There were no significant differences in cardiovascular events or major bleeding among patients with established coronary heart disease (CHD) assigned to a diary. aspirin dose of 81 mg and those who received a dose of 325 mg in the ADAPTABLE trial of 15,000 patients.
Although there was a substantial change in dose in the trial, especially from the highest dose to the lowest, lead researcher W. Schuyler Jones, MD, believes that the results support the use of the dose of 81 mg in most patients.
“While we would have liked to see greater adherence to the assigned doses, we believe the test results are reliable,” Jones said. theheart.org | Cardiology Medscape.
The real-world open-label pragmatic trial also included an innovative, low-cost design that allows researchers to identify and communicate directly with eligible patients, opening up a cost-effective new method for conducting clinical research.
Jones, a cardiologist and associate professor of medicine at Duke University Medical Center, Durham, North Carolina, presented the ADAPTABLE results on May 15 at the American College of Cardiology (ACC) virtual science session 2021. They were simultaneously published online at the New England Journal of Medicine (NEJM).
Jones noted that there were mixed signals in the results. “For example, the main analysis on the intention to treat showed a trend towards a lower all-cause death rate in the 81 mg group, but the subgroup of patients who were left with the 325 mg dose throughout the study there was a lower rate of events. But overall there was no difference. “
Jones said the researchers had received the following messages to take patients home: “If a patient is already taking 81 mg, they should probably stay at this dose given the similar study results for the main endpoint and that we find no conclusive evidence that 325 mg is better, but for patients who have tolerated 325 mg in the long term, they may want to maintain this dose, as it may be associated with a moderate benefit. “
Jones noted that, in general, patients who change dose tend to get worse, but suggested that this may have had more to do with the underlying reasons for the change rather than the different doses themselves. “For example, change often occurs after bleeding or bruising, which can also prevent an ischemic event and other diseases, such as cancer or AF [atrial fibrillation] it can also lead patients to change their dose. “
“With the caveat that this trial did not include new patients (the vast majority of patients had been taking aspirin previously) the results support the approach of starting new patients with 81 mg, which is what we have been seeing in clinical practice. evolving recently years, “he added.
Jones explained that the trial was intended to answer the simple but important question about the best dose of aspirin in patients with heart disease.
“Aspirin has been established as a suitable long – term drug for patients with ischemic cardiopathy since the eighties, but we don’t really have any good information on the right dose. “
He noted that U.S. guidelines suggest that any dose between 81 mg and 325 mg daily can be used, while European guidelines recommend 81 mg daily, although it is based primarily on observational data and expert opinion; there is little hard randomized testing.
The ADAPTABLE trial randomly assigned 15,076 patients with established heart disease to receive 81 mg or 325 mg of aspirin. Prior to randomization, 96% of those who had information available were already taking aspirin, 85% of whom were taking 81 mg.
After an average follow-up of 26 months, the main criterion of effectiveness: a compound of death from all causes, myocardial infarction (MI), or stroke – had occurred in 7.28% of the 81 mg group and in 7.51% of the 325 mg group (hazard ratio) [HR], 1.02; 95% CI: 0.91 – 1.14).
The main final safety criterion, hospitalization for major bleeding with associated blood transfusion, occurred in 0.63% of the 81 mg group and in 0.60% of the 325 mg group (FC, 1, 18; 95% CI: 0.79-1.77).
“The end point of bleeding safety seemed similar, which may be counterintuitive to what might have been expected,” Jones commented. “However, the safety endpoint was very strict. We have not yet analyzed all the less serious ADRs. [adverse drug event]/ bleeding data, but in general it seems to be balanced “.
He added: “Most cardiologists probably wouldn’t have expected to see much difference in effectiveness between these two doses, but perhaps they would have anticipated a lower bleeding rate with the low dose. I was a little surprised to see such a bleeding rate. low in the 325 -mg group “.
Patients assigned to 325 mg had a higher incidence of dose change (41.6%) than those assigned to 81 mg (7.1%) and were more likely to discontinue treatment (11.1% vs. 7.0 %). This resulted in fewer median days of exposure to the assigned dose in the 325 mg (434 vs. 650 days) group.
“This was an open study and these studies always suffer a certain degree of infidelity with the assigned treatment group,” Jones said. “At ADAPTABLE, this was unbalanced in the fact that a much larger number of patients went from 325 mg to 81 mg than the other way around.”
“But our results reflect what happens in normal life,” he added. “People behaved in the study like they do in the real world. Sometimes they changed the dose and sometimes they stopped taking aspirin altogether. So I think the results are an accurate representation of the real world.”
A dose-based sensitivity analysis that the patient actually reported taking showed a higher risk of death, MI, or stroke in patients who took 81 mg than those who took 325 mg (HR, 1.25; 95%, 1.10 – 1.43). But, as with any postrandomization analysis, this approach has many inherent biases, Jones warned.
Design of innovative studies
The ADAPTABLE study used an innovative, low-cost design, which involved direct communication with the patients themselves.
Through the National Patient-Centered Clinical Research Network (PCORnet), a group of 40 U.S. centers committed to collecting data in a common format, invitations were sent to enroll in the study to eligible patients identified from the medical records. Consent and chance were made on the patient’s web portal.
Participants bought the aspirin themselves at the assigned dose and all follow-up was done virtually or by telephone, with the results verified remotely (based on patient reports, electronic medical records, and insurance claims). without award.
“This is a fairly orderly way of doing clinical research, which allows us to conduct a trial of 15,000 patients on a very tight budget,” Jones commented.
He estimated the trial cost between $ 18 million and $ 19 million. “No industry funder would have sponsored this study on aspirin and a typical trial with many patients performed in the traditional way would have cost at least 5 or 10 times more,” he said.
“This is the first time this type of study has been done in the United States on such a large scale and it opens up this method for future research.”
He explained that this design, which communicates directly with patients, somewhat limits the questions that can be addressed. “Because the patients themselves buy over-the-counter aspirin, this is a question they were not inclined to answer that way.”
Another innovative design feature was the inclusion of “partner patients,” with one patient designated by each center to be part of the trial organization. “This helped keep research relevant in what patients care about.
They also helped with the recruitment strategy and communication with the participants. I think this is something we need to continue and prioritize in clinical research in the future, ”Jones noted.
Proponents of the study at the ACC presentation congratulated the researchers on conducting such an innovative trial.
Donald Lloyd-Jones, MD, president of preventive medicine at Northwestern University Feinberg School of Medicine, Chicago, Illinois, said: “This is truly a great pioneering pragmatic trial and we will have to see more in the next few years. most important of this judgment for me is that you did it and that you showed us many of the promises and some of the pitfalls of these great pragmatic designs. “
Akshay Desai, MD, associate professor of medicine, Harvard Medical School, Boston, Massachusetts, added, “This was an innovative approach to answering an important question for daily clinical practice.”
On the results of the study, Lloyd-Jones said, “Perhaps the results were not too surprising, and I certainly approve of his cautious status quo statement about patients being left with the dose they have.”
But he suggested that the safety results of the bleeding were perhaps a little unexpected, as they were a little lower in the lower dose group, and asked if there was a sensitivity analysis that analyzed the bleeding by protocol. Jones replied that this was planned.
Desai also raised questions about the “unusual bleeding endpoint,” noting that bleeding rates were much lower than expected compared to other clinical trials.
Jones responded that the final criterion for bleeding with transfusion of blood products was chosen to allow investigators to accurately identify these events in claims codes. He said the endpoint probably reflected GUSTO’s classification of severe bleeding.
In a editorial which accompanies the publication of ADAPTABLE to NEJM, Colin Baigent, FMedSci, says the study provides a proof of principle that large pragmatic randomized trials can be conducted in the United States.
But Baigent, who is a professor of epidemiology and director of the Population Health Research Unit of the Medical Research Council at the University of Oxford, UK, says the high degree of dose switching is going on. producing during the trial results in some uncertainty about the results.
“Since the change was not likely to be random, the bias derived from this degree of crossing could have hidden a real difference in efficiency or safety (or both) and, moreover, cannot be concluded either. that the lack of any significant difference between the two dose groups implies the equivalence of the effects of the doses, ”he writes.
He suggests that a pilot study may have identified a preference for the 81 mg dose and allowed for methods to facilitate the equipment, such as an execution period with both doses, and that only patients who adhere at random should be considered. .
But Baigent concludes that the ADAPTABLE trial is an “important success” as it paves the way for low-cost randomized trials in the United States, which should allow many more clinical questions to be answered.
The trial was supported by an award for patient-centered results
American College of Cardiology (ACC) 2021 Scientific Sessions. Filed May 15, 2021.