New Oral Anticoagulant for Atrial Fibrillation

Abstract & Commentary

By John P. DiMarco, MD, PhD, Professor of Medicine, Division of Cardiology, University of Virginia, Charlottesville. Dr. DiMarco does research for Medtronic, is a consultant for Medtronic, Novartis, and St. Jude, and is a speaker for Boston Scientific.

Source: Granger CB, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-992.

This report is from the ARISTOTLE trial, which was just reported at the recent European Society of Cardiology meeting in Paris. Apixaban is a new direct oral factor Xa inhibitor with a favorable pharmacokinetic profile. This study compared apixaban to adjusted-dose warfarin in patients with nonvalvular atrial fibrillation. The trial had a double-blind, double-dummy trial design. Patients were randomly assigned to treatment with either apixaban or adjusted-dose warfarin. The primary objective was to compare apixaban to warfarin for reducing the risk of ischemic or hemorrhagic stroke or systemic embolism in atrial fibrillation patients. The primary safety outcome was major bleeding.

Patients were eligible for enrollment if they had documented atrial fibrillation and one or more risk factors for stroke. Patients with mitral valve disease, prosthetic heart valves, recent strokes, any need for continuous high-dose antiplatelet therapy, and moderate to severe renal insufficiency were excluded. Patients with a prior history of warfarin therapy were eligible but randomization was stratified according to prior warfarin usage. Apixaban, or matching placebo, was administered with the standard dose being 5 mg twice daily. A lower dose of 2.5 mg twice daily was used in a subset of patients if they had two or more of the following characteristics: age ≥ 80 years, body weight ≤ 60 kg, or a serum creatinine greater than 1.5 mg/dL. Warfarin was administered and the dose adjusted to achieve a target INR of 2.0 to 3.0. INRs were monitored with the use of a blinded and encrypted point-of-care INR device. An algorithm was provided to guide the adjustment of warfarin or matching placebo dose.

The primary efficacy endpoints were stroke and systemic embolism. Death from any cause and myocardial infarction were key secondary efficacy endpoints. The primary safety endpoint was the occurrence of major bleeding defined as clinically overt bleeding accompanied by a decrease in hemoglobin level of at least 2 g/dL, a requirement for a two-unit packed cell transfusion, or bleeding in a critical site or resulting in death. Efficacy and safety outcomes were adjudicated on the basis of prespecified criteria by a blinded clinical events committee.

Over a 40-month period, 18,201 patients were recruited at 1034 international sites. The groups were well balanced with regard to baseline characteristics with a median age of 70 years, a 65%:35% male:female gender ratio, and a means CHADS2 score of 2.1. Notably, 30% of the patients in both groups had CHADS2 scores ≥ 3. Vitamin K antagonists had previously been used in 57% of the patients and 19% had a history of a prior stroke, TIA, or systemic embolism.

The reduced dose of apixaban (2.5 mg twice daily) or placebo was administered to 428 patients in the apixaban group and 403 patients in the placebo group. Study drug discontinuation was observed in 25.3% of the patients on apixaban vs 27.5% in patients on placebo. Patients on warfarin had an INR in the therapeutic range, a median of 66% of the time.

Stroke or systemic embolism occurred in 212 patients in the apixaban group for an annual rate of 1.27%. In comparison, stroke or systemic embolism occurred in 265 patients in the warfarin group yielding a rate of 1.6% per year. The hazard ratio for the apixaban group was 0.79 with a 95% confidence interval of 0.66 to 0.95. The P value for noninferiority was less than 0.001 and equal to 0.01 for superiority. Hemorrhagic stroke was 49% lower in the apixaban group than in the warfarin group and ischemic or unclassifiable stroke was 8% lower in the apixaban group. The rate of fatal or disabling stroke was 0.5% per year in the apixaban group compared to 0.71% per year in the warfarin group. Among the patients who had ischemic strokes, hemorrhagic transformation was noted in 12 patients on apixaban and 20 patients on warfarin. Fatal strokes were noted in 42 patients in the apixaban group and 67 patients in the warfarin group. All-cause mortality was lower in the apixaban group (3.52% per year) than in the warfarin group (3.94% per year). There was no significant difference in the rate of myocardial infarction between the two groups (0.53% and 0.61%).

Major bleeding occurred at an annual rate of 2.13% in the apixaban group compared to 3.09% in the warfarin group. The rate of intracranial hemorrhage was reduced to 0.33% per year in the apixaban group compared to 0.80% per year in the warfarin group (hazard ratio 0.42; 95% confidence interval, 0.30 to 0.58; P < 0.0001). The rate for any bleeding was 25.8% per year in the warfarin group compared to only 18.1% in the apixaban group. Fatal bleeding occurred in 34 patients in the apixaban group compared to 55 patients in the warfarin group.

Subgroup analysis showed consistent beneficial effects of apixaban across all major subgroups. Overall, reported adverse events were equally distributed between the two groups. There were no differences in the frequency of abnormalities in liver function tests or liver related serious adverse events between the two groups.

The authors conclude that in patients with nonvalvular atrial fibrillation, apixaban is superior to warfarin for the prevention of stroke or systemic embolism with less risk for bleeding and a lower overall mortality.


This is the third large clinical trial showing that a new oral anticoagulant is noninferior or superior to warfarin for stroke prevention in patients with nonvalvular atrial fibrillation. Dabigatran, a direct thrombin inhibitor, was assessed in the RE-LY trial and the result of that trial led to dabigatran's FDA approval last year. Earlier this summer, the ROCKET AF trial compared rivaroxaban, a factor Xa inhibitor, to warfarin in a similar group of patients. The ARISTOTLE trial reported here again shows that a factor Xa inhibitor compares favorable to warfarin for this indication. I suspect that both rivaroxaban and apixaban will join dabigatran as being approved for this indication within the next year. Several similar agents are also in the clinical development pipeline.

These trials have been enormous, each enrolling more than 18,000 patients. It's unlikely there will be more than one or two such trials for each agent. There are no head-to-head comparisons available or, to my knowledge, planned directly comparing the new agents. Conclusions or claims based on comparisons across different trials are likely to be uncertain. I think we can say that the new agents at the tested doses are at least as effective and safe as adjusted-dose warfarin and certainly they will be easier to prescribe. If the increased cost of the new agents were not a factor, I would likely pick one and use it for initial therapy in most patients with nonvalvular atrial fibrillation. Right now, I don't see evidence that any of the new agents will be clearly superior, but we should watch closely for any later arising problems that may be seen during general usage.