American College of Cardiology

American College of Cardiology

Source:

Jones WS, et al. Joint American College of Cardiology/Journal of the American College of Cardiology Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; May 15-17, 2021 (virtual meeting).

Disclosures: Jones reports he received grants from Boehringer Ingelheim and Merck, personal fees from Bristol Myers Squibb and Medscape and grants and personal fees from Bayer and Janssen. Please see the study for the other authors’ relevant financial disclosures. Baigent reports he received grants from Boehringer Ingelheim.
May 15, 2021
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ADAPTABLE provides answers on aspirin dosing, conduct of pragmatic trials

Source:

Jones WS, et al. Joint American College of Cardiology/Journal of the American College of Cardiology Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; May 15-17, 2021 (virtual meeting).

Disclosures: Jones reports he received grants from Boehringer Ingelheim and Merck, personal fees from Bristol Myers Squibb and Medscape and grants and personal fees from Bayer and Janssen. Please see the study for the other authors’ relevant financial disclosures. Baigent reports he received grants from Boehringer Ingelheim.
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Among patients with atherosclerotic CVD, there was no difference in CV events or major bleeding according to aspirin dose, researchers reported at the American College of Cardiology Scientific Session.

The open-label, pragmatic, randomized controlled ADAPTABLE trial was the first to use PCORnet, a network established by the Patient-Centered Outcomes Research Institute for comparative effectiveness research. The results were simultaneously published in The New England Journal of Medicine.

Aspirin
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W. Schuyler Jones

“Despite its widespread use, there is not clear evidence to support the best dose of daily aspirin,” W. Schuyler Jones, MD, interventional cardiologist, director of the Duke University Cardiac Catheterization Laboratory, medical director of Duke Heart Center Clinical Research Unit and investigator at the Duke Clinical Research Unit, said during a presentation. “U.S. guidelines have not specified which dose is most appropriate for patients with heart disease. Our study was designed to answer a simple important clinical question: In people with preexisting heart disease, is a strategy of 81 mg or 325 mg of daily aspirin better?”

Patients with ASCVD at 40 centers and one health plan were recruited to participate through their electronic health record systems, Jones said. Through the network’s patient portal, each patient was randomly assigned to aspirin 325 mg daily or 81 mg daily, and purchased their medication over the counter. Patients had an early encounter through the portal to assess compliance and had routine follow-up encounters by email (87.4%) or phone (12.6%) every 3 to 6 months, according to the researchers.

“We identified patients with preexisting heart disease via electronic records queries termed a computable phenotype,” Jones said during the presentation. “Patients were enrolled using a multimodal, multi-touch approach, and participants used the online patient portal to enroll, provide electronic consent and self-randomize to 81 mg or 325 mg of daily aspirin. The computable phenotype allowed our study partners to generate listings of eligible patients with known cardiovascular disease and at least one common enrichment risk factor so that screening could be minimal, and the approach could be pragmatic, generalizable and large-scale.”

The researchers planned to enroll 20,000 patients, but in 2017, after an analysis of recruitment rates and event rates, they reduced the size of the trial to 15,000 patients.

Of the 15,076 patients (median age, 68 years; 69% men; 9% Black) in the study, 96% reported taking aspirin before enrollment, and of those, 85.3% were taking 81 mg daily, 2.3% were taking 162 mg daily and 12.2% were taking 325 mg daily. Median follow-up was 26.2 months (interquartile range, 19-34.9).

During the study period, the primary effectiveness endpoint of all-cause death, hospitalization for MI or hospitalization for stroke occurred in 7.28% of those assigned aspirin 81 mg daily and in 7.51% of those assigned aspirin 325 mg daily (HR = 1.02; 95% CI, 0.91-1.14; P = .75), the researchers found.

The primary safety endpoint of hospitalization for major bleeding associated with a blood product transfusion — which Jones said was easier to ascertain in a pragmatic trial than traditional bleeding measures, and roughly correlated with Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) severe bleeding — occurred in 0.63% of the 81 mg group and 0.6% of the 325 mg group (HR = 1.18; 95% CI, 0.79-1.77; P = .41), Jones said during the presentation.

There were also no differences between the groups in the individual components of the primary effectiveness endpoint, and there was no difference in primary effectiveness endpoint in any prespecified subgroups, he said.

Dose switching was more common in the 325 mg group than in the 81 mg group (41.6% vs. 7.1%), Jones said, and the median days of exposure to the assigned dose was less in the 325 mg group than in the 81 mg group (434 days vs. 650 days).

In a sensitivity analysis based on doses patients reported taking regardless of randomization, the primary effectiveness endpoint occurred more often in those who actually took 81 mg aspirin compared with those who actually took 325 mg aspirin (HR = 1.25; 95% CI, 1.1-1.43), Jones said during the presentation, noting the corresponding bleeding analysis has not yet been performed.

“As with any post-randomization analysis, this approach has many inherent biases, and further explorations of dose-switching and adherence to study dose are warranted,” Jones said.

At a press conference, Jones said the key message for patients is that “aspirin is safe and effective for patients with established heart disease, and there really doesn’t seem to be a difference between the two doses. I would advise doctors to tell patients that if they are on 81 mg, they should stay on it; if they discontinued aspirin and resume it, they should restart at 81 mg because we didn’t find any conclusive evidence that 325 mg is better; and there is a signal that if the patient can tolerate 325 mg, potentially they should stay on it if they discuss it with their physician.”

Donald M. Lloyd-Jones

“This is a pioneering large pragmatic trial, and we’re going to need to see more of these over the next few years,” Donald M. Lloyd-Jones, MD, SM, FACC, FAHA, chair of the department of preventive medicine, Eileen M. Foell Professor and professor of preventive medicine, medicine and pediatrics at Northwestern University Feinberg School of Medicine, said during a discussion after the presentation. “There were some clear limitations [with] the open-label design and the unfortunate large crossover, and perhaps fewer Black Americans and fewer women than we might have desired. Nonetheless, the most important legacy of this trial for me is that you did it, and you showed us many of the promises and some of the pitfalls of these large pragmatic designs.”

In a related editorial published in NEJM, Colin Baigent, FMedSci, professor of epidemiology at the Nuffield department of population health at Oxford University and director of the Medical Research Council Population Health Research Unit, wrote that the trial “is a major achievement ... because it has shown a method of conducting trials efficiently and at low cost in the United States, and this method can now be adapted and used more widely. This should allow many more clinical questions to be answered, with obvious benefits to health care consumers.”

He wrote the trial itself was less successful because so many patients from the 325 mg group switched doses, often before the early encounter, which means that “bias arising from this degree of crossover could have obscured a true difference of efficacy or safety (or both).”

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