Presented by Dr. Schuyler Jones, assistant professor of medicine, Duke University, and a member of the Duke Clinical Research Institute in the first Late Breaking Clinical Trial session, “Aspirin Dosing: A patient-centric Trial Assessing the Benefits and Long-term Effectiveness (ADAPTABLE)” asked a key question that many patients and physicians, PAs, and NPs face every day: Is 81 mg or 325 mg of aspirin more effective for secondary prevention for patients with pre-existing or established cardiovascular disease?
When comparing 81 mg to 325 mg in 15,076 trial participants within ADAPTABLE, the lower dose was found to be just as effective, with no significant difference in major bleeding or cardiovascular events, and the majority of patients’ being compliant with and preferring the lower dose versus the regular dose. Due to the higher adherence when taking “baby aspirin,” Dr. Jones emphasized that beginning with ASA 81 mg may be the best option for patients with pre-existing or established Approximately 9% of participants were Black, 3% Hispanic, and 1% Asian.
The trial results have been long awaited. Earlier research provided conflicting results. Some study results have suggested that low-dose ASA may lower bleeding risk, while regular-dose ASA may be a more effective prophylactic regimen in reducing myocardial infarctions and stroke.
As the discussants of the ACC presentation emphasized, ADAPTABLE is a landmark trial for another crucial reason. ADAPTABLE is a pragmatic study that engaged patients throughout the trial. In traditional clinical trials, people with common comorbidities are often excluded. The ADAPTABLE trial had few exclusion criteria and included participants with common comorbidities, including hypertension, congestive heart failure, dyslipidemia, and diabetes. A key takeaway from this trial is that it provides proof of principle regarding “real-world” trials, showing that large, randomized, pragmatic studies can be successfully conducted in the US. The results may be more generalizable to the general public regarding the correct ASA dose, potentially preventing thousands of deaths secondary to CVD or thousands of major bleeds.
ADAPTABLE Results Benefit from Meaningful Patient Engagement
The ADAPTABLE trial sets another key milestone through its meaningful engagement of patients throughout the study. The trial established a new patient engagement model by including patient partners, called Adaptors, as part of the study team, ensuring that patients were able to provide their perspectives and feedback throughout the trial, including informing the research questions, collection of patient-reported outcomes, and study protocol design.
All Adaptors were key members of their own healthcare teams and have healthcare expertise as patients who are living with chronic disease. Some also have professional or personal clinical research expertise. Adaptors helped to create and review recruitment materials, the informed consent form, a study portal for trial participants, and the study protoco
l. Patients were actively engaged in the development and conduct of the study, including review and revision of patient-facing materials, contribution to the creation of study updates for participants in lay language, including on social media platforms. Adaptors participated in investigator and steering committee meetings, work groups, and conferences and shared their experiences as Adaptable Patient Partners in presentations, articles, and blogs. They also contributed as authors in articles published in peer-reviewed medical journals.
Trial participants were able to access a study portal to learn about the trial, provide their informed consent online, be enrolled online or by phone, and have all their study visits conducted remotely or via phone. Although the study took place from April 2016 to June 2019 and thus before the COVID-19 pandemic, the trial implemented an innovative technique that makes onsite study visits unnecessary, overcoming a major obstacle in this age of COVID-19.
This study identified eligible participants via electronic health records and health claims data through PCORnet, the National Patient-Centered Clinical Research Network (PCORnet), which comprises health plan clinical research and patient-powered research networks across the US, funded by the Patient-Centered Outcomes Research Institute (PCORI).
Trial Limitations
The discussants praised the trial’s “real-world,” pragmatic design, and the ADAPTABLE trial provides a model of meaningful patient engagement. However, the trial also had some important limitations. Due to its open-label design, it was not possible to blind the study drug, which may have impacted drug adherence, discontinuation, and the switching of ASA dose, leading to inherent bias. Before the trial began, of those who were taking ASA already (over 95%), 85% were taking ASA 81 mg. During the trial, many participants did switch drug doses, with most switching from ASA 325 to 81 mg.
Dr. Jones emphasized the importance of a direct comparison between 81 mg and 325 mg, stressing that the investigators encouraged participants to remain on their assigned study dose. He acknowledged that the differing impact of the doses is admittedly less clear due to dose switching by study participants; yet, he stressed that many participants in both dose groups remained on their assigned dose for more than a full year. Further research might analyze what motivates patients to switch assigned dosages. Another limitation of the study was the lack of sufficient racial diversity among trial participants.
Primary Effectiveness and Safety Outcomes
The primary effectiveness outcome, comprised of hospitalization for MI or stroke or all-cause mortality, occurred with 590 patients receiving ASA 81 mg and 569 patients for those on the 325 mg dose, for an HR of 1.02 (CI 0.91-1.14).
The primary safety outcome was hospitalization for major bleeding, requiring transfusion, impacting 53 participants (0.63%) on the 81 mg dose and 44 participants (0.60%) on the 325 mg dose, for an HR of 1.18 (CI 0.79-1.77).
The investigators reported that the results remained consistent across gender, age, race and ethnicity, chronic kidney disease or diabetes mellitus co-morbidities, or prior dual antiplatelet therapy.
References
Jones WS, Mulder H, Wruck LM, Pencina MJ, KRIPalani S, Muñoz D, et al., for the ADAPTABLE Team. Comparative effectiveness of aspiring dosing in cardiovascular disease. N Engl M Med. May 15, 2021. DOI: 10.1056/NEJMoa2102137. Accessed on May 15, 2021 at https://www.nejm.org/doi/full/10.1056/NEJMoa2102137.
Baigent C. Pragmatic trials–need for ADAPTABLE design. May 15, 2021. DOI: 10.1056/NEJMe2106430. Accessed on May 15, 2021. https://www.nejm.org/doi/full/10.1056/NEJMe2106430
American College of Cardiology. Cover story: Big data ADAPTABLE trial reveals a new future for clinical trial
s. Cardiology Magazine. April 19, 2021. Accessed on May 15, 2021 at https://www.acc.org/latest-in-cardiology/articles/2021/04/01/01/42/cover-story-big-data-adaptable-trial-reveals-a-new-future-for-clinical-trials.
Uhlenbrauck G, Schulman J, Jernigan K, McAdams P, Singler L. Models of engagement: patients as partners in clinical research. Applied Clinical Trials. February 8, 2018. Accessed on May 15, 2021 at https://www.appliedclinicaltrialsonline.com/view/models-engagement-patients-partners-clinical-research.
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