Results from real-world studies are not intended for comparisons with clinical trials. Real-world studies were observational trials. Differences in study designs, patient populations, outcome definitions, and methods of collecting data make it difficult to make comparisons with clinical trials or with each other. Real-world data should be viewed as complementary information.
Stroke, bleeding, and mortality risks in elderly Medicare beneficiaries treated with dabigatran or rivaroxaban for nonvalvular atrial fibrillation.6
Note
There are no randomized head-to-head comparisons of PRADAXA and rivaroxaban for safety
and efficacy.
Objective
Assess primary outcomes of:
- Thromboembolic stroke
- Intracranial hemorrhage
- Major extracranial bleeding, including gastrointestinal bleeding
- Mortality
Method
- Retrospective, observational FDA- & CMS-funded analysis under SafeRx program
- 118,891 patients ≥65 years old with NVAF enrolled in Medicare
- PRADAXA 150 mg BID or rivaroxaban 20 mg QD
- From November 2011- June 2014
- Differences in baseline characteristics were adjusted using stabilized inverse probability of treatment weights based on propensity scores
Effects of
PRADAXA 150 mg vs rivaroxaban 20 mg
in elderly Medicare beneficiaries study
Primary Outcomes
|
Crude (unadjusted) incidence rate per 1000 person-years (No. of events)
|
Adjusted incidence rate difference per 1000 person-years‖
|
Hazard ratio (95% CI)
|
|
PRADAXA (n=52,240)
|
Rivaroxaban (n=66,651)
|
Crude
|
Adjusted
|
Thromboembolic stroke
|
9.7 (150)
|
7.7 (156)
|
1.8
|
0.80 (0.64, 1.00)
|
0.81 (0.65, 1.01)
|
Intracranial hemorrhage
|
3.7 (58)
|
5.8 (118)
|
2.3
|
1.58 (1.15, 2.16)
|
1.65 (1.20, 2.26)
|
Major extracranial bleeding event
|
26.6 (413)
|
39.4 (796)
|
13.0
|
1.47 (1.31, 1.66)
|
1.48 (1.32, 1.67)
|
Gastrointestinal
|
23.3 (362)
|
32.5 (656)
|
9.4
|
1.39 (1.22, 1.58)
|
1.40 (1.23, 1.59)
|
Mortality
|
22.2 (346)
|
24.7 (500)
|
3.1
|
1.12 (0.98, 1.29)
|
1.15 (1.00, 1.32)
|
‖Adjusted incidence rate difference = (rivaroxaban adjusted rate) – (PRADAXA adjusted rate).
Results
Compared to PRADAXA, treatment with rivaroxaban was associated with
increased rates of intracranial hemorrhage, major extracranial bleeding,
including major gastrointestinal bleeding, and mortality. Rivaroxaban use
was associated with a non-significant reduction in thromboembolic stroke.
Limitations
- Mean follow-up time of <4 months led to a smaller sample size at longer
durations of use
- Participants restricted to patients aged ≥65 years—while this age group
accounts for 80% of patients with NVAF, the comparative effects of
treatment with PRADAXA and rivaroxaban could be different in younger
populations
- Study was observational, and so may also be subject to residual
confounding by unmeasured factors
-
Study examined first-time users of PRADAXA and rivaroxaban; results could
differ in patients switching from warfarin to a NOAC
Funding/Support: This study was performed as part of the SafeRx project, a joint initiative of the Centers for Medicare & Medicaid
Services (CMS) and the US Food and Drug Administration (FDA), and was funded through an interagency agreement. Role of
the Funder/Sponsor: The authors are employees or contractors of the CMS or the FDA; however, other officials at the CMS
and the FDA had no role in the design and conduct of the study; collection, management, analysis, and interpretation of
the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Disclaimer: The views expressed are the authors’ and not necessarily those of the FDA, the CMS, or the Department of Health and Human Services.
FDA Mini-Sentinel Assessment7
50,000+ NVAF Patients
The U.S. FDA retrospective observational assessment of a NOAC
investigated actual rates of GI
and intracranial hemorrhage for new users of PRADAXA and warfarin.
Sponsored by the FDA
Pilot project to create an active surveillance system using pre‑existing electronic healthcare data from multiple sources to assess the safety of approved drugs and other medical products.
Key Study Findings7
- Bleeding rates associated with PRADAXA did not appear to be higher than those associated with warfarin
FDA Medicare Study8
134,000+ NVAF Patients
The U.S. FDA retrospective observational study evaluated the safety and effectiveness of PRADAXA vs. warfarin in
patients 65 years or older.
Pooled analysis of PRADAXA 150 mg BID/75 mg BID vs. warfarin in FDA Medicare Study¶8
Key Study Findings8
Ischemic Stroke |
Intracranial Hemorrhage |
Death |
Major GI Bleeding |
Major Bleeding |
Lower Risk |
Lower Risk |
Lower Risk |
Increased Risk |
Similar Risk** |
¶Because of covariate imbalances between dabigatran and
warfarin cohorts after stratification by dose, patients were
rematched within strata defined by daily dabigatran dose,
resulting in a total of 67,098 patients in each cohort rather
than 67,2017 from the primary analysis.8
**
The rate of major bleeding was analyzed by pooling 75-mg and 150-mg dose results.
Meta-analysis of 20 Studies††9
A systematic review and meta-analysis of retrospective observational studies of 711,000+ NVAF patients.
Key Study Findings9
Ischemic Stroke |
Intracranial Hemorrhage |
Death |
Any GI Bleeding |
Major Bleeding |
Lower Risk |
Lower Risk |
Lower Risk |
Increased Risk |
Lower Risk |
††
Studies analyzed 75-mg, 110-mg, and 150-mg dose results. While studied in the RE‑LY® pivotal trial, the 110-mg
dose is not approved for use in patients with NVAF.9
Meta-analysis included data from: Department of Defense study10 and Brigham and Women's study.11
US Administrative Claims Study‡‡12
A retrospective analysis of the safety and effectiveness of PRADAXA vs. warfarin.
Pooled analysis of PRADAXA 150 mg/75 mg BID vs warfarin in US Administrative Claims Study12
Key Study Findings12
Stroke/SE |
Ischemic Stroke |
Intracranial Hemorrhage |
Major GI Bleeding |
Major Bleeding |
Similar Risk |
Similar Risk |
Lower Risk |
Similar Risk |
Lower Risk |
Findings were generally similar to those of the RE‑LY® Trial, with
the exception of GI bleeding, which was significantly higher in
patients treated with PRADAXA vs. warfarin in RE‑LY.
‡‡Other NOACs were included in this study: rivaroxaban and apixaban.12
Are you a formulary decision maker?
Visit the PRADAXA Real-World Data Portal where you can:
- Access the latest assessments of PRADAXA in real-world studies
- Review analyses to help inform your formulary decisions
- Download studies to review at your convenience
- Receive e-mail notifications when new studies are added
HR=hazard ratio; CI=confidence interval.
References: 1. Pradaxa [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. 2. Data on file.
Boehringer Ingelheim Pharmaceuticals, Inc. 3. Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L; for the Randomized
Evaluation of Long-Term Anticoagulation Therapy Investigators. Newly identified events in the RE‑LY Trial [Letter to the Editor].
N Engl J Med. 2010;363(19):1875-1876. 4. Connolly SJ, Wallentin L, Yusuf S. Additional events in the RE‑LY Trial [Letter to the Editor].
N Engl J Med. 2014;371(15):1464-1465. 5. Connolly SJ, Wallentin L, Ezekowitz MD, et al. The long-term multicenter observational
study of dabigatran treatment in patients with atrial fibrillation (RELY-ABLE) study. Circulation. 2013;128(3):237-243.
6. Graham DJ, Reichman ME, Wernecke M, et al. Stroke, bleeding, and mortality risks in elderly Medicare beneficiaries
treated with dabigatran or rivaroxaban for nonvalvular atrial fibrillation. JAMA Intern Med. 2016;176(11):1662-1671.
7. Southworth MR, Reichman ME, Unger EF. Dabigatran and Postmarketing Reports of Bleeding. N Engl J Med. 2013;368:1272-1274.
8. Graham DJ, Reichman ME, Wernecke M, et al. Cardiovascular, bleeding, and mortality risks in elderly Medicare patients
treated with dabigatran or warfarin for non-valvular atrial fibrillation. Circulation. 2015;131(2):157-164. 9. Carmo J, Moscoso Costa
F, Ferreira J, Mendes M. Dabigatran in real-world atrial fibrillation. Meta-analysis of observational comparison studies with
vitamin K antagonists. Thromb Haemost.
2016;116(4):754-763. 10. Villines TC, Schnee J, Fraeman K, et al. A comparison of the safety and effectiveness of
dabigatran and warfarin in non‑valvular atrial fibrillation patients in a large healthcare system. Thromb Haemost. 2015;114(6):1290-1298. 11. Seeger JD, Bykov K, Bartels DB, et al. Safety and effectiveness of dabigatran and warfarin in routine care of
patients with atrial fibrillation. Thromb Haemost. 2015;114(6):1277-1289. 12. Yao X, Abraham NS, Sangaralingham LR, et al.
Effectiveness and safety of dabigatran, rivaroxaban, and apixaban versus warfarin in nonvalvular atrial fibrillation. J Am Heart Assoc. 2016;5(6):1-19.