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

By Michael Hayden, Michael P. Pignone, C. Phillips, C. Mulrow. Annals of Internal Medicine, 2002

597 citations recorded by the source corpus.

Cardiovascular disease, including ischemic coronary heart disease, stroke, and peripheral vascular disease, is the leading cause of morbidity and death in the United States (1). In 1997, the age-adjusted mortality rate due to coronary heart disease, cerebrovascular disease, and atherosclerotic disease was 194 per 100 000 persons, which is equivalent to more than 500 000 deaths per year (1). The estimated direct and indirect costs of coronary heart disease and stroke were $145 billion for 1999 (2). Although the benefit of aspirin for patients with known cardiovascular disease is well established (3), the question of whether aspirin reduces the risk for cardiovascular disease in persons without known cardiovascular disease is controversial. Two early randomized trials of aspirin in healthy men, the U.S. Physicians' Health Study (PHS) and the British Male Doctors' Trial (BMD), had conflicting results regarding whether aspirin reduced the risk for myocardial infarction. Neither trial had sufficient power to precisely estimate major harms, such as gastrointestinal bleeding and hemorrhagic stroke (4, 5). The results of these randomized, controlled trials were available to the members of U.S. Preventive Services Task Force at the time of their 1996 recommendation (4, 5). At that time, the Task Force found insufficient evidence to recommend for or against routine aspirin prophylaxis for the primary prevention of myocardial infarction in asymptomatic persons (6). Two additional large primary prevention trials were published in 1998, and another was reported in January 2001 [7-9]. In light of the new evidence, the U.S. Preventive Services Task Force sought to reassess the value of aspirin for the primary prevention of cardiovascular events. The Task Force's assessment was performed in partnership with the Agency for Healthcare Research and Quality, Rockville, Maryland, and investigators from the RTI-UNC Evidence-based Practice Center, Research Triangle Park, North Carolina. For this review, we examined three key questions: 1) Does aspirin chemoprevention in patients without known cardiovascular disease reduce the risk for myocardial infarction, stroke, and death? 2) Does aspirin chemoprevention increase major gastrointestinal bleeding, hemorrhagic strokes, or both? 3) What is the balance of benefits and harms for aspirin therapy in patients with different levels of risk for coronary heart disease? The analytic framework of the review can be found in Appendix Figure 1. Methods Identification of Relevant Trials We searched MEDLINE from 1966 to May 2001 to identify studies examining aspirin's ability to prevent cardiovascular events and its likelihood of causing adverse effects. The literature search and data extraction are detailed in the Appendix. Quality Assessment We assessed the quality of the trials that examined the benefits of aspirin therapy, considering methods of randomization, blinding, analysis by intention to treat, follow-up rates, and crossover of assigned interventions. To look for differences in estimates of effect, we then performed meta-analyses using only the trials considered to be of good quality. Modeling We used our best estimates of the beneficial and harmful effects of aspirin chemoprevention to model its impact on populations of patients with different levels of risk for coronary heart disease. We estimated beneficial effects by using the odds ratios calculated from the meta-analyses; estimates of harmful effects were derived from other systematic reviews, supplemented by studies identified in our literature searches. We based our estimates on 1000 persons receiving aspirin for 5 years and used 95% CIs from the meta-analyses to produce plausible ranges around our point estimates. We also examined how these effects may differ for elderly persons, women, and patients with hypertension or diabetes. Statistical Analyses For individual trials, we calculated estimates of unadjusted odds ratios with 95% CIs (10). Because not all of the trials presented their outcomes using the same means of categorization, we contacted the investigators in some cases to determine the actual numbers of certain events and recalculated summary measures to improve comparability. We performed meta-analysis using the DerSimonian and Laird random-effects model in RevMan (Cochrane Collaboration, Oxford, United Kingdom) (11). Heterogeneity was assessed by using graphs of the outcomes and the MantelHaenszel chi-square test. Data Synthesis Literature Searches The results of our search strategy are shown in the Appendix. We identified 5 randomized, controlled trials that had been designed to assess the efficacy of aspirin in the primary prevention of cardiovascular disease: the British Male Doctors' Trial (BMD), the Physicians' Health Study (PHS), the Thrombosis Prevention Trial (TPT), the Hypertension Optimal Treatment Trial (HOT), and the Primary Prevention Project (PPP) (4, 5, 7-9). We excluded 2 large trials that examined the effect of aspirin in patients with diabetes or with stable angina because more than 10% of the participants had definite or suspected vascular disease (12, 13). From our search for articles on adverse effects, we identified 9 articles that examined the effect of aspirin on gastrointestinal bleeding and hemorrhagic stroke (3, 14-21). Trial Characteristics The characteristics of the 5 randomized trials, which included a total of more than 50 000 patients, are shown in Table 1. The duration of the trials ranged from 3 to 7 years. Only 2 trials (HOT and PPP) included women. Aspirin dosage was 500 mg daily in BMD and 162 mg or less per day in the other 4 trials. Most participants were middle-aged, although 4 of the 5 trials included substantial numbers of patients who were 70 to 80 years of age. Table 1. Summary of Primary Prevention Trials Assessment of Study Quality Overall, the quality of the trials examining the effectiveness of aspirin was high. All 5 trials concealed allocation of randomization. Researchers and participants were blinded in 3 trials (PHS, HOT, and TPT). In BMD and PPP, participants were not blinded and were not given placebo pills. Analyses in all trials were by intention to treat. Fewer than 1% of participants were lost to follow-up in BMD, PHS, and TPT, and 2.6% were lost to follow-up in HOT. In PPP, 7.7% of patients were lost to clinical follow-up, but data on vital status were obtained from census offices for 99.3% of the total sample. During BMD, 39% of participants in the aspirin group discontinued therapy, primarily because of dyspepsia; 11% of participants assigned to no therapy began taking aspirin during the course of the trial. In contrast, in PHS, 14% of participants crossed over to the opposing treatment groups but rates of gastrointestinal discomfort did not differ significantly in each group. In PPP, 19% of patients assigned to aspirin discontinued taking it (8% due to side effects) and 7% of patients assigned to no aspirin were taking aspirin at the trial's conclusion. Crossover rates were not explicitly reported in TPT and HOT, although approximately 50% of patients participating in TPT withdrew for unreported reasons. However, the rate of withdrawal in TPT did not differ between the treatment and control groups. On the basis of these features, we rated the quality of PHS, TPT, and HOT as good and the quality of BMD and PPP as fair. Effect of Aspirin on Coronary Heart Disease All trials had point estimates suggesting that aspirin prevented total coronary heart disease events, defined as nonfatal myocardial infarction or death due to coronary heart disease (fatal myocardial infarction or sudden death) (Table 2). In PHS and TPT, aspirin use was associated with increases in sudden death that did not reach statistical significance: 22 events with aspirin versus 12 events with placebo in PHS (odds ratio, 1.83 [95% CI, 0.91 to 3.71]) (4), and 18 events with aspirin versus 11 with placebo in TPT (odds ratio, 1.65 [CI, 0.78 to 3.51]) (22). Table 2. Effect of Aspirin on Risk for Coronary Heart Disease in Primary Prevention Trials Meta-analysis of the 5 trials for the combined outcome of confirmed nonfatal myocardial infarction or death from coronary heart disease produced a summary odds ratio of 0.72 (CI, 0.60 to 0.87) (Figure 1). The MantelHaenszel test suggested possible heterogeneity (P = 0.089), reflecting the anomalous result of BMD. In that study, no difference was found in the rate of myocardial infarction between the intervention and control groups. Figure 1. Meta-analysis of total coronary heart disease events. P Mortality data for coronary heart disease (fatal myocardial infarctions and sudden death) from HOT and PPP were not reported separately in the main papers but were obtained from the authors (Hannson L. Personal communication, 2000; Roncaglioni C. Personal communication, 2001). Of the 5 trials, only PHS reported a statistically significant decrease in risk with aspirin (odds ratio, 0.64 [CI, 0.42 to 0.99]). Cumulative mortality rates for coronary heart disease in the placebo group were low, ranging from 0.15% in HOT to 2.7% in BMD and TPT. Meta-analysis of the 5 trials found a summary odds ratio of 0.87 (CI, 0.70 to 1.09) (Figure 2, top). There was no significant heterogeneity in trial results (P > 0.2). Figure 2. Meta-analysis of the effect of aspirin on coronary heart disease mortality (top), fatal and nonfatal stroke events (middle), and all-cause mortality (bottom). P Effect of Aspirin on Stroke It is difficult to interpret the overall effect of aspirin on stroke because the effect differs according to stroke subtype (Table 3). Data from secondary prevention trials suggest that aspirin prevents ischemic strokes but show that aspirin can also cause hemorrhagic stroke. The effect of aspirin on the total incidence of stroke depends on the patient's underlying risk for each stroke subtype (23). Overall stroke rates were lower than expected (based on age and risk

Subfields: Cardiology and Cardiovascular Medicine, Endocrinology, Diabetes and Metabolism, Surgery

View Paper: https://www.semanticscholar.org/paper/3f81815efbd0d1a3f291d569f995a9bb771692ca