Does ADAPTABLE Inform Aspirin Dosing for Secondary Prevention?

This transcript has been edited for clarity.

Michelle L. O'Donoghue, MD, MPH: Hi. I'm Dr Michelle O'Donoghue, reporting for Medscape. Today the first of our late-breaking clinical trials sessions aired at the 2021 virtual meeting of the American College of Cardiology. There was a lot of excitement about the presentation of the ADAPTABLE trial, and here to discuss the top-line results is Dr Schuyler Jones from Duke University. Welcome.

Schuyler Jones, MD: Thanks for having me, Michelle.

O'Donoghue: Could you walk our listeners through the rationale as well as the overall study design? Then we'll get into the findings.

Are the Results Actionable?

Jones: ADAPTABLE was a large pragmatic study, the first randomized controlled trial (RCT) in the United States using the PCORnet (the National Patient-Centered Clinical Research Network) infrastructure. We randomly assigned patients with established heart disease and at least one common "enrichment" (or risk) factor to receive 81 mg or 325 mg of aspirin daily and followed them for 26 months. We know that aspirin is the most commonly used medication for heart disease, yet despite some observational analyses and some RCT results from patients post–myocardial infarction (MI) or in those who have had percutaneous coronary intervention (PCI), we didn't have evidence for the optimum dose for patients with stable ischemic heart disease. That's what we set out to find.

We randomized 15,076 patients across 40 centers. The patients looked pretty similar to the patients we take care of in practice: a median of 68 years old with common comorbidities such as hypertension, hyperlipidemia, and diabetes. About one fourth of them were taking dual antiplatelet therapy.

We found no difference in the primary effectiveness endpoint, which was all-cause death, hospitalization for MI, or hospitalization for stroke. We also found no difference in major bleeding, defined as hospitalization for bleeding that required a blood product transfusion. Thus, overall there were no differences between the dosage groups. Because of this generally neutral trial result, we recommend that patients remain on 81 mg of aspirin if they're currently taking 81 mg or are resuming aspirin. We did see a moderate signal of benefit for patients who stayed on 325 mg and tolerated it, so we recommend that they continue with the 325 mg and talk to their clinicians.

O'Donoghue: There are a lot of interesting things to dig into here. First of all, congratulations. One of the reasons people were very interested to see this trial presented was because of the pragmatic design. And I do want to discuss that in more depth but, taking a step back and thinking about the aspirin question, some may be saying, well, is this really an unanswered question? Did we not already know the answer to this? You mentioned the observational studies, and we've certainly had a large amount of observational data through the years that suggested no greater efficacy with the higher dose of aspirin, and perhaps a signal toward more bleeding. More recently, we had CURRENT–OASIS 7, a randomized trial suggesting that, at least for a month after acute coronary syndrome, there was no greater efficacy for the higher dose. I believe that overall bleeding was the same, but there was a signal toward more gastrointestinal bleeding perhaps with the higher dose of aspirin. But I guess we don't have anything in the long-term follow-up space; is that correct?

Jones: That's right. When we designed this study, a National Cardiovascular Data Registry paper had just been published that showed that 60% of people who were discharged after MI and PCI were sent home on 325 mg of aspirin. As you know, there's a lot of inertia that occurs with changing doses of medications, including aspirin, so a lot of these patients stayed on the 325 mg dose. By the time we enrolled our population, primarily in 2017 and 2018, 85% of patients were taking 81 mg, the low dose. That was something we didn't expect; we thought it would be a little bit closer to 50%.

O'Donoghue: Certainly, we see a lot of regional differences. I think the United States has traditionally had a higher use of the 325 mg dose than our colleagues overseas. Let's talk a bit more about the pragmatic design. So much attention has been paid to the astronomical cost of conducting clinical trials, so I believe that you are to be commended for building this design within an existing infrastructure. Of course, some of the challenges that come with that include that it was an open-label study, which always introduces some concerns about bias, and that outcomes were collected without adjudication. Walk us through the outcome reporting and your thoughts on how reliable that component was for the ADAPTABLE results.

Jones: We collected information from electronic health records, from private insurance plans — we had three private insurance partners — and the Centers for Medicare & Medicaid Services. So we were able to create a data matrix that allowed us to query these datasets for endpoints. We used previously validated endpoint algorithms to identify MI, stroke, and major bleeding. The major bleeding endpoint wasn't the most common one that I adjudicated every day, but it was kind of necessary; we needed to create something we could actually program and capture in the dataset. That's why we tagged it with a blood transfusion.

O'Donoghue: To your point, it is notable that when we talk about the safety of the 325 mg vs 81 mg dose, on the bleeding side, you're restricting that to hospitalizations for bleeding that require transfusion. Is that correct? And beyond that, I suppose we don't have information about the nature of the bleeding. In CURRENT–OASIS 7, for example, there was a suggestion toward more gastrointestinal bleeding. We're not going to be able to get that level of granularity from this trial, correct?

Jones: There will be some evaluation of that. We have the reasons patients discontinued aspirin. The reasons are varied; some involved preference, some was because of other medical illnesses like atrial fibrillation or cancer that led people to change, but about 20% revolved around bleeding or bruising, and we will be evaluating that.

Crossover and Ticagrelor

O'Donoghue: That will be great to see. I'm sure you'll have a lot more analyses to come. I'm thinking about enteric coating, which is a hot topic, and whether that influences efficacy or safety, and body weight and other factors that may come into play as well. One important point that has been raised is that there was a high degree of crossover. That is certainly one of the challenges of having an open-label study. What proportion of patients crossed over from the high dose to the low dose, and what are the implications of this?

Jones: There definitely was dose-switching, and it was more common in the 325 mg group. At some point during the study, about 41% of our participants switched from 325 mg to 81 mg, whereas about 7% switched from 81 mg to 325 mg. So we saw differential switching. We think that may have implications for how we interpret the results. We're also looking at all the information as we do analyses on adherence and switching, and the outcomes associated with that.

O'Donoghue: Since the recommendations for ticagrelor are to use 100 mg or less of aspirin, were those patients excluded from the study? Can the results be extrapolated to that patient population?

Jones: We set out to not have many exclusion criteria. In fact, at the time we designed the protocol, Adrian Hernandez said that we really didn't want to have more than one or two criteria. We posted the protocol publicly to allow anyone and everyone to look at it, and by far the most common concern from cardiologists was that they didn't feel good about randomizing patients who were on ticagrelor to the higher dose. So we excluded those patients, just as we excluded those taking oral anticoagulants. Thus, to answer your question, no — the study isn't applicable to patients who are on ticagrelor.

Patient Insights

O'Donoghue: You posted the protocol publicly to get open feedback. Another interesting part of this was that you really tried to engage patients in the overall design of the study. Touch on that and how that may have helped you conduct the study overall.

Jones: That was, by far, one of the most fun parts of this process. We learn incredible lessons when we partner with our patients to design and conduct research studies. We had nine patient partners, one from each of the nine research networks. Each network nominated one. They met every other week throughout the entire study; they looked at the protocol, they revised the protocol, they looked at the patient-facing materials; they helped design the internet patient portal; and they are co-authors on the New England Journal of Medicine (NEJM) paper. That part of it was really a neat piece.

When we were sending initial contacts to eligible patients, one of our patient partners got the invitation and said, what are you guys doing? This is a white envelope from Duke University or some other university. It looks like a hospital bill. Why would I ever open this? So they helped us redesign the invitation. We put colorful pictures and used language that spoke to the patient. Having patient partners was quite an enlightening part of our experience and a great piece of ADAPTABLE.

O'Donoghue: It certainly has opened our eyes to so many aspects of clinical trials that have been ignored in the past. Certainly, this was an important learning experience through ADAPTABLE. No doubt it will be looked at for future trials trying to implement these types of design changes.

Congratulations on the trial as well as the NEJM paper. We look forward to seeing more analyses as we go along. Wrapping up for Medscape, this is Dr Michelle O'Donoghue.

Michelle O'Donoghue is a cardiologist at Brigham and Women's Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Michelle loves spending time outdoors with her family but admits with shame that she's never strapped on hockey skates.

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