Is Weight-Based Dosing of Aspirin Needed for Effective Primary Prevention?

Body weight has an important influence on how effective low-dose aspirin is for primary prevention of cardiovascular events, according to results of a meta-analysis of randomized trials.

A benefit from using low-dose aspirin—75 to 100 mg—was observed in people weighing 50 to 69 kg (110 to 152 lbs), but not in those who were either lighter or heaver, researchers led by Peter Rothwell, MD, PhD (University of Oxford, England), report in a study published online last week in the Lancet.

In fact, low-dose aspirin was associated with harm in people who weighed at least 70 kg (154 lbs), who saw greater case fatality of a first cardiovascular event (OR 1.33; 95% CI 1.08-1.64), and in people who weighed less than 50 kg, who had a greater risk of all-cause death (HR 1.52; 95% CI 1.04-2.21).

Conversely, aspirin doses of 325 mg or more reduced cardiovascular events only in people with a higher weight (P = 0.017 for interaction).

“We also found that the effects of aspirin on sudden cardiac death and cancer showed dose–weight interactions, suggesting that the one-dose-fits-all strategy for daily aspirin is unlikely to be optimal,” Rothwell et al say. “The substantial reductions in cardiovascular events and death at optimal doses for weight highlight the potential to improve effectiveness and argue for a more tailored dosing strategy.”

Katherine Theken, PharmD, PhD (University of Pennsylvania, Philadelphia), who co-wrote an editorial accompanying the study with Tilo Grosser, MD (University of Pennsylvania), also touched on the potential for a more personalized approach to using aspirin.

“This provides some evidence that it might be beneficial to increase aspirin doses in people of higher body weights,” she told TCTMD. “Obviously we still need to do some more research to better understand both the benefit and the risk of potentially increasing aspirin dosing, but I think this might lead to increasing of aspirin dosing in a lot of people because we do have a lot of individuals who weigh more than 70 kg.”

If physicians start increasing aspirin dose in heavier individuals, Theken added, “we also need to keep an eye out for an increased risk of the adverse events of bleeding that are also associated with aspirin.”

Aspirin’s Modest Benefits

According to the authors, the modest benefits seen with aspirin for the long-term prevention of cardiovascular events could be related to underdosing among larger individuals and overdosing among smaller individuals.

To examine how weight and other measures of body size influence the relationship between aspirin and clinical outcomes, the investigators looked at patient-level data from 10 randomized trials of aspirin in the setting of primary prevention, which included a total of 117,279 patients. Low doses of aspirin were those 100 mg or less and high doses were those 325 mg or more.

The relationship between low-dose aspirin and reduced cardiovascular events weakened as body weight increased (P = 0.0072 for interaction). Moreover, low-dose aspirin was associated with a benefit only in those weighing 50 to 69 kg (HR 0.75; 95% CI 0.65-0.85). The elevated risk of major bleeding on low-dose aspirin disappeared when individuals weighed at least 90 kg (198 lbs).

Obviously we still need to do some more research to better understand both the benefit and the risk of potentially increasing aspirin dosing, but I think this might lead to increasing of aspirin dosing in a lot of people because we do have a lot of individuals who weigh more than 70 kg. Katherine Theken

Although other measures of body size also modified the relationship between low-dose aspirin and cardiovascular outcomes, weight was the most informative, according to the authors.

Higher doses of aspirin, on the other hand, were associated with a reduction in cardiovascular events only in heavier individuals. A 325-mg dose was associated with fewer CV events in those weighing at least 70 kg (HR 0.83; 95% CI 0.70-0.98) and, in people weighing at least 90 kg, a 500-mg dose was associated with a lower risk of CV events or death (HR 0.52; 95% CI 0.30-0.89). With higher doses of aspirin, the risk of major bleeding tended to increase with weight, Rothwell et al report.

The researchers also found that weight influenced the relationship between aspirin and long-term risks of colorectal cancer, with benefits lost at higher body weights.

“Our findings that the clinical effectiveness of low-dose aspirin is reduced in people of greater weight and height, and that this association is reversed with higher doses, suggest the existence of a therapeutic window related to body size within which a given daily dose is most effective,” the authors write.

Questions About Current Practice

The study could have implications for practice, they say. “Widespread use of 325 mg aspirin once a day in the USA, and elsewhere, is questionable in low-weight individuals given the effectiveness of lower doses and the apparent hazards of excess dosing.”

Moreover, the fact that low-dose aspirin was not effective in the 80% of men and roughly 50% of women who weighed at least 70 kg “questions the use of once-daily low doses of aspirin irrespective of weight, particularly in people who smoke or are taking enteric-coated aspirin,” they argue. “More data on the weight dependence of the effects of standard-release, low-dose aspirin would be helpful, but in larger individuals, any advantage of enteric coating in reducing upper gastrointestinal tract side effects must be weighed against the loss of effect on cardiovascular events.”

Further research, however, is needed to validate the findings from this study, Rothwell et al say, noting that future comparisons of aspirin and other antiplatelet or antithrombotic regimens should be stratified by body size.

Theken agreed with the need for additional research about weight-based aspirin dosing, but said the study highlights a key issue in an era that is seeing a greater push toward precision medicine.

“I think this is an important study that’s kind of a step in the right direction, where it’s something that as far as tailoring therapy to a patient weight is a very easy thing to take into consideration,” she said. “So I think it’s really exciting from that standpoint that we can better understand how to personalize our therapy to the patient.”