July 15, 2020Open Access
Apixaban for Stroke Prevention in Atrial Fibrillation: Why are Event Rates Higher in Clinical Practice than in Randomized Trials?—A Systematic Review
Key Result
Patients treated with apixaban in observational studies had a higher risk of stroke and systemic embolism compared to those in randomized controlled trials (RR 1.62), reflecting higher baseline risk profiles in clinical practice.
Study Design
Type
Systematic Review (n=167,156)
Structured PICO
Do differences in patient characteristics and apixaban dosing (2.5 mg vs 5 mg twice daily) explain the higher thromboembolic event rates observed in clinical practice compared to randomized trials?
P
Population
167,156 patients with atrial fibrillation taking apixaban for stroke prevention, included in 18 observational studies and 2 randomized controlled trials.
E
Exposure
Apixaban 2.5 mg twice daily
C
Comparator
Apixaban 5 mg twice daily
O
Outcome
Rates of stroke/systemic embolism, major bleeding, and mortalityhard clinical
Higher thromboembolic event rates with apixaban in clinical practice compared to RCTs are likely driven by higher baseline patient risk profiles and appropriate use of the reduced 2.5 mg dose in sicker patients, rather than solely inappropriate off-label dosing.
Main Result
Relative Risk: 1.62 (95% CI 1.19–1.64)
Absolute Event Rate: 1.8% vs 1.4%
Limitations
- Conclusion is based on analyses of nonrandomized data
- Indirect comparisons included only two randomized studies
- Proportion of off-label use was not reported by individual observational studies
- Modest number of patients were prescribed the 2.5-mg dose of apixaban in the RCTs
- Design does not provide definitive information on the criteria that should be used in clinical practice to select patients for apixaban dose reduction
Abstract
BACKGROUND: Recent reports suggest an important contribution from frequent off-label use of apixaban 2.5 mg twice daily to the higher rates of thromboembolic events observed in observational studies (OSs) relative to in randomized controlled trials (RCTs), and consequently, advocate against such use in all patients. OBJECTIVES: To examine factors contributing to the higher thromboembolic event rates, we estimated the prevalence of off-label use in contemporary practice, and compared patient characteristics and rates of stroke/systemic embolism, major bleeding, and mortality by apixaban dose and by study design in a systematic review and meta-analysis. RESULTS AND DISCUSSION: -VASc scores (mean 3.6 vs. 2.9) versus those in RCTs. We observed a consistent pattern of higher rates of thromboembolic events, bleeding, and mortality in patients treated with 2.5 versus 5 mg twice daily apixaban in both OSs and RCTs. CONCLUSION: The higher risk profiles of patients in OSs versus RCTs, and higher rates of both bleeding and mortality not attributable to thromboembolism in patients treated with apixaban 2.5 versus 5 mg twice daily suggest that differences in patient characteristics are additional important contributors to the higher than expected thromboembolic event rates in clinical practice.