By Michael H. Crawford, MD
SYNOPSIS: An analysis of the AUGUSTUS trial comparing a P2Y12 inhibitor plus four combinations of double or triple therapy with apixaban, aspirin, and a vitamin K antagonist in patients with atrial fibrillation and a recent acute coronary event or percutaneous coronary intervention has shown that a P2Y12 inhibitor plus apixaban exhibited the lowest rate of major adverse events and major bleeding events.
SOURCE: Berwanger O, Wojdyla DM, Fanaroff AC, et al. Antithrombotic strategies in atrial fibrillation after ACS and/or PCI: A 4-way comparison from AUGUSTUS. J Am Coll Cardiol 2024;84:875-885.
The optimal regimen for patients with atrial fibrillation (AF) and a recent acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) is unclear. Thus, the investigators from the AUGUSTUS trial sought to use the AUGUSTUS data to compare the four major treatment regimens that have been considered in this population.
In brief, AUGUSTUS was an international, multicenter, 2 by 2 factorial, randomized clinical trial comparing apixaban with warfarin and, also, aspirin with placebo in patients with AF who had a recent ACS or underwent PCI (or both) on background therapy with a P2Y12 inhibitor.1 In this analysis, the investigators reported the results of a post hoc four-way analysis comparing simultaneously four randomized groups with respect to both safety and efficacy outcomes.
The groups were composed of the following therapeutic agents added to a P2Y12 antiplatelet agent: vitamin K antagonist (VKA), apixaban, VKA plus aspirin, and apixaban plus aspirin. Exclusion criteria were another need for anticoagulation, severe renal insufficiency, history of intracranial hemorrhage, ongoing bleeding, or coronary bypass surgery. The primary outcome was a composite of death, major bleeding, or hospitalization for cardiovascular (CV) causes over a six-month follow-up. Secondary endpoints were the individual components of the primary endpoints.
From 33 countries, 4,614 patients were enrolled (mean age 71 years; 29% women). The primary outcome occurred in 22% of those treated with apixaban, in 27% of those treated with apixaban plus aspirin, in 28% of those treated with VKA, and in 33% of those treated with VKA plus aspirin (P < 0.0001). Major bleeding occurred in 8% of patients taking apixaban, in 15% of patients taking apixaban plus aspirin, in 12% of patients taking VKA, and in 20% of patients taking VKA plus aspirin (P < 0.0001). Hospitalization for CV causes occurred in 15% of those taking apixaban, in 17% of those taking apixaban plus aspirin, in 18% of those taking VKA, and in 20% of those taking VKA plus aspirin (P = 0.018). There was no difference in mortality between the four groups. Also, there were no differences in outcomes based on the qualifying event.
The authors concluded that in patients with AF and a recent episode of ACS or a PCI or both, an antithrombotic regimen of apixaban plus a P2Y12 inhibitor without aspirin provided the lowest incidence of major adverse events and major bleeding compared to regimens including VKA, aspirin, or both.
Commentary
The original AUGUSTUS trial compared apixaban plus placebo to VKA plus placebo, showing the superiority of the former to prevent bleeding events with no diminution in CV events prevention.1 Also, it showed that the placebo reduced bleeding compared with aspirin when paired with either anticoagulant. The combination of the original AUGUSTUS trial results with four other smaller trials of other similar agents resulted in a meta-analysis that demonstrated the superiority of adding a direct oral anticoagulant (DOAC) vs. VKA to therapy with a P2Y12 agent.2
Meta-analyses suffer from biases in that they are limited to the outcomes available from the trials included and the heterogeneity of the patient populations studied. The current analysis of the AUGUSTUS trial overcomes these disadvantages of meta-analyses and includes the added dimension of triple therapy with aspirin and a P2Y12 inhibitor plus either apixaban or a VKA. It demonstrated that dual therapy is superior to triple therapy for the combined primary endpoint, which included ischemic and bleeding events, and that apixaban is superior to VKA for dual therapy with a P2Y12 inhibitor.
There are limitations to this analysis of AUGUSTUS. It is an ad hoc study with a different primary outcome compared to the original trial. There were too few patients to explore other less frequent outcomes, such as stent thrombosis. Also, it mainly was a study of clopidogrel, since few patients were taking prasugrel or ticagrelor. However, it reinforces the conclusion of the prior meta-analysis that a DOAC plus a P2Y12 inhibitor is the best current therapy for patients with AF and a recent ACS episode or PCI.
Michael H. Crawford, MD, is a Professor of Medicine and Consulting Cardiologist, University of California Health, San Francisco.
An analysis of the AUGUSTUS trial comparing a P2Y12 inhibitor plus four combinations of double or triple therapy with apixaban, aspirin, and a vitamin K antagonist in patients with atrial fibrillation and a recent acute coronary event or percutaneous coronary intervention has shown that a P2Y12 inhibitor plus apixaban exhibited the lowest rate of major adverse events and major bleeding events.
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