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An 81-mg dose of daily aspirin isn't less effective than 325 mg for secondary cardiovascular prevention, according to the ADAPTABLE trial, although its legacy may be largely in being the first large pragmatic U.S.-based cardiology trial.

Composite incidence of death from any cause and hospitalization for MI or stroke came out at a similar 7.28% with the lower dose and 7.51% with the higher dose (HR 1.02, 95% CI 0.91-1.14). Results were similar across patient subgroups, reported Schuyler Jones, MD, of the Duke Clinical Research Institute in Durham, North Carolina, and colleagues.

Hospitalization for major bleeding with transfusion of a blood product, the primary safety endpoint, occurred in 0.63% and 0.60% of patients, respectively (53 vs 44 patients, HR 1.18, 95% CI 0.79-1.77).

Patients doing well on their current dose should be fine to stay there, with no mandate to switch, Jones concluded at the American College of Cardiology (ACC) virtual meeting. The data were simultaneously published in the .

But for patients starting or restarting aspirin, the 81-mg dose "is probably right, due to better tolerability," Jones said, since there was no conclusive evidence that the higher dose is better.

Nearly 42% of the group randomized to 325 mg switched to the lower dose, often on the recommendation of their physician, whereas 7.1% moved to the higher dose from 81 mg under the open-label design.

Clinicians' prevailing beliefs and perspectives on the best dose were likely at play, Jones suggested. Primary prevention guidelines that downgraded aspirin and that recommended a 81-mg dose both came out during the course of the trial, he noted. "So I think that made it more challenging."

However, it is what happens frequently in clinical practice, noted ACC press conference discussant Jane Linderbaum, APRN, CNP, of the Mayo Clinic in Rochester, Minnesota.

"It's a matter of shared decision-making with the patient and their priority medical needs; to be very clear about what they're taking and why they're taking it," she said. "We all know that patients oftentimes change doses and types of medication on their own without medical advisement and that's something we need to be very conscious and pragmatic about in our practices."

The only prespecified analysis to look at the impact of dose switching, though, supported the higher dose. With actual administered dose looked at as a time-dependent covariate, patients on 81-mg aspirin had a higher risk of a primary endpoint event than those who took 325 mg (HR 1.25, 95% CI 1.10-1.43).

"There was at least a signal that if patients tolerate 325 mg, potentially staying on that dose and speaking to their clinician and staying on that dose may be the right thing," Jones said at the press conference.

However, Jones cautioned about the clear biases in switching and noted that the group would be doing more digging in exploratory analyses.

Bigger Implications

"The hope was that this trial would once and for all answer [what is the best] aspirin dose," noted Erin Michos, MD, MHS, of the Johns Hopkins School of Medicine and School of Public Health in Baltimore, who was not involved with the trial.

The trial may have delivered only modestly in that regard due to the issue with crossover, but it was seen as a big win for clinical trial design.

"The most important legacy of this trial is that you did it," said session discussant Daniel Lloyd-Jones, MD, of Northwestern University in Chicago.

Michos agreed. "The really key thing about this trial, and why I'm still, despite the neutral results, really excited about this...what accomplished with the trial design," she said. "It was really unique for a cardiovascular outcome trial of this scale, at least in the United States. I really think it will set the stage for how we design future cardiovascular trials."

The pragmatic, open-label trial included a total of 15,076 patients identified at -participating centers through electronic health records as having established atherosclerotic cardiovascular disease and at least one risk factor. They were contacted, enrolled, and followed for a median of 16.2 months, all through electronic means without dedicated office visits for the trial.

It used a range of innovative and low-cost methods to do this, noted Colin Baigent, MD, of the Medical Research Council Population Health Research Unit at the University of Oxford in England, in an accompanying .

"[F]or example, algorithms were used to interrogate electronic health record data to identify eligible patients within the National Patient-Centered Clinical Research Network (PCORnet); patients could access a Web portal to give informed consent and be notified of their aspirin regimen (which they simply purchased themselves); and all trial visits were done virtually or by telephone, with outcomes ascertained remotely and without adjudication," he wrote.

Similar large pragmatic trials have been carried out in other countries, like ASCEND in the U.K. and in Scandinavia, Baigent pointed out.

Michos noted that there are already other pragmatic trials underway in the U.S., such as the 20,000-patient trial.

As to how to prevent adherence problems in future trials, Baigent noted that a pilot study could have been the answer, uncovering patients' preference for the 81-mg dose so that the design could have been changed to include a run-in period with only adherent patients being considered for randomization.

"ADAPTABLE is a major achievement, however, because it has shown a method of conducting trials efficiently and at low cost in the United States, and the method can now be adapted and used more widely," he concluded. "This should allow many more clinical questions to be answered, with obvious benefits to healthcare consumers."