Aspirin for the Primary Prevention of Cardiovascular Events: An Update of the Evidence for the U.S. Preventive Services Task Force

Cardiovascular disease (CVD) is the leading cause of death in the United States; it is the underlying or contributing cause in approximately 58% of deaths. In 2003, 1 in 3 adults had some form of CVD. In adults age 40 years or older, the lifetime risk for CVD increases to 2 in 3 for men and more than 1 in 2 for women. Mortality data from 2003 showed that CVD was an underlying cause of death in 1 of every 2.7 deaths, accounting for roughly 2.5 million deaths; the mortality rate from CVD was 308.8 per 100000 (1). The epidemiology of CVD events is different for men and women. Men have a higher risk for coronary heart disease and tend to have these events at a younger age than women. Men have a lifetime risk of 49% for a coronary heart disease event after the age of 40 years; for women, the lifetime risk is 32%. The median age for a first myocardial infarction is 65.8 years for men and 70.4 years for women. Women are more likely to die as a result of a myocardial infarction; 38% of women die within 1 year of their first myocardial infarction versus 25% of men. This may in part be because women are likely to be older when they have their first myocardial infarction (1, 2). Although incidence rates of stroke are higher among men than women, more women die of stroke than men because of their longer life expectancy. According to the Framingham data (2), the 10-year risk for initial ischemic stroke at age 55 years is 1.8% for women and 2.4% for men; at age 65 years, the risk increases to 3.9% for women and 5.8% for men. The lifetime risk for ischemic stroke for persons between the ages of 55 and 75 years is greater for women than for men (approximately 17% to 18% for women and 13% to 14% for men). After age 75 years, the risk decreases to 14% for women and 8% for men. In 2002, the U.S. Preventive Services Task Force (USPSTF) strongly recommended that clinicians discuss aspirin with adults who are at increased risk for coronary heart disease (3). The previous USPSTF recommendation for the prophylactic use of aspirin to prevent CVD was based on data from 5 randomized controlled trials (RCTs) that showed a 28% reduction in myocardial infarctions with aspirin use. Only 2 of the 5 studies included women. In 2005, data from the Women's Health Study (4) provided important information about the benefit of aspirin for women. The Women's Health Study was a trial of 39876 women randomly assigned to receive aspirin or placebo and followed for 10 years for cardiovascular events. With the availability of new data on benefits for women, the USPSTF decided to update its previous recommendation by reevaluating the evidence for aspirin use in the primary prevention of CVD, with a focus on sex-specific harms and benefits. This review updates the previous review and focuses on new evidence on the benefits and harms of aspirin for the primary prevention of CVD published since the 2002 USPSTF review and recommendation (3). Analytic Framework and Key Questions In consultation with the USPSTF, we developed an analytic framework (Figure 1). From this analytic framework, we developed the following key questions (KQs): Figure 1. Analytic framework: aspirin to prevent cardiovascular events. CHD = coronary heart disease; CVD = cardiovascular disease; GI = gastrointestinal; KQ = key question. KQ1a. Does aspirin use in women without known cardiovascular disease decrease coronary heart events, strokes, death from coronary heart events or strokes, or all-cause mortality? KQ1b. Does aspirin use in men without known cardiovascular disease decrease coronary heart events, strokes, death from coronary heart events or strokes, or all-cause mortality? KQ2a. Does aspirin use in women increase gastrointestinal bleeding or hemorrhagic strokes? KQ2b. Does aspirin use in men increase gastrointestinal bleeding or hemorrhagic strokes? Methods Data Sources and Searches For evidence on the benefits of aspirin for the primary prevention of CVD events (KQ1), we performed a literature search in PubMed by using the Medical Subject Heading terms aspirin and cardiovascular diseases. For evidence on the harms of aspirin for the primary prevention of CVD events (KQ2), we used the terms aspirin, cardiovascular diseases, gastrointestinal hemorrhage, and cerebral hemorrhage. We searched for studies published between 1 January 2001 and 28 August 2008. We limited our search to English-language studies, human studies, and studies of nonpregnant adults and to the following study types for benefits: RCT, meta-analysis, and systematic review. For evidence on harms, we limited our search to RCTs, casecontrol studies, meta-analyses, and systematic reviews. In addition to the literature search, we looked for other relevant studies in the Cochrane Central Register of Controlled Trials, through the examination of reference lists from included and other important articles, and through consultation with experts. Study Selection Two reviewers independently reviewed the titles, abstracts, and full articles and selected articles on the basis of predefined inclusion criteria. We resolved disagreements on inclusion by consensus or by involving a third reviewer, if necessary. In general, we included studies that evaluated aspirin versus control for the primary prevention of cardiovascular disease events in adults, had a study population of patients without a history of CVD or who were not at very high risk for CVD (such as patients with atrial fibrillation) and was generalizable to the U.S. primary care population, and calculated risk estimates for 1 of the following outcomes: myocardial infarction, stroke, death from myocardial infarction or stroke, or all-cause mortality for benefits and gastrointestinal bleeding, serious bleeding episodes, hemorrhagic stroke, or cerebral hemorrhage for harms. We accepted studies that included patients with a history of CVD or patients who were at very high risk for CVD only if those studies reported separate results for patients without a history of CVD or who were not at very high risk for CVD. Data Extraction and Quality Assessment Two reviewers independently abstracted and quality-rated the included articles. We extracted the following data: geographic location, duration of therapy, proportion of female patients, dosage, control, blinding, outcome adjudication, additional therapies, demographic characteristics, and effect estimates on the previously listed outcomes. We evaluated the quality of the individual studies by using previously published USPSTF criteria on internal and external validity (Appendix Table) (57). We evaluated RCTs on adequacy of randomization; maintenance of similar groups (includes attrition, crossovers, adherence, and contamination); loss to follow-up; equality, reliability, and validity of measurements; clarity of intervention definitions; and appropriateness of outcomes. We evaluated systematic reviews on comprehensiveness of sources considered, search strategy used, explicit selection criteria, standard appraisal of included studies, validity of conclusions, recency, and relevance. We excluded studies of poor quality. We determined generalizability of the study sample to the United States by consensus of 3 reviewers after discussions with the USPSTF on similarities between the health care system in the study country and that of the United States. Considerations about whether a population would be similar to the U.S. population include baseline risk for cardiovascular disease, general health status of the population, and the availability of acute medical care and treatment in a health system with available tertiary care centers. Appendix Table. U.S. Preventive Services Task Force Hierarchy of Research Design and Quality Rating Criteria Data Synthesis We synthesized the studies qualitatively and organized them by key question. We did not synthesize quantitatively because of the availability of a good-quality meta-analysis by Berger and colleagues (8). We discuss the results of this meta-analysis in the Results section. Role of the Funding Source The general work of the USPSTF is supported by the Agency for Healthcare Research and Quality. This specific review did not receive separate funding. Results Our literature search initially identified 726 potentially relevant articles (Figure 2). We excluded most studies because either the sample population comprised only patients at very high risk for CVD or with a history of CVD or the study did not evaluate aspirin for the primary prevention of CVD. We also excluded studies that were duplicates or provided no new information, were not of appropriate study design, or did not report outcomes of interest. We ultimately included 4 studies, which we discuss. The 4 studies provided information on both benefits and harms. Figure 2. Study flow diagram. Key Question 1 Does aspirin use in men and women without known cardiovascular disease decrease coronary heart events, strokes, death from coronary heart events or strokes, or all-cause mortality? New evidence from controlled trials is limited to 1 study in women, the Women's Health Study (4), that reported benefit in the reduction of ischemic strokes with aspirin use. The Women's Health Study was a good-quality, double-blind RCT that evaluated the risks and benefits of aspirin for the primary prevention of cardiovascular disease. The investigators reported a benefit from aspirin use for the reduction of strokes (relative risk [RR], 0.83 [95% CI, 0.69 to 0.99]), specifically ischemic strokes (RR, 0.76 [CI, 0.63 to 0.93]), and no statistically significant benefit in the reduction of combined cardiovascular events, myocardial infarctions, death from CVD, or all-cause mortality. We considered this study to be of good quality because a blinded end point committee of physicians reviewed medical records for all reported end points, analyses were completed by using an intention-to-treat process, and the follow-up rate was high. The investigators did not re