Apixaban Trial Stopped due to Bleeding Risk

Bristol-Myers Squibb Company and Pfizer have discontinued the Phase 3 APPRAISE-2 clinical trial in patients with recent acute coronary syndrome (ACS) treated with apixaban or placebo in addition to mono or dual antiplatelet therapy. The study was stopped early based on the recommendation of an independent Data Monitoring Committee (DMC), which found clear evidence of a clinically important increase in bleeding among patients randomized to apixaban. The increase in bleeding was not offset by clinically meaningful reductions in ischemic events.

The APPRAISE-2 Trial (Apixaban for Prevention of Acute Ischemic Events—2), one of nine clinical trials evaluating apixaban in patients at risk of ischemic events, was designed to include approximately 10,800 patients with a recent ACS based in 40 countries. In the trial, which was coordinated by Duke Clinical Research Institute in the US and Uppsala Clinical Research Center in Sweden, patients were randomized to apixaban 5 mg twice daily or placebo.

The companies informed the APPRAISE-2 investigators, ethics review boards, and regulatory health authorities of the decision to stop the study. Enrollment will be stopped and patients will be taken off of the study drug, and the lead investigators will complete a full evaluation of the available data set and the results will be made public.

"We remain committed to the development of apixaban in other patient populations,” said Brian Daniels, MD, senior vice president at Bristol-Myers Squibb, in a press release. The company is focused on the rolling submission of data for the prevention of stroke in patients with atrial fibrillation who are expected or demonstrated to be unsuitable for treatment with warfarin to the FDA and the application to the European Medicines Agency for venous thromboembolism (VTE) prevention. Other ongoing studies investigating apixaban in different patient populations are being monitored by independent data monitoring committees and are continuing, he noted.

“Our recommendation to discontinue APPRAISE-2 concerns only the population of high-risk ACS patients receiving anti-platelet therapy enrolled in APPRAISE-2,” said Robert Harrington, MD, Duke Clinical Research Institute, and co-chair of the APPRAISE-2 Steering Committee. “Recent Phase 3 clinical trials of apixaban have demonstrated promising results in patients with VTE and atrial fibrillation. We look forward to reviewing the complete APPRAISE-2 data, when it is available, to better understand this apparently different risk profile in patients with ACS.”

Based on the APPRAISE-2 recommendation, the DMC for APPRAISE Japan, a Phase 2 study in ACS patients, has also recommended discontinuation for APPRAISE Japan.

For more information:

• Apixaban in Acute Coronary Syndromes
• Apixaban, an Oral, Direct, Selective Factor Xa Inhibitor, in Combination With Antiplatelet Therapy After Acute Coronary Syndrome
• Bleeding forces Pfizer, BMS to halt apixaban study

What was your reaction in hearing that the trial had been stopped due to bleeding risks? What are your concerns regarding patients who began a therapeutic course of apixiban for ACS?