By Michael H. Crawford, MD, Editor
Synopsis: A randomized, placebo-controlled trial of adding aspirin to oral anticoagulant therapy in patients with chronic coronary artery disease at high risk of atherothrombotic complications and major bleeding was stopped early because aspirin increased the risk of all-cause mortality. In addition, aspirin was associated with an increase in atherothrombotic complications and major bleeding.
Source: Lemesle G, Didier R, Steg PG, et al. Aspirin in patients with chronic coronary syndrome receiving oral anticoagulation. N Engl J Med. 2025; Aug 1. doi: 10.1056/NEJMoa2507532. [Online ahead of print].
The appropriate antiplatelet therapy for patients with chronic coronary artery disease (CAD) who have an indication for oral anticoagulant (OAC) therapy is unclear, especially in patients with prior coronary artery stents who are at risk of in-stent thrombosis. Thus, these investigators from 51 centers in France conducted the Assessment of Quitting vs. Using Aspirin Therapy In Patients with Stabilized CAD (AQUATIC) study of patients who require long-term OAC.
The aim of AQUATIC was to assess the efficacy and safety of adding 100 mg/day of aspirin to OAC compared to OAC alone in chronic CAD patients who had coronary artery stenting more than six months previously, who were considered high-risk for a coronary atherothrombotic event, and who had an indication for OACs. AQUATIC is a prospective, double-blind, randomized, placebo-controlled trial, which was conducted by a data safety and monitoring board. Outcomes were adjudicated by an independent committee. Adults enrolled had one or more coronary stents placed more than six months prior to enrollment. Also, the subjects had one or more of the following: multivessel disease, chronic kidney disease, previous stent thrombosis, peripheral artery disease, or a complex percutaneous intervention (PCI), such as left main, three or more stents, bifurcating lesions requiring two stents, stents > 60 mm long, or complete occlusion stenting.
The subjects were randomized to 100 mg/day of aspirin or placebo in addition to their baseline OAC. They were seen every six months for up to 48 months. The primary efficacy outcome was a composite of cardiovascular (CV) mortality, myocardial infarction (MI), stroke, systemic emboli, coronary revascularization, or acute limb ischemia. The primary safety outcome was major bleeding. Secondary endpoints included all-cause mortality, atherothrombotic events, and net adverse events. Data analysis was by intention-to-treat.
From 2020 to 2024, 872 patients were enrolled (mean age 72 years, 85% men) and 89% were taking an OAC for atrial fibrillation (AF). The trial was stopped early at 2.2 years because of high all-cause mortality in the aspirin arm. The primary composite endpoint was 17% in the aspirin group and 12% with placebo (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.07 to 2.18; P = 0.02). All-cause mortality was 13% aspirin vs. 8% placebo (HR, 1.72; 95% CI, 1.44 to 2.58; P = 0.01) and major bleeding was 10% aspirin and 3% placebo (HR, 3.35; 95% CI, 1.87 to 6.00; P < 0.001). Net adverse events were 29% aspirin and 17% placebo (HR, 1.85; 95% CI, 1.39 to 2.46; P < 0.001) and atherothrombotic events were 11% aspirin and 9% placebo (HR, 1.27; 95% CI, 0.83 to 1.95; P = NS). The authors concluded that among patients with chronic CAD at high atherothrombotic risk receiving OACs, the addition of aspirin increased the risk of the composite of CV mortality, MI, stroke, systemic emboli, coronary revascularization, and acute limb ischemia. Also, all-cause mortality and major bleeding were significantly increased.
Commentary
In chronic CAD patients, single antiplatelet therapy is recommended by most guidelines after a period of dual antiplatelet therapy for a short period of time, depending on patient characteristics and the type of revascularization procedure. However, about 15% of such patients have an indication for OAC therapy, usually because of AF. Recent observational studies have shown that antiplatelet therapy in patients taking OACs increased the bleeding risk compared to OACs alone. These trials were open-label studies in low-risk populations and showed no benefit of dual therapy for preventing atherothrombotic events. Patients with a history of complex percutaneous coronary interventions (PCI) are at high risk for atherothrombotic events, and antiplatelet therapy may be important for minimizing the risk of stent thrombosis. Thus, there is a strong pharmacological rationale for continuing antiplatelet therapy in such patients even if they need to be on an OAC.
In the AQUATIC study, dual antiplatelet therapy and OAC therapy did not reduce the number of adverse events, including atherothrombotic events. However, atherothrombotic events were < 12% in both groups and the incidence of stent thrombosis was < 1% in both groups. Regardless, AQUATIC does not support adding aspirin to OAC therapy in chronic CAD patients at high risk for atherothrombotic events.
There are limitations to AQUATIC that should be considered. The study was stopped early because of a significant increase in all-cause mortality in the dual therapy group. This may have reduced the statistical power of the study. The centers supplying patients all were in France, so the results may not apply to other population groups. Also, there were few women in the study. In addition, AQUATIC only studied the addition of aspirin, not a P2Y12 inhibitor, which many believe is superior to aspirin regarding safety and efficacy.
The strengths of the study include that the researchers allowed all OAC agents (apixaban, 60%; rivaroxaban, 25%; dabigatran, 5%; and vitamin K antagonists, 10%). Although AF was common, they included patients with other indications for OACs. By choosing post-PCI CAD patients with high-risk features, the investigators increased the number of adverse events by seven- to eight-fold, but the results probably would apply to lower-risk patients.
Michael H. Crawford, MD, is Professor Emeritus of Medicine and Consulting Cardiologist, UCSF Health, San Francisco.
