Meta-Analysis Throws More Shade Aspirin’s Way

A new meta-analysis has added evidence questioning the utility and efficacy of prophylactic low-dose aspirin for preventing cardiovascular events in people who don’t have atherosclerotic cardiovascular disease (ASCVD), whether or not they’re also taking statins, and finds that at every level of ASCVD risk the aspirin carries a risk of major bleeding that exceeds its potentially protective benefits.

In a study published online in JACC: Advances, the researchers, led by Safi U. Khan, MD, MS, analyzed data from 16 trials with 171,215 individuals, with a median age of 64 years. Of the population analyzed, 35% were taking statins.

“This study focused on patients without ASCVD who are taking aspirin with or without statin therapy to prevent ASCVD events,” Dr. Khan, a cardiovascular disease fellow at Houston Methodist DeBakey Heart and Vascular Institute, told this news organization. “We noted that the absolute risk of major bleeding in this patient population exceeds the absolute reduction in MI by aspirin across different ASCVD risk categories. Furthermore, concomitant statin therapy use further diminishes aspirin’s cardiovascular effects without influencing bleeding risk.”

Across the 16 studies, people taking aspirin had a relative risk reduction of 15% for MI vs. controls (RR .85; 95% confidence interval [CI], .77 to .95; P < .001). However, they had a 48% greater risk of major bleeding (RR, 1.48; 95% CI, 1.31-1.66; P < .001).

The meta-analysis also found that aspirin, either as monotherapy or with a statin, carried a slight to significant benefit depending on the estimated risk of developing ASCVD. The risk of major bleeding exceeded the benefit across all three risk-stratified groups. The greatest benefit, and greatest risk, was in the groups with high to very-high ASCVD risk groups, defined as a 20%-30% and 30% or greater ASCVD risk, respectively: 20-37 fewer MIs per 10,000 with monotherapy and 27-49 fewer with statin, but 78-98 more major bleeding events with monotherapy and 74-95 more with statin.

And aspirin, either as monotherapy or with statin, didn’t reduce the risk of other key endpoints: stroke, all-cause mortality, or cardiovascular mortality. While aspirin was associated with a lower risk of nonfatal MI (RR, .82; 95% CI, .72 to .94; P ≤. 001), it wasn’t associated with reducing the risk of nonfatal stroke. Aspirin patients had a significantly 32% greater risk of intracranial hemorrhage (RR, 1.32; 95% CI, 1.12-1.55; P ≤ .001) and 51% increased risk of gastrointestinal bleeding (RR, 1.51; 95% CI, 1.33-1.72; P ≤ .001).

“We used randomized data from all key primary prevention of aspirin trials and estimated the absolute effects of aspirin therapy with or without concomitant statin across different baseline risks of the patients,” Dr. Khan said. “This approach allowed us to identify aspirin therapy’s risk-benefit equilibrium, which is tilted towards more harm than benefit.”

He acknowledged study limitations included using study-level rather than patient-level meta-analysis, and the inability to calculate effects in younger populations at high absolute risk.

The investigators acknowledged the controversy surrounding aspirin use to prevent ASCVD, noting the three major guidelines: the 2019 American College of Cardiology/American Heart Association and the 2021 European Society of Cardiology guidelines for aspirin only among asymptomatic individuals with high risk of ASCVD events, low bleeding risk, and age 70 years and younger; and the United States Preventive Services Task Force guidelines, updated in 2022, recommending individualized low-dose aspirin only among adults ages 40-59 years with 10-year ASCVD risk of 10% or greater and a low bleeding risk.

The findings are not a clarion call to halt aspirin therapy, Dr. Khan said. “This research focuses only on patients who do not have ASCVD,” he said. “Patients who do have ASCVD should continue with aspirin and statin therapy. However, we noted that aspirin has a limited role for patients who do not have ASCVD beyond lifestyle modifications, smoking cessation, exercise, and preventive statin therapy. Therefore, they should only consider using aspirin if their physicians suggest that the risk of having a cardiovascular event exceeds their bleeding risk. Otherwise, they should discuss with their physicians about omitting aspirin.”

The study confirms the move away from low-dose aspirin to prevent ASCVD, said Tahmid Rahman, MD, cardiologist and associate director of the Center for Advanced Lipid Management at Stony Brook (N.Y.) Heart Institute. “The study really continues to add to essentially what we already know,” he said. “There was a big push that aspirin, initially before the major statin trials, was the way to go to prevent heart disease, but with later studies, and especially now with newer antiplatelet therapies and longer duration of medication for people with both secondary prevention and primary prevention, we are getting away from routine aspirin, especially in primary prevention.”

Lowering LDL cholesterol is the definitive target for lowering risk for MI and stroke, Dr. Rahman said. “Statins don’t lead to a bleeding risk,” he said, “so my recommendation is to be aggressive with lowering your cholesterol and getting the LDL as low possible to really reduce outcomes, especially in secondary prevention, as well as in high-risk patients for primary prevention, especially diabetics.”

He added, however, lifestyle modification also has a key role for preventing ASCVD. “No matter what we have with medication, the most important thing is following a proper diet, especially something like the Mediterranean diet, as well as exercising regularly,” he said.

Dr. Khan and Dr. Rahman have no relevant disclosures.

This article originally appeared on, part of the Medscape Professional Network.

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