Antithrombotic regimens with P2Y12 inhibitors and apixaban led to fewer hospitalizations and less bleeding than regimens with vitamin K agonists and aspirin in atrial fibrillation patients who were part of the AUGUSTUS study. The new post-hoc AUGUSTUS analysis was published Monday online ahead of the Sep 3 issue of the Journal of the American College of Cardiology, with authors led by Otavio Berwanger, MD, PhD, from the George Institute for Global Health UK and Imperial College London, UK, and the Academic Research Organization (ARO), Brazil. Challenging population Patients with atrial fibrillation (AF) and an acute coronary syndrome (ACS) or who have undergone percutaneous coronary intervention (PCI) are at a high-risk group for bleeding and ischemic events, the authors noted. Finding optimal antithrombotic regimens for these patients has remained “challenging in clinical practice,” with “several thousand” different combinations that can be used, they added. The AUGUSTUS study is the only randomized clinical trial comparing antithrombotic regimens for this population using a 2 x 2 factorial design, comparing the direct oral anticoagulant (DOAC) apixaban with vitamin K antagonist (VKA) and aspirin with placebo, the authors noted. The current analysis’ findings reinforce the original AUGUSTUS conclusion — which in turn informed international guidelines — that a DOAC plus a P2Y12 inhibitor is the preferred regimen for prevention of ischemic events while limiting bleeding events in this high-risk population, versus other regimens including aspirin, warfarin or both, said the authors. New 4-way analysis The latest analysis randomized 4,614 AUGUSTUS subjects within a median 6.6 days of ACS or PCI, all of whom were treated with a P2Y12 inhibitor. Patients using anticoagulants for other conditions, with severe renal insufficiency, a history of intracranial hemorrhage, recent or planned coronary artery bypass graft surgery, coagulopathy or ongoing bleeding and contraindication to a VKA, apixaban, P2Y12 inhibitor or aspirin were excluded. The patients then underwent a new 4-way analysis comparing safety and efficacy outcomes in each group, including; 1,153 patients given apixaban plus placebo; 1,153 on apixaban plus aspirin; 1,154 on VKA plus placebo and 1,154 on VKA plus aspirin. At baseline, the 4 groups were of similar median age (70 years in the apixaban plus placebo group and 71 years in the other cohorts), had similar sex weighting (with females making up 27.1% of the apixaban plus placebo cohort, 31% of the apixaban plus aspirin group, 28.4% of the VKA plus placebo patients, and 29.4% of the VKA plus aspirin subjects) and had similar racial weighting (from 91% to 92.8% across the groups). Fewer hospitalizations, less bleeding on P2Y12 inhibitor + apixaban without aspirin Overall, 1.1% had prior bleeding episodes (0.7% on apixaban plus placebo; 1.9% on apixaban plus aspirin; 1% on VKA plus placebo; 0.7% on VKA plus aspirin, respectively), 88.3% were medicated for hypertension (88.8%; 88.3%; 88.2%; 87.8%, respectively), 42.8% has heart failure (41.9%; 42.7% ; 44%; 42.5%, respectively) and 13.8% had suffered stroke, transient ischemic attack or thromboembolism (14.9%; 13.6%; 14.4%; 12.4%, respectively). The primary endpoint — a composite of all-cause death, major or clinically relevant nonmajor bleeding, or hospitalization for cardiovascular causes over 6-months follow-up — occurred in 21.9% of the apixaban plus placebo group; 27.3% of those on apixaban plus aspirin; 28% on VKA plus placebo and 33% on VKA plus aspirin (P value <0.0001 overall; with all pairwise comparisons statistically significant except apixaban plus aspirin vs. VKA plus placebo). “Rates of individual exploratory outcomes, such as cardiovascular death, stroke, myocardial infarction, definite or probable stent thrombosis, and urgent revascularization, were similar between the 4 randomized groups,” the authors said. However, the apixaban plus placebo group had lower event rates than the other three antithrombotic strategies when it came to major or clinically relevant nonmajor bleeding (7.8% of the apixaban plus placebo group; 14.6% in apixaban plus aspirin; 12% of VKA plus placebo; and 20% of VKA plus aspirin; P <0.001) and hospitalizations (21.4%; 24.7%; 26.6%; and 27.4%, respectively; P = 0.0031). There was no difference between the 4 randomized groups with respect to all-cause death, said the researchers. The current study’s findings “reinforce the idea that a regimen that includes a DOAC plus a P2Y12 inhibitor represents the preferred option for prevention of ischemic events while limiting bleeding events in this high-risk patient population” compared with other regimens including aspirin, warfarin, or both, the authors concluded. “Future trials should test other antithrombotic strategies, including the avoidance of aspirin immediately after ACS/PCI to further refine the trade-off between efficacy and safety outcomes in this high-risk population,” they added. “Until then, a regimen that includes a DOAC plus a P2Y12 inhibitor without aspirin after a few days from the index ACS/PCI represents the preferred option for the prevention of ischemic events while limiting bleeding events.” In an accompanying editorial, authors led by Eunice Yang, MD, PhD, from the Inova Schar Heart and Vascular Institute, VA, and Johns Hopkins School of Medicine, MD, noted, “Whereas the study findings bolster the amassed results of other individual clinical trials, these findings are particularly relevant because the study period follows the first 6 months after ACS or PCI, a time that represents the interval with the highest risk for in-stent thrombosis during which triple therapy may offer the most benefit.” They went on to list practical considerations when applying the current findings, stressing that patients were pretreated with aspirin for around a week after the ACS or PCI event and enrolment in the trial. “Given this pretreatment with aspirin, we advise against the immediate initiation of only double therapy after the index coronary event because the risks and benefits of the lack of aspirin early after an index event are not clear.” Future studies will likely also include newer therapeutic options for anticoagulation, including oral factor XIa inhibitors in AF and coronary artery disease, the editorialists added. Sources: Berwanger O, Wojdyla DM, Fanaroff A, 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. Yang E, Bhatt DL, Atwater B. Bleeding and Thrombosis in Patients With Atrial Fibrillation After Acute Coronary Syndrome or Percutaneous Coronary Intervention. J Am Coll Cardiol 2024;84:886-888. Image Credit: Uladzislau – stock.adobe.com