Apixaban – Another warfarin replacement?
DURHAM, NORTH CAROLINA. Although there is no evidence that otherwise healthy lone afibbers have an increased risk of ischemic stroke, it is clear that atrial fibrillation (AF) patients with heart failure, diabetes or hypertension have a significantly increased risk and this risk is further magnified if the patient has already suffered a heart attack or stroke. To date, oral anticoagulation with vitamin K antagonists such as warfarin (Coumadin) is still considered to be the best preventive therapy for patients at risk for stroke. Unfortunately, warfarin interacts with many foods and drugs and treatment requires constant, costly monitoring. Its use also substantially increases the risk of hemorrhagic stroke and major internal bleeding, particularly in older people, a group that, ironically, is also most at risk for an ischemic stroke. Effective warfarin therapy is based on maintaining an INR (international normalized ratio) between 2.0 and 3.0. In real life this ratio is only achieved on a continuous basis in about 50 to 60% of patients. Too low a ratio increases the risk of ischemic stroke, while too high a ratio increases the risk of hemorrhagic stroke and major bleeding. >p> Warfarin acts by inhibiting the activation of the vitamin K-dependent coagulation factors V, VII, and X in the extrinsic and common pathways of the coagulation cascade. Research aimed at replacing warfarin has focused on developing new pharmaceutical drugs which will inhibit specific coagulation factors. A latest entry to the field is apixaban (Eliquis) a direct inhibitor of factor Xa, the first member of the common pathway in the coagulation cascade.

A study comparing apixaban (5 mg twice daily) with aspirin (81 – 324 mg/day) in a group of 5600 AF patients found that apixaban reduced the relative risk of stroke and systemic embolism by about 50% when compared to aspirin (yearly event rates 1.6% with apixaban and 3.7% with aspirin) without significantly increasing the risk of major bleeding.

A very large scale study (ARISTOTLE) comparing apixaban to warfarin has now been completed. It involved 18,200 patients with AF and at least one additional risk factor for ischemic stroke. The average (median) age of the patients was 70 years and 35% were female. Most of the participants (85%) had persistent or permanent AF and had a CHADS2 score of at least 1 (mean score of 2.1). All in all, the trial involved a group of very sick people, in no way comparable to a group of otherwise healthy afibbers. Almost 90% were being treated for hypertension, 35% had heart failure or abnormally low left ventricular ejection fraction, over 30% had experienced a prior heart attack, stroke, TIA (transient ischemic attack) or systemic embolism, and 25% had diabetes. None of the study participants had a CHADS2 score of 0.

The participants were randomized to receive standard therapy with oral warfarin (INR range of 2.0 to 3.0) or 5 mg twice daily of apixaban (2.5 mg twice daily for elderly or frail persons and those with impaired kidney function). The warfarin-treated patients were within INR target range 66% of the time (median value). During an average (median) follow-up of 1.8 years, 212 patients (1.3%/year) in the apixaban group experienced a stroke, TIA or systemic embolism as compared to 265 patients (1.6%/year) in the warfarin group. The rate of major bleeding was 2.13%/year in the apixaban group compared to 3.09%/year in the warfarin group. The incidence of hemorrhagic stroke (intracranial bleeding) was 0.24%/year in the apixaban group compared to 0.47%/year in the warfarin group. The incidence of major gastrointestinal bleeding was 0.76%/year in the apixaban group and 0.86%/year in the warfarin group. Overall, 1009 patients (6.13%/year) in the apixaban group and 1168 patients (7.20%/year) in the warfarin group died (from any cause) or suffered a stroke, systemic embolism or major bleeding during follow-up.

The ARISTOTLE AF investigators conclude that apixaban is superior to warfarin in regard to preventing stoke and systemic embolism and non-inferior in all other aspects where a comparison was made. NOTE: This study was funded by Bristol-Myers Squibb and Pfizer and all the investigators have substantial financial ties to the pharmaceutical industry.

Granger, CB, Wallentin, L, et al. Apixaban versus warfarin in patients with atrial fibrillation. New England Journal of Medicine, September 4, 2011 [Epub ahead of print]