This post is authored by Christopher P. Cannon, MD, FACC, editor-in-chief of the Science and Quality section of CardioSource.org and an associate physician in the Cardiovascular Division at Brigham and Women's Hospital in Boston. He also is an associate professor of medicine at Harvard Medical School and a senior investigator of the Thrombolysis in Myocardial Infarction (TIMI) Study Group.

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Bristol-Myers Squibb and Pfizer last Wednesday announced that they 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. Apixaban is an investigational oral factor Xa inhibitor, a new class of agents being studied for the prevention and treatment of blood clots. The trial, which is one of nine clinical trials evaluating apixaban in patients at risk of ischemic events, was stopped after clear evidence emerged that patients randomized to apixaban saw a significant increase in bleeding, without a “meaningful reductions in ischemic events.”

Apixaban also is in Phase 3 trials as a treatment for prevention of stroke in patients with atrial fibrillation compared with warfarin (the ARISTOTLE trial) and for venous thromboembolism prevention. Apixaban recently was found to provide as significant as a 54% reduction in stroke or systemic embolism compared with aspirin in patients with atrial fibrillation who were unsuitable for warfarin. The ongoing studies will continue in non-ACS indications, says Bob Harrington, MD, FACC, co-chair of the APPRAISE-2 Steering Committee and a member of the ACC Board of Trustees. He notes that concerns about apixaban only extend to the high-risk ACS patients who were enrolled in the APPRAISE-2 study.

Implications
This trial was the first large trial to report on the combination of an anticoagulant on top of aspirin and/or clopidogrel.  Three Phase II trials so far have shown that there is a tight balance of efficacy to safety (APPRAISE I, ATLAS-ACS TIMI 46, and RE-DEEM). We have all been wary of triple therapy... we know that the combination of ASA, clopiodgrel and warfarin has increased risk of bleeding, and now we see similar issues of increased risk of bleeding with adding an oral Xa inhibitor. Ongoing trials with different agents will see if there can be a benefit with an acceptable bleeding risk.

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