A major trial was stopped early after excess deaths, providing the strongest evidence yet that dual therapy can do more harm than good for some.
Taking aspirin alongside an anticoagulant increased all-cause mortality risk by 72%, researchers have found.
It was also associated with a more than 50% increase in the risk of cardiovascular death, myocardial infarction, stroke, systemic embolism, coronary revascularisation or acute limb ischemia.
The AQUATIC trial, which was presented at this year’s European Society of Cardiology conference, set out to find the appropriate antithrombotic regimen for patients with chronic coronary syndrome following stent implantation.
It was a double-blind, randomised, placebo-controlled trial of nearly 900 adults, recruited from over 50 medical centres in France between 2020 and 2024.
All had chronic coronary syndrome, were at high atherothrombotic risk, had undergone a stent implantation more than six months prior and were undertaking long-term oral anticoagulation therapy.
In a 1:1 ratio, participants received 100mg daily aspirin or placebo alongside their current oral anticoagulant.
“I think this will stand as an important, practice changing paper for a good few years to come,” Professor Jason Kovacic, Director and CEO of the Victor Chang Cardiac Research Institute, Chair and Professor of Medicine at UNSW Sydney, told The Medical Republic.
He explained that the study was very welcome, providing robust data that speaks directly to a real-life clinical scenario where previous management guidelines have been lacking.
“[The study] is comprehensively in favour of anticoagulation only as the best therapy for these patients,” he said.
Death from any cause occurred in 13% in the aspirin group compared to 8% in the placebo group (HR 1.72).
Major bleeding occurred in 10% of the aspirin group and 3% in the placebo group (HR 3.35).
The study suggested there was no difference in stent thrombosis risk, which is the primary clinical reason to leave patients on aspirin following stent implantation, Professor Kovacic said.
“What was really compelling was that there were two stent thrombosis events in the trial; one in the group that was on anticoagulation only, and one in the group that was on anticoagulation plus aspirin,” he said.
He explained that patients with significant atherosclerosis would also traditionally be prescribed long-term aspirin, but the study found no difference between the two treatments in terms of atherothrombotic events.
“In fact, it tended to be higher in the group receiving aspirin as well as anticoagulation, and it trended towards actually being lower numbers in the group on anticoagulation only, although that didn’t reach statistical significance,” he said.
Patients attended follow ups every six months for a minimum of 2 years, but the median treatment duration was only 1.7 years.
The trial had to be stopped early due to an excess number of deaths amongst those taking aspirin with their anticoagulation therapy.
“I really commend the Data and Safety Monitoring Board of this study and the investigators because there was clear harm in the aspirin plus anticoagulation arm,” Professor Kovacic said.
Nearly 60 patients in the aspirin group died during the trial.
“We like to see a couple of well conducted international trials to support a finding, but given the data is so strong here and there’s such a clear signal of harm, you’d expect that it would be difficult to ever do this study again,” he said.
“It’s too early for this to be trickling down into guidelines, but it has changed my clinical practice.
“I had a few patients that fitted the trial criteria that were on an anticoagulant and aspirin, and I had a few patients that were on an anticoagulant only. And my practice was not consistent, but now, those that fit the clinical criteria have been stopping their aspirin.”
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This may be the definitive study in the field and be that data used for the next era of patient management, he explained.
The mean age was 72 years and over 70% had a history of myocardial infarction. At baseline, more than two thirds were receiving antiplatelet therapy.
Direct oral anticoagulants were used in 90% of patients, with the rest using a vitamin K agonist, at a variety of doses. Apixaban was the most common anticoagulant medication, followed by rivaroxaban.
Around 85% of the cohort were male.
“There’s no reason, either based on the data or on clinical intuition, to suspect that the data is not applicable to women, but nevertheless, we must take it into account that the numbers of women in the study are relatively small,” Professor Kovacic said.
Several previous trials have shown the efficacy of combining antiplatelet therapy and low-dose oral anticoagulants in patients with chronic coronary syndrome and have noted that the dual-pathway strategy carries an increased risk of bleeding.
These trials, which Professor Kovacic said were not comprehensive, were open-label and included low-risk populations in which not all patients had undergone coronary-artery stent implantation.
