Editor's Note: The following commentary is based on Granger C.B., Alexander J.H., McMurray J.J., et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2011;365:981-992.

Introduction

Atrial fibrillation (AF) is a major cause of stroke. Vitamin K antagonists are highly effective in stroke prevention in AF, though their use is limited by bleeding complications, food and drug interactions, need for monitoring, and difficulties in maintaining patients within the narrow therapeutic range. Apixaban, a direct oral Factor Xa inhibitor, requires no monitoring and has been previously demonstrated to reduce the risk of stroke without increasing the risk of bleeding when compared to aspirin in patients with AF who were not considered candidates for warfarin therapy.⁽¹⁾ The ARISTOTLE trial compared apixaban to warfarin for the prevention of stroke in patients with AF.⁽²⁾

Methods

This double-blind, double-dummy randomized controlled trial enrolled patients with paroxysmal, persistent, or permanent AF, and at least one of the following risk factors: age >75 years; prior stroke, transient ischemic attack, or systemic embolization; recent symptomatic heart failure or ejection fraction <40%, diabetes; or hypertension. Key exclusion criteria include moderate to severe mitral stenosis, other conditions that require anticoagulation (i.e. prosthetic heart valves), stroke within the last 7 days, need for aspirin at doses >165 mg a day or need for dual antiplatelet therapy, and severe renal insufficiency (serum creatinine >2.5 mg/dl). Patients were randomly assigned to receive either apixaban (or matching placebo) or warfarin to an INR goal of 2.0-3.0 (or matching placebo). The dose of apixaban was 5 mg twice daily, except for a subgroup of patients who received 2.5 mg twice daily if two or more of the following criteria were present: age >80, body weight <60 kg, or creatinine >1.5 mg/dl. The primary efficacy outcome was stroke or systemic embolization. Secondary efficacy outcomes included death from any cause and myocardial infarction. The primary safety outcome was major bleeding as defined by the International Society on Thrombosis and Haemostasis and the secondary safety outcomes was a composite of major bleeding and clinically relevant non-major bleeding. Outcomes were adjudicated by committee members blinded to study-group assignments. The study was powered for non-inferiority and the primary and secondary efficacy outcomes analyzed using intention-to-treat principles.

Results

A total of 18,201 patients were enrolled between December 2006 and April 2010 with 9120 randomized to the apixaban group. The median age of the enrollees was 70 years, 35.3% were female, 84.7% had persistent of permanent AF, and the mean CHADS₂ score was 2.1 + 1.1. The most frequent additional stroke risk factors included hypertension in 87.4%, heart failure or reduced left ventricular systolic function in 35.5%, and age >75 in 31.2%. Approximately 57% of patients had previously received vitamin K antagonists.

In the apixaban group, 95.3% of patients received 5-mg twice daily dosing while the remainder received the 2.5 mg twice daily dose. Median and mean times in the therapeutic INR range for those patients in the warfarin group were 66.0% and 62.2%, respectively.

The primary efficacy outcome of stroke or systemic embolization occurred in 212 patients in the apixaban group (1.27% per year) and 265 patients in the warfarin group (1.60% per year) (hazard ratio in the apixaban group 0.79; 95% confidence interval (CI) 0.66 to 0.95; P<0.001 for non-inferiority and P=0.01 for superiority). The rate of hemorrhagic stroke was reduced by 49% in the apixaban group (P<0.001) with a 29% reduction in the risk of fatal or disabling stroke. Additionally, the rate of death was significantly decreased in the apixaban group (hazard ratio 0.89; 95% CI, 0.80 to 0.99; P=0.047) with non-significant declines in the rate of death from cardiovascular causes, non-cardiovascular causes, and the risk of myocardial infarction.

Major bleeding occurred at a rate of 2.13% per year in the apixaban group and 3.09% per year in the warfarin group (hazard ratio 0.69; 95% CI, 0.60 to 0.80; P<0.001). In those patients in the apixaban group, intracranial hemorrhage was reduced by 58% (P<0.001) and the net clinical outcome of the combined endpoint of stroke, systemic embolism, or major bleeding was also significantly reduced (hazard ratio 0.77; 95% CI 0.69-0.86; P<0.001).

Analysis of 21 predefined subgroups demonstrated a consistent reduction in the primary efficacy outcome across all major subgroups with no significant interactions. Similar findings were observed for the primary safety outcome of major bleeding but with interactions favoring less bleeding in those patients in the apixaban group with a history of diabetes or moderate to severe renal impairment. There were no unexpected major side effects of apixaban and the rate of discontinuation of the drug was lower in the apixaban group than in the warfarin group.

Summary

Compared to warfarin, apixaban reduced the risk of stroke or systemic embolization by 21%, major bleeding by 31%, and death from any cause by 11% in patients with AF. Furthermore, the drug appeared well tolerated with discontinuation rates lower than warfarin. For every 1000 patients treated with apixaban instead of warfarin for 1.8 years, the authors calculated that stroke would be prevented in 6 patients, major bleeding in 15 patients, and death in 8 patients.

Commentary

Apixaban represents an important addition to the limited armamentarium of stroke prevention therapies for patients with AF. Compared to dabigatran and rivaroxaban, apixaban is the only one that can claim superiority over warfarin for stroke prevention, bleeding, and mortality together.^(3,4) Differences in study populations and trial design may explain some of the disparities between these new agents. Limitations to the use of apixaban may include the inability to monitor drug effect, lack of a commercially available reversing agent, and a cost expected to exceed that of warfarin. However, the advent of antithrombotic therapies more effective and safer than warfarin raises important questions concerning the threshold of risk needed for anticoagulation initiation, the continued use of warfarin in well-controlled individuals, and the cost-effectiveness of these drugs from a societal perspective.

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References

1. Connolly S.J., Eikelboom J., Joyner C., et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806-17.
2. Granger C.B., Alexander J.H., McMurray J.J., et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2011;365:981-992.
3. Connolly S.J., Ezekowitz M.D., Yusuf S., et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2009; 361:1139–1151.
4. Patel M.R., Mahaffey K.W., Garg J., et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. N Engl J Med 2011; 365:883-891.

Keywords: Anticoagulants, Atrial Fibrillation, Factor Xa, International Normalized Ratio, Stroke, Warfarin

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