LOS ANGELES—Apixaban, a novel anticlotting agent, reduced the risk of stroke by greater than 50% compared with aspirin among patients with atrial fibrillation who were unsuitable for vitamin K antagonist therapy, researchers reported at the 2011 International Stroke Conference.
The study results, which were simultaneously published in the February 10 online New England Journal of Medicine, showed that apixaban, a factor Xa inhibitor, lowered the risk of stroke or systemic embolism without significantly increasing the risk of major bleeding or intracranial hemorrhage.
“Apixaban is well tolerated compared to aspirin, without evidence of liver toxicity,” said study coauthor Hans-Christoph Diener, MD, PhD, Chairman of the Department of Neurology, University Duisburg-Essen in Germany. “For atrial fibrillation patients unsuitable for vitamin K antagonists, apixaban has a favorable risk profile.
“The relative risk reduction in favor of apixaban was 55% for the primary end point of stroke or systemic embolism,” Dr. Diener continued. “Bleeding complications were identical…. If you treat 1,000 patients per year with apixaban compared with aspirin, you save 21 strokes, three deaths, and 33 vascular hospitalizations. And the price you pay is two more major bleeds.”
A new drug could have a significant clinical impact among patients with atrial fibrillation, as these patients have a five times higher stroke risk than persons without atrial fibrillation. However, many such patients do not receive effective thromboprophylaxis therapy. The most effective class of anticlotting agents, vitamin K antagonists, which include warfarin, are more efficacious than aspirin but have a narrow therapeutic window and require anticoagulation monitoring and dose adjustments. Aspirin, though inexpensive and easy to use, does not provide sufficient stroke risk prevention in high-risk patients.
“The risk of stroke can be decreased by 70% to 80% with anticoagulation,” said Dr. Diener. “The problem is that warfarin is very difficult to handle. About half of all patients refuse to take it, because it is cumbersome to do International Normalized Ratio (INR) control, and people are afraid of bleeds. These people are treated with aspirin, but aspirin reduces the risk of stroke by only about 20%. So there is room for improvement. The big advantage of apixaban is that it is taken daily, orally, and the dose is independent of body weight, race, and age, and you don’t need to monitor coagulation.”
AVERROES Trial for Stroke
The Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial was conducted at 522 medical centers in 36 countries. The study, led by Stuart J. Connolly, MD, included 5,599 patients with atrial fibrillation who had an increased risk of stroke and either were not suitable candidates for, or were unwilling to receive, vitamin K antagonist therapy. Key exclusion criteria were the presence of conditions other than atrial fibrillation for which the patient required long-term anticoagulation, valvular disease necessitating surgery, a serious bleeding event within the previous six months, or a high risk of bleeding, among others.
In the month prior to screening, about 75% of patients had been taking aspirin, and 15% were taking a vitamin K antagonist. About 40% of all patients had previously received, but had discontinued, vitamin K antagonist therapy; from this group, 42% had discontinued use because the INR could not be maintained in the therapeutic range.
All participants were randomly assigned to receive apixaban (5 mg twice daily) or aspirin (81 to 324 mg/day). The mean follow-up was 1.1 years, and the primary outcome measure was ischemic or hemorrhagic stroke or systemic embolism.
Comparing Apixaban and Aspirin for Stroke Prevention
After reviewing results of the first analysis of efficacy, the data and safety monitoring committee recommended early study termination after one year in May 2010. The committee observed a treatment benefit in favor of apixaban for the primary outcome that exceeded 4 SD.
The researchers observed 51 primary outcome events among patients who had received apixaban and 113 among those who had taken aspirin. The corresponding rates of ischemic stroke were 1.1% per year and 3% per year, respectively. The death rate was 3.5% per year in the apixaban group and 4.4% per year in the aspirin group. The hospitalization rate for cardiovascular causes was lower in the apixaban group (12.6% per year), compared with the aspirin group (15.9% per year).
Regarding adverse events, 44 major bleeding events (1.4% per year) occurred in patients taking apixaban and 39 (1.2% per year) among participants taking aspirin. Subjects taking apixaban also had 188 minor bleeding events, compared with 153 minor events in those taking aspirin. In addition, 11 cases of intracranial bleeding occurred in persons taking apixaban, and 13 such cases occurred in those taking aspirin.