A large-scale trial showed that the anticoagulant apixaban was more effective than warfarin in preventing stroke and systemic embolism in patients with atrial fibrillation. Moreover, apixaban resulted in substantially less bleeding and lower mortality.
These results were presented at the European Society of Cardiology Congress in Paris on August 28 and published simultaneously online in The New England Journal of Medicine.
The study was funded by the makers of apixaban, Bristol-Myers Squibb, Co. and Pfizer Inc.
The trial, called ARISTOTLE, included 18,201 patients from 1034 clinical sites in 39 countries. Patients were randomized to receive either apixaban or warfarin at 5 mg twice daily for an average of 1.8 years.
“[W]hen compared to warfarin..., apixaban resulted in an additional 21% relative reduction in stroke or systemic embolism,” said lead study author Christopher B. Granger, MD, of Duke University. “It also resulted in a 31% relative reduction in major bleeding, as well as an 11% relative reduction in overall mortality.”
The improvement in stroke prevention was statistically significant (P = 0.011), as was the lower rate of major bleeding (P < 0.001) and the lower mortality (P = 0.047). Hemorrhagic stroke was reduced by about 50%.
The benefits of stroke reduction and lower rates of bleeding were consistent across all major subgroups and despite the heterogeneity that exists in the quality of warfarin use across the world, according to John Alexander, MD, a study co-author and Duke cardiologist.
The number of events prevented per 1000 people, which indicate absolute risk reduction, was also impressive, Dr Alexander said. Apixaban prevented 6 patients from having a stroke, 15 patients from having major bleeding, and 8 patients from dying.
“There is an enormous unmet need for treatment of patients at risk for stroke associated with atrial fibrillation,” Dr Granger said. “Only about half of patients who should be treated are being treated. The disparity exists because warfarin treatment has several limitations.”
These limitations include regular blood tests to monitor and adjust warfarin dose, as well as the need to avoid certain foods and medications that interfere with warfarin's efficacy. Warfarin has also been shown to increase bleeding risk, including intracranial hemorrhage.
“Our study indicates treatment with apixaban is more effective than warfarin in preventing stroke, without the need for anticoagulation monitoring,” said the study committee's co-chair Lars Wallentin, MD, of the Uppsala Clinical Research Center University Hospital in Sweden.
The study also shows apixaban is safer than warfarin, Dr Wallentin said. “Our findings show a single dose of apixaban accomplishes the same stroke prevention goal as adjusted-dose warfarin, with a substantially lower risk of all types of bleeding across different ages and with lower rates of discontinuation.”
Though these results suggest apixaban is a promising drug, it is important to note that other studies of apixaban have produced mixed results.
A study published in The New England Journal of Medicine on July 24 showed that apixaban increased major bleeding in patients with acute coronary syndrome, without reducing recurrent ischemic events.
A study presented at the American Stroke Association’s International Stroke Conference 2011 found apixaban to be “far superior” to aspirin at preventing stroke in atrial fibrillation patients who could not use vitamin K antagonists.
The ADVANCE-2 study suggested apixaban was more effective at preventing venous thromboembolism than enoxaparin in patients who had elective total knee replacement surgery. However, the earlier ADVANCE study indicated apixaban was not more effective than enoxaparin.
And a study presented at the European Society of Cardiology Conference in 2008 found that apixaban lowered the incidence of heart attack, stroke, chest pain, or death from cardiovascular problems when compared to placebo. However, the drug did not lower the incidence significantly, and it caused major bleeding when administered at high doses.