 2022 [cited 18 July 2022]. Available from: https://www.fda.gov/science-research/science-and-research-special-topics/real-world-evidence

3. Perspectives on Real World Evidence Data ​
Prospective
registries/non-
interventional studies
● Understanding of treatment patterns, adherence/
persistence, safety, comparative effectiveness
resource use and patient reported outcomes
Retrospective
comparative clinical or
claims database studies
● Understanding of treatment patterns, persistence,
safety, effectiveness, healthcare resource use
Roberts MH, Ferguson GT. Real-World Evidence: Bridging Gaps in Evidence to Guide Payer Decisions. Pharmacoecon Open. 2021 Mar;5(1):3-11. doi: 10.1007/s41669-020-00221-y. PMID: 32557235; PMCID: PMC7895868.

4. Rivaroxaban Provides a Consistent and​ Unique
Dataset Covering the Full Patient-Risk Spectrum ​
1. Beyer-Westendorf J et al, Blood 2014;124;955–962; 2. Tamayo S et al, Clin Cardiol 2015;38:63–68;​ 3. Coleman C et al, Int J Card Med 2015;203:882–884; 4. Camm AJ et al, Eur Heart J 2015;doi:10.1093/eurheartj/ehv466​

5. Rivaroxaban is evidenced across the full
CHADS2-scores risk spectrum.
*Major bleeding definition according to ISTH; #modified ISTH definition (additionally included surgical revision from bleeding);​ ‡major bleeding defined by the Cunningham algorithm6; §No major bleeding cohort (representative of
>98% of the patient population)​
1. Patel MR et al, N Engl J Med 2011;365:883–891; 2. Beyer-Westendorf J et al, Blood 2014;124;955–962; 3. Beyer-Westendorf J et al. Presented at ESC 2013: abstract P4870; 4. Tamayo S et al, Clin Cardiol 2015;38:63–68;
5. Camm AJ et al, Eur Heart J 2015;doi:10.1093/eurheartj/ehv466;​ 6. Cunningham A et al, Pharmacoepidemiol Drug Saf 2011;20:560–566​
Trial Randomized
clinical trial
ROCKET AF1*
n=7,111
Prospective
registry
Dresden NOAC2,3#
n=1,200
Retrospective
database
US DoD PMSS4‡
n=27,476
Observational
study XANTUS5*
n=6,784
Mean CHADS​2
score
3.5 2.4 2.2§ 2.0
RISK

6. XANTUS
A real-world, prospective, observational study of patients treated
with rivaroxaban for stroke prevention in atrial fibrillation
A. John Camm, Pierre Amarenco, Sylvia Haas, Susanne Hess, Paulus Kirchhof, Silvia Kuhls, Martin van Eickels, Alexander G.G. Turpie, the XANTUS Investigators, XANTUS: a real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial
fibrillation, European Heart Journal, Volume 37, Issue 14, 7 April 2016, Pages 1145–1153, https://doi.org/10.1093/eurheartj/ehv466

7. XANTUS: First Published, Prospective, International,
Observational Study of a NOAC in Non-valvular atrial fibrillation
(NVAF) Patients.
➢ Objective:
○ Investigate the safety and efficacy of rivaroxaban in routine clinical use in the
NVAF setting.
○ 311 center, 6784 patients with NVAF newly started on rivaroxaban,
○ Followed up for 1 year (at 3 months intervals).
➢ Major outcomes:
○ Major bleeding
○ Symptomatic thromboembolic events (stroke, SE, TIA, and MI)
○ All-cause death
NVAF: Non-valvular atrial fibrillation
A. John Camm, Pierre Amarenco, Sylvia Haas, Susanne Hess, Paulus Kirchhof, Silvia Kuhls, Martin van Eickels, Alexander G.G. Turpie, the XANTUS Investigators, XANTUS: a real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation, European Heart
Journal, Volume 37, Issue 14, 7 April 2016, Pages 1145–1153, https://doi.org/10.1093/eurheartj/ehv466

8. XANTUS real world evidence reflects the patients seen frequently
in general practice.
1. Camm AJ et al, Eur Heart J 2015;doi:10.1093/eurheartj/ehv466; 2. Patel MR et al, N Engl J Med 2011;365:883–891​
2

9. Xantus and ROCKET AF results
*Not intended as cross study comparison
1. Camm AJ et al, Eur Heart J 2015;doi:10.1093/eurheartj/ehv466; 2. Patel MR et al, N Engl J Med 2011;365:883–891​
1,2
Much lower incidence
of GI bleeding and
major bleeding in real
life practice.

10. Atrial fibrillation patients in ROCKET AF had higher risk of stroke than
patients in other phase III trials
1. Patel MR et al. N Engl J Med. 2011;365(10):883–891; 2. Connolly SJ et al. N Engl J Med. 2009;361(12):1139–1151; 3. Granger CB et al. N Engl J Med. 2011;365(11):981–992;

11. Atrial fibrillation patients in ROCKET AF had higher risk of stroke than
patients in other phase III trials
a. Connolly SJ et al. N Engl J Med. 2009;361(12):1139–1151; b. Patel MR et al. N Engl J Med. 2011;365(10):883–891; c. Granger CB et al. N Engl J Med. 2011;365(11):981–992;

12. XANTUS and ARISTOTLE population

13. Xantus and ARISTOTLE results
ARISTOTLE​
Efficacy 2​
*Events per 100 patient-years
1. Camm AJ et al, Eur Heart J 2015;doi:10.1093/eurheartj/ehv466; 2. Granger CB et al., N Eng J med 2011; 365:981-992.
XANTUS
Effectiveness 1

14. Xantus and ARISTOTLE results
*Events per 100 patient-years
1. Camm AJ et al, Eur Heart J 2015;doi:10.1093/eurheartj/ehv466; 2. Granger CB et al., N Eng J med 2011; 365:981-992.
XANTUS
Safety1
ARISTOTLE​
Safety 2​

15. ➢ Atrial fibrillation patients in ROCKET AF had higher risk of stroke (CHADS2 = 3.5) than
patients in other phase III trials.1-3
➢ The baseline stroke risk of patients in XANTUS (CHADS2 = 2.0) is similar to that of
other NOAC trials, such as RE-LY and ARISTOTLE (CHADS2 = 2.1).2-4
Summary
1. Patel MR et al. N Engl J Med. 2011;365(10):883–891; 2. Connolly SJ et al. N Engl J Med. 2009;361(12):1139–1151; 3. Granger CB et al. N Engl J Med. 2011;365(11):981–992; 4.A. John Camm, et al. European Heart Journal,
Volume 37, Issue 14, 7 April 2016, Pages 1145–1153.
➢ Conclusion:
○ Rate of stroke and major bleeding were low in patients receiving rivaroxaban in
routine clinical practice.4

16. The REVISIT-US study
Real-world evidence of stroke prevention in patients with non-
valvular atrial fibrillation in the United States.
Coleman CI et al. Real-world EVIdence on Stroke prevention In patients with aTrial Fibrillation in the United States [Presentation at ECAS 2016] Available
at:http://clinicaltrialresults.org/Slides/REVISIT_US_Slides.pptx​

17. The REVISIT-US study 1
➢ Objective:
○ To assess the real-world effectiveness and safety of newly-initiated rivaroxaban or
apixaban compared to warfarin in NVAF patients​.
➢ Phase III clinical trial data (ROCKET AF2 and ARISTOTLE3) demonstrated the favorable
efficacy and safety profiles of rivaroxaban and apixaban vs. vitamin K antagonists
(VKAs)​.
➢ Real-world evidence is needed to confirm the magnitude of benefits and risks in routine
clinical practice.
1. Coleman CI et al. Real-world EVIdence on Stroke prevention In patients with aTrial Fibrillation in the United States [Presentation at ECAS 2016] Available at :http://clinicaltrialresults.org/Slides/REVISIT_US_Slides.pptx​; 2.
Patel MR et al. N Engl J Med. 2011;365(10):883–891;; 3.Granger CB et al. N Engl J Med. 2011;365(11):981–992

18. The REVISIT-US study
➢ Study design:
○ Included rivaroxaban and apixaban patients starting on their individual FDA
approval dates. ​
○ Matched them to warfarin patients initiated during the same time frame.​
➢ Patients were followed until:
○ The occurrence of a primary event. ​
○ Discontinuation/switch of therapy​.
○ Disenrollment, or end of the study.​
➢ Combined endpoint of Ischemic Stroke and Intracranial hemorrhage.​
Coleman CI et al. Real-world EVIdence on Stroke prevention In patients with aTrial Fibrillation in the United States [Presentation at ECAS 2016] Available at:http://clinicaltrialresults.org/Slides/REVISIT_US_Slides.pptx​

19. 38,831 PATIENTS MET SELECTION CRITERIA ​
(RIVAROXABAN VS. WARFARIN)​
Coleman CI et al. Real-world EVIdence on Stroke prevention In patients with aTrial Fibrillation in the United States [Presentation at ECAS 2016] Available at:http://clinicaltrialresults.org/Slides/REVISIT_US_Slides.pptx​
Rivaroxaban vs Warfarin Characteristics of included patients (matched cohorts)​
Parameter​
Rivaroxaban​
(n=11,411)​
7,715 PYs*​
Warfarin ​
(n=11,411)​
6,271 PYs*​
Age in years, mean (SD)​ 70.7 (10.99)​ 70.7 (11.35)​
Male, %​ 53.6​ 53.9​
CHADS2 score, 180 day; ​
mean (SD)​
1.92 (1.08)​ 1.94 (1.08)​
CHA2DS2-VASc score, 180 day;​
mean (SD)​
3.46 (1.37)​ 3.48 (1.35)​
HAS-BLED Score, 180 day; ​
mean (SD)​
1.62 (0.69)​ 1.62 (0.71)​
Reduced dose, %​ 17.3​ NA​

20. 18,591 PATIENTS MET SELECTION CRITERIA ​
(APIXABAN VS. WARFARIN)​
Coleman CI et al. Real-world EVIdence on Stroke prevention In patients with aTrial Fibrillation in the United States [Presentation at ECAS 2016] Available at:http://clinicaltrialresults.org/Slides/REVISIT_US_Slides.pptx​
Apixaban vs Warfarin
Characteristics of included patients (matched cohorts)
Parameter
Apixaban
(n=4,083)
2,125 PYs*
Warfarin
(n=4,083)
1,951 PYs*
Age in years, mean (SD) 71.15 (11.32) 71.00 (11.25)
Male, % 53.2 53.6
CHADS2 score, 180 day;
mean (SD)
1.93 (1.07) 1.92 (1.07)
CHA2DS2-VASc score, 180 day; mean
(SD)
3.47 (1.38) 3.47 (1.35)
HAS-BLED Score, 180 day;
mean (SD)
1.65 (0.69) 1.66 (0.72)
Reduced dose, % 15.5 NA

21. The REVISIT-US study: Rivaroxaban Results
➢ Rivaroxaban was associated vs warfarin with:​
➢ Significant 47% reduction in ICH.​
➢ 29% decrease in ischemic stroke (P=NS)​.
➢ Significant 39% reduction in the combined endpoint of ICH and ischemic stroke​.
Coleman CI et al. Real-world EVIdence on Stroke prevention In patients with aTrial Fibrillation in the United States [Presentation at ECAS 2016] Available at:http://clinicaltrialresults.org/Slides/REVISIT_US_Slides.pptx​

22. The REVISIT-US study: Rivaroxaban Conclusion
➢ Rivaroxaban significantly reduced the combined endpoint of ischemic stroke and
ICH​.1
○ These results are generally consistent with that of ROCKET AF2 and XANTUS 3​.
1. Coleman CI et al. Real-world EVIdence on Stroke prevention In patients with aTrial Fibrillation in the United States [Presentation at ECAS 2016] Available at:http://clinicaltrialresults.org/Slides/REVISIT_US_Slides.pptx​ 2.
Patel MR et al. N Engl J Med. 2011;365(10):883–891; 3. Camm AJ et al, Eur Heart J 2015;doi:10.1093/eurheartj/ehv466.

23. The REVISIT-US study:Apixaban Results
➢ Apixaban was associated vs warfarin with:
➢ Significant 62% reduction in ICH vs. warfarin.​
➢ 13% increase (p=NS) in ischemic stroke vs. warfarin .​
➢ 37% reduction (p=NS) in the combined endpoint of ICH and ischemic stroke​.
Coleman CI et al. Real-world EVIdence on Stroke prevention In patients with aTrial Fibrillation in the United States [Presentation at ECAS 2016] Available at:http://clinicaltrialresults.org/Slides/REVISIT_US_Slides.pptx​

24. The REVISIT-US study: Apixaban Conclusion
➢ Apixaban didn’t significantly reduce the combined endpoint of ischemic stroke
and ICH.​1
○ Observed HRs were less consistent with those seen in ARISTOTLE 2 ,
Particularly 13% increased hazard of ischemic stroke, p=NS.
*P<0.05
1. Coleman CI et al. Real-world EVIdence on Stroke prevention In patients with aTrial Fibrillation in the United States [Presentation at ECAS 2016] Available at:http://clinicaltrialresults.org/Slides/REVISIT_US_Slides.pptx​. 2.
Granger CB et al. N Engl J Med. 2011;365(11):981–992;

25. The REVISIT-US study: Summary
Coleman CI et al. Real-world EVIdence on Stroke prevention In patients with aTrial Fibrillation in the United States [Presentation at ECAS 2016] Available at:http://clinicaltrialresults.org/Slides/REVISIT_US_Slides.pptx​
Significant
- 47%
non-
Significant
- 29%
Significant
- 39%
ICH
Ischemic Stroke
ICH
+
Ischemic Stroke
Significant
- 62%
non-
Significant
+13%
non-
Significant
- 37%
Rivaroxaban​-
Most Favorable Net
Clinical Benefit​
42%​ Difference​
Rivaroxaban​ Apixaban

26. The REVISIT-US study: Summary
➢ This study was designed to optimize internal validity (obtain the most unbiased HR
estimates), however caution is warranted when comparing these results to Phase
III trials​.1
➢ It provides reassurance that both oral agents have lower ICH rates vs. warfarin in
routine practice​.1
➢ Rivaroxaban significantly reduced the combined endpoint of ischemic stroke and
ICH.1 These results are generally consistent with that of ROCKET AF2 and
XANTUS.3
➢ Observed apixaban HRs were less consistent with those seen in ARISTOTLE 4
(particularly 13% increased hazard of ischemic stroke, p=NS)​
1. Coleman CI et al. Real-world EVIdence on Stroke prevention In patients with aTrial Fibrillation in the United States [Presentation at ECAS 2016] Available at:http://clinicaltrialresults.org/Slides/REVISIT_US_Slides.pptx​ 2.
Patel MR et al. N Engl J Med. 2011;365(10):883–891; 3. Camm AJ et al, Eur Heart J 2015;doi:10.1093/eurheartj/ehv466. 4. Granger CB et al., N Eng J med 2011; 365:981-992.

27. Safety Profile of Rivaroxaban confirmed through Real-World Evidence
regardless of Data Source
*Major bleeding definition according to ISTH; #modified ISTH definition (additionally included surgical revision from bleeding);​ ‡major bleeding defined by the Cunningham algorithm6; §No major bleeding cohort (representative of
>98% of the patient population)​
1. Patel MR et al, N Engl J Med 2011;365:883–891; 2. Beyer-Westendorf J et al, Blood 2014;124;955–962; 3. Beyer-Westendorf J et al. Presented at ESC 2013: abstract P4870; 4. Tamayo S et al, Clin Cardiol 2015;38:63–68;
5. Camm AJ et al, Eur Heart J 2015;doi:10.1093/eurheartj/ehv466;​ 6. Cunningham A et al, Pharmacoepidemiol Drug Saf 2011;20:560–566​

28. Real World Evidence with Rivaroxaban ​
➢ Prospective study XANTUS provides
unique RWE in SPAF​1
- Versus ROCKET AF: Complimentary in
Baseline Characteristics and consistent
in Outcomes​.
- Versus ARISTOTLE : Similar patient
populations might lead to similar
efficacy and safety outcomes​.
1. Camm AJ et al, Eur Heart J 2015;doi:10.1093/eurheartj/ehv466; 2. Coleman CI et al. [Presentation at ECAS 2016] Available at:http://clinicaltrialresults.org/Slides/REVISIT_US_Slides.pptx​; 3. Beyer-Westendorf J, et al.
Europace. 2016;18(8):1150-1157.
➢ Retrospective Database Analysis
REVISIT US further confirms​2
- Favorable efficacy and safety profile of
Rivaroxaban vs Warfarin​.
- Rivaroxaban significantly reduced the
combined endpoint of ischemic stroke
and ICH.
Real world Data demonstrates a consistent balance relative to the
safety and efficacy of Rivaroxaban when used in clinical practice.

29. THANK
YOU!