Original Research

Aspirin prophylaxis in patients at low risk for cardiovascular disease: A systematic review of all-cause mortality

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  • OBJECTIVE: We investigated whether aspirin reduces all-cause mortality in low-risk patients.
  • STUDY DESIGN: We systematically reviewed studies of aspirin for primary prevention to measure total mortality. We included all clinical trials, cohort studies, and case control studies that assessed primary prevention, included low-risk subjects, and measured total mortality. The quality of studies was evaluated with a standard scale.
  • DATA SOURCES: MEDLINE, the Cochrane Library, and the Internet were systematically searched for studies with the key terms primary, prevention, aspirin, myocardial infarction, stroke, and mortality. Reference lists of identified trials and reviews also were examined.
  • POPULATION: Active members in the Indiana Academy of Family Physicians 2000–2001 membership database (N = 1328).
  • OUTCOMES MEASURED: Primary outcomes were myocardial infarction, stroke, and mortality.
  • RESULTS: Three primary prevention studies met our criteria. Two clinical trials, the United States Physicians Health Study and British Doctors Study, demonstrated no significant decrease in mortality in the aspirin group alone or when results from the 2 studies were combined. The United States Physicians Health Study showed a lower rate of myocardial infarction (odds ratio [OR], 0.58; 95% confidence interval [CI], 0.47–0.71). In the Nurses Health Study, a cohort study, taking aspirin at any dose was associated with higher rates of myocardial infarction (OR, 2.34; CI, 1.92–2.86), stroke (OR, 1.84; CI, 1.39–2.44), and all-cause mortality (OR, 1.83; CI, 1.57–2.14).
  • CONCLUSIONS: There is currently no evidence to recommend for or against the use of aspirin to decrease mortality in low-risk individuals.



  • Only 3 primary prevention studies of aspirin included low-risk subjects and measured all-cause mortality.
  • Two of those studies demonstrated no significant decrease in mortality with low-dose aspirin.
  • The Nurses Health Study demonstrated a dose-dependent increase in mortality with aspirin use.
  • There is insufficient evidence for or against recommending aspirin to low-risk individuals.

Cardiovascular disease is the leading cause of death in the United States, and aspirin, a platelet aggregate inhibitor, is often recommended as prophylaxis for cardiovascular disease.1-3Clinical studies have demonstrated the benefit of aspirin use for secondary prevention of cardiovascular disease and stroke.1,4-10 In high-risk subjects, aspirin has been proven effective in primary prevention of major cardiovascular events and nonfatal ischemic heart disease.11-13 Sanmuganathan and colleagues recently reported a meta-analysis of 4 randomized trials of aspirin for primary prevention. Although they determined that aspirin treatment is safe if the coronary event rate is at least 1.5% each year and unsafe if the rate is no higher than 0.5% each year, they did not address all-cause mortality, and 2 of the 4 trials did not include low-risk subjects.9

Many physicians and patients are prescribing aspirin with the expectation of reduced mortality in high-risk and low-risk individuals. Media advertisements and health programs may not clearly delineate the population for whom aspirin has clear benefits. A recent review suggested that aspirin is likely to be effective for primary prevention in yet to be defined groups.14 This review seeks to answer 2 questions. First, are there any primary prevention studies using aspirin that included only low-risk subjects? Second, should aspirin be prescribed routinely to persons at low risk for cardiovascular disease to decrease total mortality?


Search strategy

The MEDLINE database and the Cochrane Library were systematically searched using the terms aspirin or antiplatelet therapy and primary prevention or prevention and primary and mortality. An additional search was made with primary prevention and myocardial infarction or stroke. The Internet was searched (http://www.google.com) by using the same search terms. The studies were limited to human populations. Search results consisted of abstracts, complete reviews, and reference lists from articles. Morbidity associated with aspirin use also was reviewed.

Selection criteria: end points

Only those studies that investigated primary prevention of cardiovascular disease using aspirin, had low-risk subjects, and included a measure of total mortality were part of our analysis. We used the 2001 Adult Treatment Panel III Guidelines and the recent British Medical Journal clinical evidence guidelines on primary prevention of cardiovascular disorders to define the low-risk patient.15,16 Those guidelines classified major risk factors for ischemic vascular disease as hypertension, low high-density lipoprotein cholesterol, high lowdensity lipoprotein cholesterol, family history of premature coronary heart disease, smoking, diabetes, and advancing age (men ≥ 45 years, women ≥ 55 years). We also classified those patients with past cerebrovascular events, myocardial infarction, and angina as high risk. We defined low risk as having no more than 1 of these risk factors.

Every trial was evaluated independently by each author according to the Jadad scale.17 Based on information in the original articles, we recalculated the odds ratios (ORs) for each study. The results of the 2 randomized trails were combined by means of the Mantel-Haenszel method for combining ORs, and StatXact 4 for Windows was used for the analysis.18,19 The data were used to create a forest plot of mortal-ity.19 The decision to combine studies of like type was made a priority.


MEDLINE search results for aspirin and primary prevention yielded 291 articles. Antiplatelet therapy and primary prevention yielded 64 articles. Myocardial infarction or stroke and primary prevention yielded 514 articles. Cross-referencing aspirin, prevention, and mortality yielded 690 articles. The Cochrane Library search of antiplatelet therapy and prevention and primary yielded 17 complete reviews and 6 abstracts of systematic reviews. No additional studies published or unpublished were identified through the Internet.

Five clinical trials and 1 cohort study that evaluated aspirin for primary prevention were identi-fied.11,12,20-23 One of those, a pilot study, was excluded because it did not provide mortality data for the aspirin and placebo groups.23 Two clinical trials, the Hypertension Optimal Treatment Trial and the Thrombosis Prevention Trial, did not include low-risk subjects.11,12 Although no studies were identified that included only low-risk subjects, 3 studies met our inclusion criteria. Characteristics of those 3 studies are reported in Table 1.

The US Physicians Health Study (USPHS) randomized physicians into 4 treatment groups: aspirin plus beta-carotene, aspirin plus placebo, betacarotene plus placebo, and placebo plus placebo.20 Both aspirin groups took 325 mg every other day. The mean age was 53.2 years.24 Fifty percent of the participants were current or past smokers, and 9% had hypertension. Although the rate of myocardial infarction was significantly lower in the aspirin group, there was no reduction in total cardiovascular mortality. The results are reported in Table 2. More side effects were noted in the aspirin group, including gastric ulcers, gastrointestinal bleeding, hemorrhagic stroke, and other bleeding disorders.20 No separate analysis of low-risk subjects’ risk was performed.

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