ADAPTABLE points to solutions about aspirin dose, conduct of pragmatic trials
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The ADAPTABLE trial, presented and published in May, was notable in two ways: It provided answers on aspirin dosage for patients needing secondary CVD prevention and it showed a large-scale pragmatic trial could work.
The trial of 15,076 patients did not demonstrate any differences in death, MI, stroke or bleeding between those assigned aspirin 81 mg daily and those assigned aspirin 325 mg daily. Moreover, it was the first to use PCORnet, a network established by the Patient-Centered Outcomes Research Institute (PCORI) for comparative effectiveness research.
“The controversy and inconsistency in clinical practice regarding aspirin dose for secondary prevention made this an ideal question for a pragmatic trial,” JoAnn E. Manson, MD, DrPH, FAHA, chief of the division of preventive medicine at Brigham and Women’s Hospital and professor of medicine and the Michael and Lee Bell Professor of Women’s Health at Harvard Medical School, told Cardiology Today. “General equipoise regarding efficacy and safety and the opportunity to do this important trial cost-efficiently were fortuitous circumstances. ADAPTABLE demonstrated that doing a real-world assessment of the comparative effectiveness of interventions is feasible using this type of pragmatic trial design, leveraging PCORnet and electronic health records for recruitment and follow up of the study population.”
Results-wise, ADAPTABLE showed is that a daily aspirin dose as high as 325 mg is likely not necessary in most patients requiring secondary CVD prevention. Methodologically, it showed there is a less costly way to perform major trials.
“The most important aspect of ADAPTABLE is that it provides a new platform for how to conduct a large clinical trial,” Cardiology Today Editorial Board Member Jeffrey S. Berger, MD, associate professor of medicine and surgery at NYU Grossman School of Medicine and director of the Center for the Prevention of Cardiovascular Disease at NYU Langone Health, said in an interview. “It changed the landscape for how the medical community can perform large clinical trials. The investigative team should be complimented for that; it is a big step forward. It would be impossible to continue trials in the current state, with many trials costing hundreds of millions of dollars. Testing aspirin dose was a great way to prove the concept.”
Setting up the trial
In 2015, PCORI granted $14 million to set up the first trial through PCORnet, a network that would enable researchers to use existing data sources to obtain baseline characteristics, use existing data and patient-reported outcomes during follow-up, collect and monitor data through an internet portal, and have centralized institutional review board functions, electronic consent forms and other electronic data.
“There was a high interest from the Patient-Centered Outcomes Research Institute to see whether it’s possible to do a large clinical trial that could answer a meaningful question in a very different way than done before. Meaning, leveraging electronic health records, engaging patients in a way that hadn’t been done historically, and being able to do a simple randomized trial in a so-called 21st century model with PCORnet,” Adrian F. Hernandez, MD, professor of medicine at Duke University School of Medicine, vice dean and executive director of Duke Clinical Research Institute and a member of the ADAPTABLE trial’s steering committee, told Cardiology Today.
Source: Cameron Knowles/Duke Health. Printed with permission.
Developing new approaches to conduct large-scale trials is necessary because the current model is not sustainable, W. Schuyler Jones, MD, interventional cardiologist, director of the Duke University Cardiac Catheterization Laboratory, and investigator at the Duke Clinical Research Institute, who presented the ADAPTABLE results at the American College of Cardiology Scientific Session, said in an interview.
“The cardiovascular research landscape has been dominated by these traditional studies that cost a lot of money, take a lot of time, and people who conducted them were getting less bang for their buck and asking sites to do more,” he said. “There has been a charge over the last decade to change to something that is more pragmatic, where the data that are already being collected and produced are harnessed for clinical research.”
The ADAPTABLE trial was also notable for its partnership with patient representatives, known as adaptors, who gave input on trial design, reviewed all materials patients were to receive and helped navigate patients though the network.
Aspirin dosage in patients with prior CVD was a question that needed answering and a logical fit for a pragmatic trial, Hernandez said in an interview.
“The question about what’s the right dose of aspirin has been around for literally decades,” he said. “It’s something that people make an early choice about over the counter, and it can potentially have implications for their heart health, if they have heart disease, with potential benefits of preventing MI or preventing bleeds, depending on the right dose.”
Clinical practice regarding aspirin dosing has been inconsistent, potentially exposing patients to suboptimal treatment or unnecessary risks, Manson told Cardiology Today.
“There is scientific controversy on this question, and there is sufficient variability in terms of clinician prescriptions of higher vs. lower doses of aspirin in secondary prevention to warrant a comparative effectiveness trial,” she said. “And, there are also differences in terms of what patients are choosing to do. Shortly after discharge for MI, about 60% of patients are taking higher doses. But over time, many of them are switching to the lower dose, given that more than 80% were on the lower dose at the time of randomization in this trial.”
Few differences by dosage
Among the ADAPTABLE cohort (median age, 68 years; 69% men; 9% Black), 96% reported taking aspirin before enrollment. Of those, 85.3% were taking 81 mg daily, 2.3% were taking 162 mg daily and 12.2% were taking 325 mg daily.
During the median follow-up of 26.2 months, 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 compared with 7.51% of those assigned aspirin 325 mg daily (HR = 1.02; 95% CI, 0.91-1.14; P = .75).
The primary safety endpoint of hospitalization for major bleeding associated with a blood product transfusion — which Jones said was more able to be ascertained 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 compared with 0.6% of the 325 mg group (HR = 1.18; 95% CI, 0.79-1.77; P = .41), Jones said during the ACC presentation.
Results also demonstrated no between-group differences in the individual components of the primary effectiveness endpoint, and there was no difference in the primary effectiveness endpoint in any prespecified subgroups, he said.
“The bottom line is that it is reassuring that low-dose aspirin appears to be equally effective to high-dose aspirin in reduction of major vascular events, with similar risk for bleeding, so we can continue using low-dose aspirin (81 mg) as is common standard practice for patients already taking this dose,” Cardiology Today Editorial Board Member Erin D. Michos, MD, MHS, associate professor of medicine and director of women’s cardiovascular health at the Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, said in an interview. “Additionally, for patients who are currently treated with higher-dose aspirin (325 mg) who are stable and doing well, there is not a compelling reason to automatically switch them downward to the lower dose either.”
Dose switching was more common in the 325 mg group than in the 81 mg group (41.6% vs. 7.1%), Jones said. 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, noting the corresponding bleeding analysis has not yet been performed.
“It is unclear why some patients stopped taking aspirin or decided to reduce their dose,” Robert S. Rosenson, MD, professor of medicine and director of cardiometabolic disorders at Icahn School of Medicine at Mount Sinai, told Cardiology Today. “There are other therapies that may have been causing symptoms and prompted them to make the change. For example, perhaps they were on NSAIDs for arthritis that could have caused gastritis, so they downtitrated the dose of the aspirin. The granularity of those issues is not easily addressed with this type of study design.”
‘No clear advantage’
While it remains to be seen how much the crossover affected the results, the available data suggest that 81 mg should be the preferred daily aspirin dose for patients requiring secondary CVD prevention, but there is no urgency to switch those who are benefiting from a 325 mg daily dose, experts told Cardiology Today.
“There was no clear advantage of the higher dose in terms of efficacy or safety that was demonstrated in the ADAPTABLE trial. So, I think 81 mg would be the dose to use,” Manson said. “For anyone who has been on 81 mg, the advice would be to continue 81 mg. It’s a slightly more complex message for those who are currently taking 325 mg in secondary prevention settings and are tolerating it well. It would be reasonable for them to continue what they’re currently doing, but they should talk with their clinicians about whether there’s enough evidence here to switch from 325 mg to 81 mg.”
In ADAPTABLE, patients demonstrated by their actions during the study that they preferred the lower dose, which may have implications for research about other drugs, Cardiology Today Editorial Board Member Michael Davidson, MD, professor of medicine and director of the lipid clinic at University of Chicago Medicine, said in an interview.
“One significant learning from the ADAPTABLE trial is that patients prefer lower doses of drugs even if the safety of the higher dose appears similar,” he said. “This has ramifications for many of the prevention guidelines in which higher doses of drugs are recommended (ie, statins) due to the data generated from large rigorous outcome trials.”
A caveat, Michos said, is that because of the open-label design, “patients at elevated risk of bleeding — such as those with a history of gastrointestinal bleeding or peptic ulcer disease, those with chronic kidney disease, those with thrombocytopenia, those taking NSAIDs and those older than 70 years — might be more likely to be advised to switch down to the lower dose. That may be why the bleeding risk was similar between the higher dose and the lower dose.”
Another point to consider, Manson said, is that because almost all participants had previously been taking aspirin, nearly the entire study population had already demonstrated they could tolerate aspirin, which is not the case in a secondary prevention population newly initiating aspirin use; thus, the bleeding risks of aspirin may be underestimated.
Of note, she said: “There are a few signals in the data to suggest that there may in fact be a slight advantage in efficacy with the higher dose. It’s certainly not definitive, but enough to make it not automatic to switch patients from 325 mg to 81 mg if they’re tolerating it well. I think it is going to come down to clinician judgment, the patient’s risk factors for bleeding and also patient preference. This is another lesson from ADAPTABLE: Shared decision-making with the patient, and having patient partners in the research, is so important.”
Broken barriers
The most important legacy of ADAPTABLE may be that it proved a large-scale pragmatic trial could work, experts said.
The trial “has finally broken through the barrier of requiring double-blind, placebo-controlled trials with multiple visits to track outcomes,” Davidson said. “A pragmatic design is the hope for many future CV outcome trials because the cost of the more rigorous-designed studies is not feasible to answer many of our important clinical questions.”
Michos agreed, but noted investigators need to take care that pragmatic trial designs do not exacerbate socioeconomic inequities.
“The traditional ways of recruiting, following participants and ascertaining events in large CV outcome trials are burdensome and very expensive. The pragmatic approach as used in ADAPTABLE could cut costs by one-third or so. The PREVENTABLE trial examining whether statins can help prevent dementia or physical disability is also using this approach,” she told Cardiology Today. “While overall I am a big fan of this pragmatic trial design using electronic health records, I also have some concern about pragmatic design enrollment related to socioeconomic disparities and inequity related to access to internet and mHealth technology.”
Manson noted that the VITAL trials had a pragmatic design and was able to enroll large numbers of participants from historically underrepresented backgrounds, so there are ways to ensure pragmatic designs are inclusive.
“A diverse study population can be enrolled in these pragmatic trials and they are conducive to studying a wide range of interventions. Of course, not everything can be studied in this way, there will be interventions that require intensive clinical monitoring, visits and measurements at clinical sites, and in-depth monitoring for safety. But there are so many interventions that can be tested in this very feasible, pragmatic approach,” she said. “ADAPTABLE is tremendously important in demonstrating the value of PCORnet recruitment, the use of the computable phenotype, the use of electronic database linkages for follow up, and this very pragmatic, low-cost approach.”
More avenues to explore
While ADAPTABLE answered some questions about aspirin dosage and the future of pragmatic trials, other avenues are still to be explored.
“Some questions remain,” Berger said. “What is the optimal dose of aspirin in very obese individuals? Does anyone benefit from aspirin for the prevention of a first CV event (ie, primary prevention)? In the future, I believe we will be measuring platelet activity when we determine an aspirin regimen. We will be able to use an individual’s information about platelet genetics and/or function to figure out the drug and dose they should be taking.”
The design can be adapted to other classes of medications, Rosenson said in an interview.
“The trial design could be useful for future comparative studies of BP medications,” he said. “To do a randomized, double-blind controlled trial would require tens of thousands of patients. That is impractical. This type of study design has the ability to address those kinds of questions very effectively. For example, it would be useful to study chlorthalidone, which has not been widely used in the U.S., and hydrochlorothiazide, which is often used in combination pills. Whether chlorthalidone is superior to hydrochlorothiazide is an important question that could be addressed with this type of study. As would a comparison of ACE inhibitors and angiotensin receptor blockers.”
The trial “gives us a framework of how to think about doing research differently in the future,” in terms of how to recruit patients, how to obtain data and how to achieve efficiencies, Jones said.
“This was a direct-to-participant study for which we approached nearly a half million people, which is incredible,” he said. “We enrolled 15,076 people in the U.S. at 40 centers, which is not something that typically you think about in large cardiovascular studies. So, using data that’s collected and molded into a common data format, as done with PCORnet, is very useful. We also linked Medicare data and private health insurance data. Those are tools in the toolkit to do these kinds of studies, and so I’m excited about the future of clinical trials and how we’re going to conduct them even better, faster and more efficiently in the future.”
- References:
- Jones WS, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2102137.
- Marquis-Gravel G, et al. JAMA Cardiol. 2020;doi:10.1001/jamacardio.2020.0116.
- For more information:
- Jeffrey S. Berger, MD, can be reached at jeffrey.berger@nyulangone.org; Twitter: @plateletdoc.
- Michael Davidson, MD, can be reached at mdavidso@bsd.uchicago.edu; Twitter: @mdavidsonmd.
- Adrian F. Hernandez, MD, can be reached at adrian.hernandez@duke.edu; Twitter: @texhern.
- W. Schuyler Jones, MD, can be reached at schuyler.jones@duke.edu; Twitter: @schuyler_jones.
- JoAnn E. Manson, MD, DrPH, FAHA, can be reached at jmanson@rics.bwh.harvard.edu.
- Erin D. Michos, MD, MHS, can be reached at edonnell@jhmi.edu; Twitter: @erinmichos.
- Robert S. Rosenson, MD, can be reached at robert.rosenson@mssm.edu; Twitter: @drrsrosenson.
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