July 4, 2026Circulation Population Health and Outcomes1 citations
View Full PaperBleeding Risk With Apixaban Versus Rivaroxaban: A Reference Trial Emulation Predicting the Results of COBRRA-VTE and COBRRA-AF Using US Health Care Claims
Key Result
Apixaban was associated with a 31% decreased risk of bleeding compared with rivaroxaban in patients with VTE (HR 0.69; 95% CI 0.59-0.79) and AF (HR 0.69; 95% CI 0.66-0.71).
Key Points
- This research aims to predict the bleeding risk of apixaban compared to rivaroxaban using health care claims data while emulating ongoing clinical trials.
- Emulated the COBRRA-VTE and COBRRA-AF trials using claims data from Medicare, Optum Clinformatics, and Merative MarketScan.
- Adjusted for confounding factors with 1:1 propensity score matching.
- The primary outcome was a composite of major and clinically relevant non-major bleeding events.
- In the COBRRA-VTE emulation (N=14,023 matched pairs), apixaban demonstrated a 31% decreased risk of bleeding (HR, 0.69; 95% CI, 0.59-0.79).
- For the COBRRA-AF emulation (N=176,990 matched pairs), apixaban also showed a 31% reduced risk (HR, 0.69; 95% CI, 0.66-0.71).
Study Design
Type
Cohort (n=382,026)
Multicenter
Yes
Structured PICO
Does apixaban reduce the risk of bleeding compared to rivaroxaban in patients with venous thromboembolism or atrial fibrillation?
P
Population
382,026 matched patients with venous thromboembolism (mean age 67, 55% women) or atrial fibrillation (mean age 74, 50% women) from 3 US health care claims databases.
E
Exposure
Apixaban
C
Comparator
Rivaroxaban (1:1 propensity score matching)
O
Outcome
Composite of major bleeding and clinically relevant non-major bleeding recorded in the inpatient settingsafety
In a large US claims database emulation of ongoing trials, apixaban was associated with a significantly lower risk of major and clinically relevant non-major bleeding compared to rivaroxaban in patients with VTE or AF.
Main Result
Hazard Ratio: 0.69 (95% CI 0.66–0.71)
Absolute Event Rate: 6.4% vs 9.2%
Abstract
BACKGROUND: Direct oral anticoagulants such as apixaban and rivaroxaban, have transformed the management of thromboembolic disorders. Randomized controlled trials were initiated in 2017 (COBRRA-VTE Comparison of Bleeding Risk Between Rivaroxaban and Apixaban for the Treatment of Acute Venous Thromboembolism) and 2021 (COBRRA-AF Comparison of Bleeding Risk Between Rivaroxaban and Apixaban in Patients With Atrial Fibrillation) to directly compare apixaban and rivaroxaban on the risk of bleeding in patients with venous thromboembolism (VTE) and atrial fibrillation (AF). We aimed to emulate the design and measurements of these ongoing trials and use US health care insurance claims data to predict their findings. METHODS: In cohort studies designed to emulate COBRRA-VTE (REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05264168) and COBRRA-AF (NCT05256797) in 3 US health care insurance claims databases (Medicare, Optum Clinformatics, Merative MarketScan), the risk of bleeding with apixaban was evaluated relative to the risk with rivaroxaban. Pretreatment confounding factors were adjusted for via 1:1 propensity score matching. The primary outcome was a composite of major bleeding and clinically relevant non-major bleeding (defined using International Classification of Diseases, Ninth Revision and Tenth Revision diagnosis codes) recorded in the inpatient setting. Results across databases were pooled using fixed-effects meta-analyses. Protocols were preregistered on ClinicalTrials.gov before inferential analyses were conducted. RESULTS: In the COBRRA-VTE emulation (N=14 023 matched pairs, mean age=67 years, 55% women), we observed a 31% decreased risk of bleeding for apixaban compared with rivaroxaban (incidence rate per 100 person-years: apixaban, 12.8; rivaroxaban, 19.1; hazard ratio, 0.69 95% CI, 0.59–0.79). For the COBRRA-AF emulation (N=176 990 matched pairs, mean age=74 years, 50% women), we similarly observed a 31% decreased risk for apixaban compared with rivaroxaban (incidence rate per 100 person-years: apixaban, 6.4; rivaroxaban, 9.2; hazard ratio, 0.69 95% CI, 0.66–0.71). CONCLUSIONS: In database studies that closely emulated the design and measurements of the COBRRA-VTE and COBRRA-AF trials, a substantially lower risk of bleeding with apixaban was observed, consistent with the results of COBRRA-VTE (published after completion of our analyses), and indirect comparisons from other trials.