Erin D. Michos, MD, MHS, FACC, FAHA, FASE, FASPC

ADAPTABLE attempted to answer once and for all: What is the optimal dose of aspirin for secondary prevention among patients with ASCVD? It was a clinical question in need of more evidence.  

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. Additionally, for patients who are currently treated with higher-dose aspirin (325 mg) who are stable and doing well, there also is not a compelling reason to automatically switch them to a lower dose either.

However, the caveat is that these trial results were limited by major dose switching, a problem from the open-label design. Patients and their clinicians knew what dose they were taking. So, 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.

Aspirin still remains a class I indicated therapy for the secondary prevention of ASCVD. These results don’t change that. But for decisions about which dose can be decided between patients and their clinicians based on their own unique risk factors for recurrent vascular events compared with bleeding events, patients and their clinicians should have a conversation, discuss the study results, and decide which dose makes sense for them.

Of note, contrary to prior studies, in ADAPTABLE, the authors did not see any interaction among key subgroups defined by age, sex, race/ethnicity, prior use of dual antiplatelet therapy, or coexisting diabetes or chronic kidney disease.

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.

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.

Another important key feature of the ADAPTABLE trial was its patient-centered design. Patient representatives, known as “adaptors,” served on the steering and executive committees, gave input on trial design and reviewed all patient-facing materials. This is important to make sure that any patient barriers are overcome by design considerations, and that study materials represent the diversity of the participants that are hoped to be recruited. The patient adaptors will also play a key role in dissemination of study results. Going forward, patient-centered design — trials designed with the input of patients — should be a critical component of all studies.

Jeffrey S. Berger, MD

Aspirin is one of the most commonly used medicines for the prevention of CV events. However, practice patterns are variable. Even before ADAPTABLE, there were little data to support using a higher dose than 81 mg to 100 mg daily for secondary CVD prevention, but there appeared to be widespread belief that more may be better. Hopefully, ADAPTABLE will reinforce to the medical community that there is no clinical benefit for a higher dose of aspirin.

While this study demonstrates that 325 mg is not superior to 81 mg of aspirin, we should remember that aspirin remains a cornerstone in the secondary prevention of CV events. I think some questions remain: 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; in the future, 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 most important aspect of ADAPTABLE is that it provides a new platform for how to conduct a large clinical trial. 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; it may be more difficult with a drug that people are not as comfortable with. I look forward to the challenge.

Michael H. Davidson, MD, FACC, FACP, FNLA

Some of the most frequently asked questions by patients to a preventive cardiologist involve aspirin therapy. In regards to primary prevention, the questions usually revolve around the issue if they should take aspirin. What if I have diabetes, elevated Lp(a) or pre-clinical ASCVD as documented by a high coronary calcium score, should I take aspirin 81 mg per day? This question is difficult to answer based on the lack of evidence from randomized trials. We clinicians have to provide our best judgment knowing we need more data.

Now thanks to the ADAPTABLE trial, we can at least answer the question regarding the dose for patient with ASCVD. This trial was a randomized but open label with a pragmatic design to allow flexibility to address this important question. The conclusion is that for patients with ASCVD, aspirin 81 mg was equivalent to 325 mg for prevention of major adverse events. Safety was also similar, but more patients decided to downtitrate to the lower dose vs. uptitrate to the higher dose.

This is a landmark trial for two reasons. It confirms that aspirin 81 mg is the correct dose for most patients with ASCVD, and perhaps more importantly, it has finally broken through the barrier of requiring double-blind, placebo-controlled trials with multiple visits to track outcomes. 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.

My hope is that the learnings from the ADAPTABLE trial set the stage for more pragmatic trials in the future in which an open-label design can be implemented with remote data capture through electronic medical record systems.

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. This has ramifications for many of the prevention guidelines in which higher doses of drugs are recommended (eg, statins) due to the data generated from large rigorous outcome trials.

This is potentially the beginning of a new era of CV prevention trials in which clinical decision-making can be based on high quality data that meets an appropriate standard through a pragmatic design but not to the same standard that we have been accustomed to in the past. Is it not better to get a good answer to an important clinical question than no answer at all?

Robert S. Rosenson, MD

Many patients are on long-term aspirin therapy and develop chronic anemia from gastritis or may have frequent bruising they may find unpleasant, so the question of the correct dose of aspirin for patients with CVD is an important one.

The event rates were no different between the dosage groups, but the study raises a lot of questions. The large-scale approach lowers costs, but there may be some important issues that are obscured by the nature of the study.

No. 1, we know that in patients taking enteric-coated aspirin, not everybody has an antiplatelet effect. One study of stroke survivors found that 20% of patients taking aspirin 325 mg daily and 45% taking aspirin 81 mg daily did not have an antiplatelet effect. An important issue is what type of aspirin is being taken. Coated or noncoated? Chewable or swallow-at-once?

No. 2, it is unclear why some patients stopped taking aspirin or decided to reduce their dose. 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 down-titrated the dose of the aspirin. The granularity of those issues is not easily addressed with this type of study design.

The take-home message is that low-dose aspirin is equally effective to higher-dose aspirin in patients with stable ASCVD. It’s hard to say that this is transformative because other studies have shown lower doses of aspirin are equally effective.

The trial design could be useful for future comparative studies of BP medications. To do a randomized, double-blind, controlled trial, it 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.