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Risks for Stroke, Bleeding, and Death in Patients With Atrial Fibrillation Receiving Dabigatran or Warfarin in Relation to the CHADS2 Score: A Subgroup Analysis of the RE-LY Trial
Study Questions:
What is the prognostic importance of the CHADS2 risk score in terms of stroke, bleeding, and death in patients with atrial fibrillation receiving the vitamin K antagonist warfarin and the direct thrombin inhibitor dabigatran?
Methods:
The authors reported a subgroup analysis of the RE-LY trial, a randomized, open-label study of two blinded doses of dabigatran (150 mg or 110 mg twice daily) versus open-label warfarin in patients with nonvalvular atrial fibrillation with at least one risk factor for stroke. Baseline CHADS2 score (1 point each for congestive heart failure, hypertension, age >75 years, and diabetes, and 2 points for stroke) was recorded for each subject. Endpoints included the original study primary outcome of stroke or systemic embolism, the primary safety outcome of major bleeding, and intracranial hemorrhage, vascular death, and total mortality rate. Event rates per 100 patient-years were stratified by treatment and CHADS2 risk group. Cox proportional hazards regression models were used to compare the cumulative event rates within three CHADS2 risk groups.
Results:
There were 18,112 subjects randomized to the three treatment groups. Distribution of CHADS2 scores were: low risk 0 to 1—(5,775 patients); medium risk 2—(6,455 patients); and high risk 3 to 6—(5,882 patients). Annual rates of stroke or systemic embolism in these three groups were: 0.93%, 1.22%, and 2.24%, for the low, medium, and high CHADS2 risk groups, respectively. Annual rates of other outcomes in the three CHADS2 risk groups, respectively, were: for major bleeding, 2.26%, 3.11%, and 4.42%; for intracranial bleeding, 0.31%, 0.40%, and 0.61%; and for vascular mortality, 1.35%, 2.39%, and 3.68% (p < 0.001 for all comparisons). Increasing CHADS2 score was associated with increased rates of all endpoints evaluated. While only the higher dose of dabigatran was associated with lower rates of stroke or systemic embolism than warfarin, both doses of dabigatran were associated with significantly lower rates of intracranial hemorrhage than warfarin (roughly 60% reduction). These comparisons between dabigatran and warfarin did not differ very significantly among CHADS2 risk groups.
Conclusions:
The authors concluded that higher CHADS2 scores were associated with increased risks for stroke or systemic embolism, bleeding, and death in patients with atrial fibrillation receiving oral anticoagulants.
Perspective:
When evaluating this latest report from the RE-LY study, it must be kept in mind that this subgroup analysis was not prespecified. Nonetheless, there are important messages to take away from this study. First and foremost, is the observation that CHADS2 score appears to predict not only cerebral and systemic embolism rate, as it was designed to do, but also appears to be associated with risk of major bleeding, vascular mortality, and even intracranial hemorrhage. Thus, while the CHADS2 score can be used to estimate a patient’s risk of thromboembolism in the setting of nonvalvular atrial fibrillation, it also appears to be a surrogate for the risk of complications from anticoagulation. The second important message to take from this study is the repeat observation that the risk of intracranial hemorrhage, possibly the most feared complication of anticoagulant therapy, is dramatically reduced with dabigatran compared with warfarin.
Keywords: Stroke, Intracranial Hemorrhages, Heart Failure, Risk Factors, Hypertension
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