The Assessment of Quitting versus Using Aspirin Therapy in Patients with Stabilized Coronary Artery Disease (CAD) after Stenting Who Require Long-Term Oral Anticoagulation (AQUATIC) trial was a prospective, randomized, with an anticoagulation indication (i.e., atrial fibrillation [AF]) and a chronic coronary syndrome, formerly known as stable CAD ( 1 ). The combination of these two therapies is common in North American clinical practice double-blind, placebo-controlled, parallel and commonly occurs in two ways. The first group, multicenter study conducted in France that studied the addition of low-dose aspirin (ASA) to oral anticoagulation (OAC) in patients way includes a patient who develops AF, then subsequently gets diagnosed with CAD by some diagnostic modality, prompting ASA therapy. The other way includes a patient who has been on ASA for years and develops AF, prompting OAC. The theory behind this practice is that the OAC treats the AF in patients who meet criteria, and the ASA covers the chronic coronary syndrome. Several trials published over the last decade have shown a high bleeding risk with dual-pathway therapy with a single antiplatelet agent and full-dose OAC than with OAC alone ( 2 – 5 ). However, these studies were open-label and included low-risk patients, and ultimately had little effect on the common practice of using both agents. In the trial, the investigators randomized 872 patients to receive ASA (100 mg once daily) or a placebo. For inclusion, patients had to be high risk and have undergone a percutaneous coronary intervention more than 6 months prior to enrollment. The mean age of patients was 72 years, and more than 80% were male. 72.1% of patients had a history of myocardial infarction, and the median CHA2DS2-VASc score was 4 (interquartile range, 3.0 – 5.0). The primary efficacy outcome was a composite of cardiovascular death, stroke, myocardial infarction, coronary revascularization, acute limb ischemia, or systemic embolism. The key safety endpoint was major bleeding, as defined by the International Society on Thrombosis and Hemostasis (ISTH) criteria. One would expect more bleeding events in the dual-therapy arm and fewer thrombotic events compared with placebo, which would be a logical conclusion. However, this did not occur. Instead, the trial had to be stopped prematurely because an interim analysis showed harm in the dual-therapy group.

The combination arm had a 53% higher rate of the primary efficacy endpoint (95% confidence interval [CI], 1.07–2.18), with a P value of 0.02. The bleeding outcome was even worse. Major bleeding occurred in 10.2% of patients in the ASA group and 3.4% in the placebo group (adjusted hazard ratio, 3.35; 95% CI, 1.87 to 6.00; P<0.001). The authors conclude that the dual-therapy arm was evidently worse than single OAC therapy.

Overall, several key lessons can be taken away from this trial. First, the AQUATIC trial compares well with two previous trials (EPIC CAD and AFIRE), which also found worse outcomes with combination therapy from a bleeding standpoint ( 2 , 4 ). In the EPIC CAD trial, major bleeding or clinically relevant nonmajor bleeding occurred in 23 patients (4.7%) in the edoxaban monotherapy group and in 70 patients (14.2 %) in the combination group (hazard ratio, 0.34; 95%CI, 0.22 to 0.53). Similarly, the AFIRE trial reported a lower incidence of nonmajor bleeding events in patients receiving monotherapy than those receiving combination therapy (hazard ratio, 0.58; 95%CI, 0.46 to 0.72). When similar trials find comparable results, medical community tends to be more accepting, and we become more confident in the findings. This trial showed an increase in thrombotic events in the combination arm, unlike previous trials. This finding is unique among the others and prompts us to think more. Patients were notably enrolled from May 2020 through April 2024. Perhaps the COVID-19 pandemic contributed to the observed findings. A second lesson to take away from the article is that there is little uncertainty here. The absolute difference in the primary outcome (16.9% vs 12.1%) is 4.8%, translating to a number needed to harm of just 21. From a bleeding standpoint, the absolute risk increase was 6.8% (10.2% vs 3.4%), translating to a number needed to harm of only 15. These results signify worsening bleeding outcomes in the combination group. Lastly, the authors showed that clinical questions can be answered with proper trials. Clinical studies are often designed to yield positive results for a profitable new therapy. However, this trial clearly showed that dual therapy causes more harm than good.

For decades, we assumed that patients with both AF and CAD required separate agents. However, findings from recent clinical studies, most notably the AQUATIC trial, have shown that we were wrong. With the ongoing emergence of data on combination therapy for AF and CAD, we recommend that the medical community remain open to OAC monotherapy when both diseases are present. Some places in Europe have begun implementing this practice.