Aspirin in ASCVD: Baby dose as good as high dose?

Taking low-strength aspirin at 81 mg dose daily (also known as baby aspirin) appeared to be as effective as a higher dose of 325 mg for secondary prevention in people with established atherosclerotic cardiovascular disease (ASCVD), with no difference in major bleeding outcomes, according to the ADAPTABLE* trial presented at ACC.21.

Aspirin has been the most commonly used medications to combat heart disease, said lead investigator Dr Schuyler Jones from Duke University in Durham, North Carolina, US. “Despite its widespread use … there really hasn’t been a clear answer about what is the most effective and safe dose of aspirin for these patients.”

According to Jones, the ADAPTABLE study set out to answer a simple but important question: in patients with established or pre-existing CVD, is a strategy of 81 mg or 325 mg of aspirin better?  

“In fact, it’s a decision that patients make every day when they purchase aspirin over the counter, and the correct dose may prevent thousands of deaths/heart attacks, while balancing the risk of bleeding,” he explained.

Message for patients

After 26.2 months of median follow-up, the investigators found no significant difference between the 81 mg vs 325 mg doses of aspirin with regard to the primary efficacy endpoint comprising a composite of myocardial infarction (MI), stroke, or all-cause death (7.28 percent vs 7.51 percent; hazard ratio [HR], 1.02; p=0.75). [N Engl J Med 2021;doi:10.1056/NEJMe2106430]  

The incidence of the primary safety endpoint — defined as hospitalization for major bleeding with associated blood transfusion — was also comparable between the two groups of patients (0.63 percent vs 0.60 percent; HR, 1.18, 95 percent CI, 0.79–1.77).

“Based on our findings of the generally neutral trial results, we recommend that most patients [who are already on 81 mg] do not change their aspirin dose,” Jones stated.

“If restarting aspirin, patients should choose low-dose aspirin given there is no clear evidence that higher dose is better.” 

“For patients who are currently tolerating 325 mg and have done so over time, they may want to stay on this dose as it may be associated with moderate benefit,” he added, while suggesting that “these patients should speak with their clinicians about staying on this dose.”   

Major achievement, but for trial design

ADAPTABLE was an open-label study with pragmatic design, which randomized 15,076 patients (median age 68 years) with established ASCVD to take aspirin at a dose of 81 mg or 325 mg daily.

“This is really a pioneering large pragmatic trial,” commented discussant Dr Donald Lloyd-Jones of Northwestern University Feinberg School of Medicine, Chicago, Illinois, US. “The most important legacy from this trial for me is that you did it, and that you showed us many of the promises and some of the pitfalls of these large pragmatic designs.”

“Yet, the ultimate aim of the trial was to distinguish the clinical effects of two aspirin doses,” wrote Professor Colin Baigent from the University of Oxford, UK in a linked editorial. [N Engl J Med 2021;doi:10.1056/NEJMoa2102137]

“Here, unfortunately, ADAPTABLE was less successful, not because no differences between the two dose groups were observed, but because 41.6 percent of patients who were assigned to take 325 mg daily switched to 81 mg daily.”

Not only were patients assigned to 325 mg more likely to switch dose, they were also more likely to discontinue treatment compared with those in the 81 mg group (11.1 percent vs 7.0 percent).

“Because switching was not likely to have been at random, bias arising from this degree of crossover could have obscured a true difference in efficacy or safety (or both), and moreover it is also not possible to conclude that the lack of any significant difference between the two dose groups implies equivalence of the effects of the doses,” according to Baigent.

“We made every effort to encourage them to stay on their study dose, but nevertheless people felt very strongly about it, so the differential effects of the two doses are less clear since dose switching occurred very frequently, especially in the 325 mg group,” said Jones.   

A sensitivity analysis based on the actual dose taken showed  that the risk of the composite efficacy outcome was higher in the 81 mg vs the 325 mg group (3.6 vs 2.9 events per 100 patient-years; HR, 1.25, 95 percent CI, 1.10–1.43). Nonetheless, Jones cautioned that the analysis comes with many inherent biases, as with any post-randomization analysis.

“It is imperative that we counsel our patients that aspirin is still recommended for people of ASCVD,” he urged. “[In general,] we found that there is no difference between the two doses in terms of effectiveness and safety, and we think that because the 81 mg dose had better long-term adherence, it may be the best choice for patients.”

“ADAPTABLE is a major achievement, however, because it has shown a method of conducting trials efficiently and at low cost in the US, and the method can now be adapted and used more widely,” added Baigent. “This should allow many more clinical questions to be answered.”

 

*ADAPTABLE: Aspirin Dosing: A Patient-centric Trial Assessing Benefits and Long-term Effectiveness