Aspirin use in secondary prevention of cardiovascular disease (CVD) has been well established in both men and women.1 However, aspirin use for primary prevention of CVD in women has become increasingly controversial. Up until the large-scale Women's Health Study (WHS),2 randomized clinical trials evaluating the use of aspirin for primary prevention either underenrolled or did not include women, leading to questions about the relevance of the findings to women. Findings from the WHS suggest potential sex differences in primary prevention.
Previous studies of aspirin in primary prevention in women. The WHS randomized 39,876 healthy women aged 45 years or older to 100 mg of aspirin every other day or placebo. Women were treated for 10 years to assess major cardiovascular (CV) events (myocardial infarction [MI], stroke, and CV death). Unlike previous trials done in men that found a 25% to 35% reduction in coronary events and little effect on stroke,3 the WHS found that aspirin did not lower the risk of MI or CV death but instead significantly lowered the risk of total stroke by 17% and ischemic stroke by 24%. When analyzed by age group, women aged 65 years or older had significant reductions in major CV events by 26%, MI by 35%, and ischemic stroke by 30%. Younger women aged 45 to 64 years had no reduction in MI or major CV events.2 Gastrointestinal (GI) bleeding was more common with aspirin, with a 40% increase in the risk of serious bleeds. Additionally, the risk for hemorrhagic stroke was increased by 24%.
Newer findings on aspirin for primary prevention of CVD. Three recent clinical trials and one updated meta-analysis fill several knowledge gaps regarding the use of aspirin for primary prevention of CVD. The Aspirin to Reduce Risk of Initial Vascular Events (ARRIVE) trial enrolled participants across seven European countries at moderate risk of CVD (men ≥55 y with ≥2 CVD risk factors and women ≥60 y with ≥3 CVD risk factors).4 Participants (N = 12,546; one-third women) were randomized to 100 mg aspirin or placebo daily. Over a 5-year follow-up, there were no significant differences in composite CV outcomes defined as first MI, stroke, CV death, unstable angina, or transient ischemic attack (TIA); 0.84% vs 0.88%/y, respectively; hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.81-1.13). Women randomized to aspirin were twice as likely to have GI bleeding than those randomized to placebo (HR, 2.11; 95% CI, 1.36-3.28).
Another trial, A Study of Cardiovascular Events in Diabetes (ASCEND), randomized 15,480 patients with type 2 diabetes (40% women) aged 40 years and older to 100 mg of aspirin or placebo daily.5 Participants were followed for an average of 7.4 years for serious vascular events defined as nonfatal MI or stroke, TIA, or death from any vascular cause. The use of aspirin reduced incidence of serious vascular events by 1% (8.5% vs 9.6%; rate ratio, 0.88, 95% CI, 0.79-0.97; P = .01); however, the incidence of major bleeding was increased by 1% (4.1% vs 3.2%; rate ratio, 1.29; 95% CI, 1.09-1.52; P = .003).
The Aspirin in Reducing Events in the Elderly (ASPREE) trial randomized 19,114 healthy adults (56% women) aged 70 years or older (≥65 y for blacks and Hispanics) to 100 mg of aspirin or placebo daily.6 Most participants had one or more CVD risk factors, and the study was stopped early after 4.7 years of follow-up, finding no significant difference in the primary endpoint (disability or death) or major adverse CV events (fatal coronary heart disease, MI, stroke, or hospitalization for heart failure; HR, 0.95; 95% CI, 0.83-1.08). This trial found an increased risk of major hemorrhage with aspirin compared with placebo (HR, 1.38; 95% CI, 1.18-1.62). Additionally, older persons had higher rates of all-cause mortality with aspirin (5.9% vs 5.2%), which was surprisingly primarily because of cancer-related death (3.1% vs 2.3%).
In an updated meta-analysis of the 13 primary prevention trials of aspirin with more than 164,000 participants without CVD, the authors failed to find a significant reduction in all-cause mortality (HR, 0.94 [95% credible interval [CrI], 0.88-1.01) or CVD mortality (HR, 0.94 [95% CrI, 0.83-1.05).7 The analysis did find a benefit for composite CVD outcome defined as CVD mortality, nonfatal MI, and nonfatal stroke (HR 0.89; 95% CrI, 0.84-0.95); however, the number needed to treat was 265, and the risk of bleeding was higher with aspirin (HR 1.43; 95% CrI, 1.30-1.56); number needed to harm, 210).
Taken together, the recent aspirin trials found minimal CVD benefit, which was offset by excess bleeding events in low- or moderate-risk participants, those with type 2 diabetes, and older adults aged 70 years and older. Some have speculated that the recent negative trials of aspirin may have been because of the increased use of statin therapy. Previous primary prevention trials of aspirin reported no or at most 20% statin use, whereas statin use ranged from 63% to 74% in the three recent clinical trials. Platelet aggregation or ability to clot is lower when serum cholesterol levels are lower.8 Additional analyses from ongoing and completed trials, by sex as well as by statin use, will be helpful in determining whether such an interaction exists and whether it is specific to women.
Aspirin in the prevention of noncardiovascular diseases. Previous studies have suggested that long-duration aspirin therapy (for at least 10 y) may play a role in cancer prevention, specifically colorectal cancer. These results influenced the 2016 US Preventive Services Task Force (USPSTF) guidelines, which recommend considering daily low-dose aspirin for colorectal cancer prevention in persons at high risk and without an elevated risk of bleeding.9 The ASPREE trial found no benefit for cancer, with a greater number of cancer deaths in participants aged 70 years and older who received aspirin.
Guidelines. The USPSTF primary prevention guidelines were last updated in 2016 and did not include the three recent large-scale trials.9 They recommend low-dose aspirin for primary prevention in adults aged 50 to 59 years with a 10-year CV risk of 10% or more (Level B recommendation) and for adults aged 60 to 69 years at the same risk level (Level C recommendation) in the absence of increased bleeding risk. At that time, there was insufficient evidence to recommend for or against aspirin in adults aged 70 years and older.
The 2019 American College of Cardiology (ACC) and the American Heart Association (AHA) 2019 guidelines on primary prevention of CVD are the most recent to address aspirin and include the new trial findings.10 They state that low-dose aspirin should not be initiated for primary prevention in adults aged 70 years and older or in any adult at any age with an increased risk for bleeding. Aspirin may be considered in adults aged 40 to 70 years who are at higher risk (10-y CVD risk ≥20%) and in adults with diabetes and intermediate risk (10-y CVD risk ≥10%), although this had a weak recommendation (class IIB). The estimated 10-year risk calculator (available as the mobile app ASCVD Risk Estimator Plus) uses age, sex, race, cholesterol, blood pressure, diabetes, and smoking status and estimates the future risk of MI and stroke.
A woman's 10-year CVD risk, age, and bleeding risk all need to be considered when making the decision to start low-dose aspirin, and shared decision making with the patient is essential. Based on current available evidence and until sex-specific analyses are done using the new trials, the recommendation for aspirin use in primary prevention of CVD in women should be based on the 2019 ACC/AHA guidelines.10
Financial disclosure/conflicts of interest: Dr. Shufelt and Dr. Manson report no relevant financial relationships.
This Practice Pearl, developed by the authors, provides practical information on current controversial topics of clinical interest. It is not an official position of The North American Menopause Society (NAMS). Clinicians must always take into consideration the individual patient along with any new data published since the publication of this Pearl. The Practice Pearl series is coordinated by the NAMS Practice Pearl Task Force, led by Dr. Ekta Kapoor, and approved by the NAMS Board of Trustees.
Made possible by donations to the NAMS Education & Research Fund.
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5. Study Collaborative Group ASCEND, Bowman L, Mafham M, Wallendszus K, et al. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med
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10. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice. Circulation