Apixaban vs Warfarin for Atrial Fibrillation

Abstract & Commentary

By Michael H. Crawford, MD, Editor

Source: Hohnloser S, et al. Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: Insights from the ARISTOTLE trial. Eur Heart J 2012;33:2821-2830.

Atrial fibrillation (AF) and stroke are common in patients with chronic kidney disease (CKD), but many such patients are not anticoagulated for fear of bleeding complications. In the ARISTOTLE trial of apixaban vs warfarin for stroke prevention in AF, apixaban was associated with a 21% relative risk reduction in stroke, an 11% reduction in total mortality, and a 31% reduction in major bleeding, which were all statistically significant. Since apixaban is 25% eliminated by the kidneys, a secondary analysis of ARISTOTLE based on renal function was pre-specified and is the subject of this report.

There were 7518 patients with an estimated glomerular filtration rate (GFR) > 80 mL/min (42%), 7587 (42%) with a GFR of 50-80, and 3017 (15%) with a GFR < 50. Cystatin C levels also were available in 14,884 patients, permitting a second system for calculating GFR. Comorbidities, estimated stroke risk, and estimated bleeding risk were inversely related to GFR at baseline. Also, the actual incidence of cardiovascular events and bleeding was inversely related to GFR. The annual stroke rate was 1.05% in patients with a GFR > 80, 1.46% with a GFR between 50-80, and 2.39% with a GFR < 50. Also, major bleeding increased from 1.65% to 4.8% with decreasing renal function. Apixaban was associated with fewer strokes and less major bleeding regardless of GFR. These results were consistent irrespective of the method of GFR estimation. The relative risk reduction in major bleeding on apixaban was greater in patients with a GFR < 50 (hazard ratio 0.50; 95% confidence interval, 0.38-0.66; P = 0.005). The authors concluded that in patients with AF, decreasing GFR was associated with a higher risk of cardiovascular events and bleeding. Apixaban as compared to warfarin reduced these risks regardless of renal function, with the greatest benefit seen in reducing major bleeding in those with impaired renal function.


Of the new oral anticoagulants, apixaban is the only one to show superiority to warfarin in stroke reduction and safety. This prespecified subgroup analysis of ARISTOTLE represents the largest experience with AF in patients with CKD: more than 10,000 patients. The results were consistent with those of the main trial, despite the fact that a low GFR markedly increased the risk of a vascular event and bleeding complications. The risk of stroke and major bleeding more than doubled at GFRs < 50.

The authors postulate that the higher risk of bleeding on warfarin in CKD patients has diminished enthusiasm for treating these patients with oral anticoagulants. In this study, apixaban was shown to be superior to warfarin, especially in those with GFR < 50. This may change the enthusiasm level for anticoagulation in CKD patients with AF given the higher rate of cardiovascular events in these patients and the availability of a safer agent than warfarin. The study employed half of the usual dose of apixaban in those with a serum creatinine > 1.5 mg/dL, age > 80 years, or weight < 60 kg. Both dabigatran and rivaroxaban have similar dose adjustments for renal compromise, but not for age or weight. Dabigatran and apixaban are dosed twice a day, whereas rivaroxaban has the advantage of once daily dosing. My prediction is now that apixaban has been approved by the FDA, it will be the go-to agent for oral anticoagulation in patients with AF and CKD.