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Study Summary

Patients with atrial fibrillation undergoing percutaneous coronary intervention (PCI) are uniquely characterized by substantial risks for coronary thrombotic, cardioembolic, and bleeding complications. In two recent studies, RE-DUAL PCI and PIONEER, a novel therapeutic strategy consisting of dual therapy with a direct oral anticoagulant (DOAC) combined with an antiplatelet agent was superior to triple therapy for the outcome of bleeding without incremental harm for ischemic events. The AUGUSTUS trial examined the use of apixaban in such patients and, in contrast to prior designs, directly compared apixaban versus vitamin K antagonist (VKA) and aspirin versus placebo in a 2X2 factorial randomization (see accompanying Hurst's Central Illustration) with stratification according to according to elective PCI or acute coronary syndrome. The trial included 4614 patients with a primary outcome of major or clinically relevant non-major bleeding. While designed as a non-inferiority trial, pre-specified hierarchal testing examined superiority of apixiban versus VKA after non-inferiority end points were met. Over 6 months, apixiban significantly reduced risks of the primary bleeding end point (10.5% versus 14.7%; P <0.001 for non-inferiority and superiority). Concordant reductions were observed for all-cause death or hospitalization. In the second comparison, aspirin significantly increased bleeding risk (16.1% versus 9.0% with placebo P <0.001) with numerical trends for lower rates of myocardial infarction (2.9% versus 3.6%) and stent thrombosis (0.5% versus 0.9%).

Commentary

Study Strengths: While the safety of a DOAC plus a single antiplatelet regimen has been established in prior studies, the AUGUSTUS study is the first trial to directly compare the effects of DOAC versus VKA and the use of aspirin versus placebo. Dosing of apixiban using either 5mg or 2.5mg based on standard criteria was identical to that used in clinical practice in patients with atrial fibrillation alone.

Study Limitations: While the comparison of aspirin versus placebo was double-blinded, therapy with either VKA or apixiban was open-label. Although patients randomized to placebo sustained less bleeding than those receiving aspirin, there was a trend towards increased ischemic events and the study was not powered to examine this end point.

Next Steps/Clinical Perspective: This trial establishes the safety of apixiban as part of the treatment of patients with atrial fibrillation and recent PCI or acute coronary syndrome. Although physicians were allowed their choice of P2Y12 inhibitor, 93% chose clopidogrel, thereby limiting generalizability to more-potent agents such as ticagrelor or prasugrel. While the current evidence base supports a default strategy of DOAC with clopidogrel in most patients with atrial fibrillation undergoing PCI, triple therapy with aspirin may be warranted among those at highest thrombotic and low bleeding risk.

Trial Reference

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Lopes  RD, Heizer  G, Aronson  R, et al. Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation. N Engl J Med. doi: 10.1056/NEJMoa1817083

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