Abstract
BackgroundA number of novel oral anticoagulants (direct thrombin inhibitors or factor Xa inhibitors) are in clinical use for various indications. The dosing regimens differ between twice-daily and once-daily dosing for the prevention of stroke in patients with atrial fibrillation. With the availability of the results from four phase 3 studies (>70,000 patients), we explored whether twice-daily or once-daily dosing provides better risk-benefit balance among novel oral anticoagulants.MethodsWe conducted a strict, stepwise, fixed-effects meta-analysis with predefined heterogeneity quality criteria to generate the most appropriate common estimates for twice-daily (BID) or once-daily (QD) dosing regimens. An indirect comparison of these dosing regimens with fixed-effects meta-analysis common estimates (where available), or individual compound results, was done respectively.ResultsComparing indirectly BID vs QD dosing regimens resulted in hazard ratios (HR [95% confidence interval]) for stroke and systemic embolism of 0.75 (0.58–0.96) for dabigatran 150 mg BID, and 0.91 (0.73–1.13) for apixaban BID vs the QD dosing regimen. For ischemic stroke, the HR of BID vs QD was 0.85 (0.69–1.05). For intracranial hemorrhage, BID vs rivaroxaban QD was 0.57 (0.37–0.88) and, vs edoxaban QD, 0.81 (0.54–1.22). Due to heterogeneity, common estimates for major bleeding QD or BID were not justified, therefore indirect comparison of regimens were not possible. All non-vitamin K antagonist oral anticoagulants reduced all-cause mortality vs warfarin with a HR of 0.90 (0.86–0.96) without differences between regimen.ConclusionsBased on the available phase 3 study evidence, the twice-daily dosing regimen of non-vitamin K antagonist oral anticoagulants appears to offer a more balanced risk-benefit profile with respect to stroke prevention and intracranial hemorrhage.
Highlights
For stroke prevention in patients with atrial fibrillation (AF), four landmark phase 3 trials with non-vitamin K antagonist oral anticoagulants (NOACs, previously referred to as new or novel oral anticoagulants) have been published [1,2,3,4,5], each showing that NOACs were more or effective, while providing an improved safety profile compared with warfarin
We conducted a prespecified fixed-effects meta-analysis (FEM) of four published pivotal phase 3 trials for the prevention of stroke and systemic embolism with novel oral anticoagulants: the Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY), Rivaroxaban oncedaily oral direct Factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET-AF), the Apixaban for the reduction of Stroke and other thromoboembolic events in subjects with atrial fibrillation (ARISTOTLE), and Global study to assess the safety and effectiveness of edoxaban (DU-176b) versus standard practice of dosing with warfarin in patients with atrial fibrillation (ENGAGE-AF) trials [1,2,3,4,5]
With a HR of 0.90, all NOACs showed a 10% reduction in allcause mortality when compared with warfarin (Tables 2 and 3)
Summary
For stroke prevention in patients with atrial fibrillation (AF), four landmark phase 3 trials with non-vitamin K antagonist oral anticoagulants (NOACs, previously referred to as new or novel oral anticoagulants) have been published [1,2,3,4,5], each showing that NOACs were more or effective, while providing an improved safety profile compared with warfarin (target international normalized ratio 2–3).One important differentiating aspect between the NOACs studied is the dosing regimen, daily (QD) or twice-daily (BID) dosing, which will be part of the decision-making process to select the most appropriate drug for a particular patient. Apart from the dosing schedule, there are other essential clinical factors, such as age, grade of renal impairment, and overall risk of bleeding, which guide the selection of a specific NOAC. In this manuscript, we will concentrate on the dosing regimen (BID vs QD) because our hypothesis is that, for these NOACs. Clearance: non-renal/renal of absorbed dose if normal renal function. With the availability of the results from four phase 3 studies (.70,000 patients), we explored whether twice-daily or once-daily dosing provides better risk-benefit balance among novel oral anticoagulants
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