Indirect Comparisons of New Oral Anticoagulant Drugs for Efficacy and Safety When Used for Stroke Prevention in Atrial Fibrillation

Study Questions:

What is the relative safety and efficacy of dabigatran etexilate (two doses), rivaroxaban, and apixaban, compared with each other for stroke prevention in atrial fibrillation (AF)?

Methods:

Lacking any direct head-to-head comparison data, the authors used data from large phase III clinical trials of stroke prevention in atrial fibrillation (AF) for the new oral direct thrombin inhibitor dabigatran, and the oral factor Xa inhibitors rivaroxaban and apixaban. Using the data from the RE-LY, ROCKET-AF, and ARISTOTLE clinical trials, the authors performed a Bucher method for indirect comparisons using a common comparator. This statistical method allows for estimating hazard rate ratios and corresponding uncertainties. The authors assessed proportions/risk for all baseline demographic and clinical characteristics, and then compared the different studies in terms of risk differences to quantify any difference between the trials. The endpoints of interest were the primary efficacy endpoint of all stroke and systemic embolism, and the primary safety endpoint for all trials except the ROCKET-AF study was major bleeding by International Society on Thrombosis and Hemostasis (ISTH) criteria.

Results:

The authors reported that there was a significantly lower risk of stroke and systemic embolism (by 26%) for dabigatran at the higher dose (150 mg BID) compared with rivaroxaban. No differences were found for apixaban versus dabigatran or rivaroxaban. For the endpoint of ischemic stroke, there were no differences among the new oral anticoagulants. Apixaban had a significantly lower rate of bleeding compared with dabigatran at the higher dose (150 mg BID) (by 26%), and rivaroxaban (by 34%); but not lower than dabigatran 110 mg BID. For the endpoints of major or clinically relevant bleeding, apixaban was again better than rivaroxaban (by 34%). Dabigatran 110 mg BID was associated with less major bleeding (by 23%) and intracranial hemorrhage (by 54%) than rivaroxaban. Myocardial infarction rates did not differ between dabigatran (at both doses) and apixaban.

Conclusions:

The authors concluded that, notwithstanding the limitations of an indirect comparison study, they found no profound significant differences in efficacy between apixaban and dabigatran etexilate (both doses) or rivaroxaban. The authors also observed that dabigatran 150 mg BID was superior to rivaroxaban for some efficacy endpoints, whereas major bleeding was significantly lower with dabigatran 110 mg BID or apixaban. Finally, the authors pointed out that only a head-to-head direct comparison of the different new oral anticoagulants would fully answer the question of efficacy/safety differences between the new drugs for stroke prevention in AF.

Perspective:

It is very important to keep in mind the limitations of a study such as this. Re-analysis of clinical trial data will obviously recapitulate the same findings. It is important to remember that such an analysis does not present new or additional findings, but rather an alternative method to interpreting the existing findings. Nonetheless, given the robust and rigorous nature of these studies, this paper offers a best-available-data observation on the relative safety and efficacy of the new oral anticoagulants. At this point, the major clinical decision to make for patients in atrial fibrillation remains anticoagulation versus none. For those patients whom the clinician decides to anticoagulate, the next decision is warfarin versus a novel oral anticoagulant. It is currently premature to identify which, if any, of these new agents is superior to the others.

Clinical Topics: Anticoagulation Management, Dyslipidemia, Lipid Metabolism, Novel Agents

Keywords: Myocardial Infarction, Stroke, Thrombin, Morpholines, Thiophenes, Warfarin, Pyrazoles, Pyridines, Hemostasis, Blood Coagulation, Intracranial Hemorrhages, beta-Alanine, Benzimidazoles, Thrombosis, Embolism, Factor Xa, Pyridones


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