Bristol-Myers Squibb Company (NYSE: BMY) and Pfizer Inc. (NYSE: PFE) announced that results from a prespecified subanalysis of the ARISTOTLE trial were published in Circulation, the peer-reviewed journal of the American Heart Association.
Results from this subanalysis showed that the reductions in stroke or systemic embolism, number of major bleeding events and mortality demonstrated with Eliquis® (apixaban) compared to warfarin in the ARISTOTLE trial were consistent across subgroups defined based on levels of International Normalized Ratio (INR) control in patients with nonvalvular atrial fibrillation.
“Concerning the quality of warfarin treatment, there is a large variation in time in therapeutic range among different countries and centers, which affects outcomes. This subanalysis was conducted to determine whether the treatment effects of apixaban were similar in centers and patients with high quality warfarin care,” said study lead author Dr. Lars Wallentin of Uppsala University in Uppsala, Sweden. “These additional analyses supported that the primary results of ARISTOTLE were consistent across a broad range of quality of warfarin management.”
Variations in time in therapeutic range (TTR) can affect outcomes for atrial fibrillation patients being treated with Vitamin K antagonists such as warfarin for stroke prevention, leading to an increased risk of stroke when INR levels are below, or bleeding when INR levels are above, the therapeutic range. For patients in the ARISTOTLE trial, the quality of warfarin management was defined by TTR, with a target INR of 2.0 – 3.0. In the ARISTOTLE trial, patients in the warfarin group had an INR in the therapeutic range (2.0 to 3.0) for a median of 66.0% of the time. For context, the median time for INR in the therapeutic range varies across the globe. In clinical practice settings in the United States, it is approximately 57-59%.
The ARISTOTLE trial randomized 18,201 patients from 1,034 clinical centers in 39 countries. In this subanalysis, for each patient, a center average TTR (cTTR) was estimated using a linear mixed model based on the real TTRs in warfarin treated patients with a fixed effect for country and random effect for center. Study centers were placed into one of four similarly sized quartile groups based on cTTR (<60.5%; 60.6%-66.3%; 66.4%-71.1%; and >71.2%). The rates of stroke or systemic embolism, major bleeding and mortality were consistently lower with Eliquis than warfarin across the cTTR quartiles. Similar results were seen when an individual TTR (iTTR), predicted using a model including patient characteristics, was examined in a post-hoc analysis.
While demonstrating consistency across a broad range of warfarin control, results of this subanalysis suggest a trend toward reduction of the treatment effects at centers and in patients with predicted excellent INR control. In these centers, interaction tests are less reliable because of low numbers of events, and thereby lack statistical power.
Based on the results of the subanalysis, the benefits of Eliquis compared with warfarin for stroke or systemic embolism, bleeding, and mortality appear similar across the range of centers’ and patients’ quality of INR control.
About ARISTOTLE Trial Design
The ARISTOTLE study was designed to demonstrate the efficacy and safety of Eliquis versus warfarin for the prevention of stroke or systemic embolism in patients with nonvalvular atrial fibrillation. In ARISTOTLE, 18,201 patients were randomized (9,120 patients to Eliquis and 9,081 to warfarin). ARISTOTLE was an active-controlled, randomized, double-blind, multi-national trial in patients with nonvalvular atrial fibrillation or atrial flutter, and at least one additional risk factor for stroke. Patients were randomized to treatment with Eliquis 5 mg orally twice daily (or 2.5 mg twice daily in selected patients, representing 4.7 percent of all patients) or warfarin (target INR range 2.0-3.0), and followed for a median of 1.8 years.
About Atrial Fibrillation
Atrial fibrillation is the most common cardiac arrhythmia (irregular heart beat). It is estimated that more than 5.8 million Americans and 6 million individuals in Europe have atrial fibrillation. Nonvalvular atrial fibrillation, or NVAF, is the most common type of atrial fibrillation. The lifetime risk of developing atrial fibrillation is estimated to be approximately 25 percent for individuals 40 years of age or older. One of the most serious medical concerns for individuals with atrial fibrillation is the increased risk of stroke, which is five times higher in people with atrial fibrillation than those without atrial fibrillation. In fact, 15 percent of all strokes are attributable to atrial fibrillation in the U.S. Additionally, strokes due to atrial fibrillation are more burdensome than strokes due to other causes. Atrial fibrillation-related strokes are more severe than other strokes, with an associated 30-day mortality of 24 percent and a 50 percent likelihood of death within one year in patients who are not treated with an antithrombotic.
Eliquis® (apixaban) is an oral direct Factor Xa inhibitor. By inhibiting Factor Xa, a key blood clotting protein, Eliquis prevents thrombin generation and blood clot formation. Eliquis is approved to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation in the United States, European Union, Canada, Japan, Korea, Mexico, Columbia, Russia, Israel and Australia. Eliquis is approved for prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery in a total of 17 regions: Argentina, Australia, Brazil, Canada, Colombia, European Union (which includes 27 member states plus Iceland and Norway), Hong Kong, India, Indonesia, Israel, Peru, Russia, South Korea, Switzerland, Thailand, Turkey and the United Arab Emirates.
About the Bristol-Myers Squibb/Pfizer Collaboration
In 2007, Pfizer and Bristol-Myers Squibb entered into a worldwide collaboration to develop and commercialize Eliquis, an investigational oral anticoagulant discovered by Bristol-Myers Squibb. This global alliance combines Bristol-Myers Squibb’s long-standing strengths in cardiovascular drug development and commercialization with Pfizer’s global scale and expertise in this field.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases.
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