Aspirin for the Primary Prevention of Cardiovascular Events: A Systematic Evidence Review for the U.S. Preventive Services Task Force
Cardiovascular disease (CVD) is the leading cause of mortality in the United States, accounting for about 1 in 3 deaths (1, 2) The evidence of net benefit of aspirin in secondary prevention is clear (3) and guidelines consistently recommend aspirin for persons with previous myocardial infarction (MI) or stroke (48) For primary prevention, however, guidelines vary about whether, and to which groups, aspirin should be recommended (6, 815) Recently, the U.S. Food and Drug Administration (16) stated that the primary prevention of MI should not be an indication for aspirin in any risk group (16) In 2009, the U.S. Preventive Services Task Force (USPSTF) (17) endorsed aspirin for the primary prevention of CVD in sex age and outcome specific recommendations. The current systematic review updates the evidence on the benefits of aspirin for the primary prevention of cardiovascular events with data from new trials. It also evaluates evidence for effect modification in subpopulations and varying aspirin dosages, formulations, and durations of use. This review was used in conjunction with additional evidence about harms (18) a decision model (19) and concurrent reviews on aspirin and colorectal (20) and other types of cancer (21) to update USPSTF recommendations. Companion articles addressing these complementary issues should also be considered for a complete picture of the benefits and harms of aspirin for primary prevention of CVD. Methods We developed an analytic framework (Appendix Figure 1) that examined the effect of aspirin in reducing MI, stroke, or all cause mortality (key question 1) and on associated increases in gastrointestinal bleeding, hemorrhagic stroke, or other serious harms (key question 2) This review addresses only key question 1; key question 2 is addressed in a review by Whitlock and colleagues (22) in this week's Annals. Potential effect modification in subpopulations was addressed a priori. Detailed methods and secondary outcome analyses are available in our full report (18) Appendix Figure 1. Analytic framework with key questions. CVD= cardiovascular disease; MI= myocardial infarction; NSAID= nonsteroidal anti inflammatory drug; PPI=protein pump inhibitor; SSRI= selective serotonin reuptake inhibitor. Data Sources and Searches We searched MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials from January 2008 to January 2015, which was supplemented by checking reference lists from relevant systematic reviews. Study Selection Two reviewers independently reviewed 3396 citations and 65 full text articles against a priori inclusion criteria (Appendix Figure 2) We included randomized, controlled trials (RCTs) and controlled clinical trials that examined the primary prevention of CVD with oral aspirin (a minimum of 75 mg every other day for 1 year or more) compared with placebo or no treatment in adults aged 40 years or older. We excluded interventions that included nonaspirin antithrombotic medications or aspirin as cotreatment with another active intervention. For multifactorial trials, we combined groups in which no evidence of interaction was found (23) and excluded cotreatment groups (24) Appendix Figure 2. Summary of evidence search and selection. KQ= key question. Data Extraction and Quality Assessment One reviewer extracted study level data into standardized evidence tables, and a second checked data accuracy. Two independent reviewers critically appraised eligible articles using predefined criteria (25, 26) and a third resolved disagreements. Data Synthesis and Analysis We examined 4 primary beneficial outcomes based on a priori decisions and the availability or consistency of outcome reporting across trials: nonfatal MI; nonfatal stroke (all types) CVD mortality, which was defined as a composite of death due to MI, stroke, and CVD; and all cause mortality. Due to the rarity of cardiovascular and all cause mortality events >1% but <10% we used the MantelHaenszel fixed effects model as the primary statistical analysis method (27) We assessed statistical heterogeneity using the I 2 statistic. For estimating absolute risk reduction and exploring potential variability among candidates for aspirin chemoprevention, we calculated absolute effects by simulating control group event rates for our primary outcomes. We simulated the event rate per 1000 person years by dividing the number of events for each outcome by the person years at risk (calculated by multiplying the sample size of the control group by the mean follow up years) thereby assuming constant risks over time. We selected the minimum, median, and maximum event rates (excluding outliers and zeros) for each outcome and calculated the range of expected control event rates after aspirin intervention using the pooled relative risks (RRs) from the included CVD primary prevention trials evaluating aspirin doses of 100 mg or less per day (28) Subpopulation Methods A priori subpopulations included age, sex, diabetes, smoking, race/ethnicity, CVD risk, decreased anklebrachial index, elevated blood pressure, and elevated lipid levels. We abstracted subgroup analyses for these groups and considered their credibility based on the timing of planned analysis, interaction testing for heterogeneity of treatment effect, baseline comparability, and control for confounders (29) To minimize confounding, we emphasized within study comparisons over between study comparisons. We evaluated subgroup analyses qualitatively because those reported were too limited to pool. Role of Funding Source Agency for Healthcare Research and Quality staff provided oversight for the project and assisted in external review of the companion draft evidence synthesis. The USPSTF liaisons helped with scoping issues but were not involved in the conduct of the review. Results Description of Included Trials We found 11 eligible RCTs (2 good quality and 9 fair quality) that tested the benefits of aspirin for the primary prevention of cardiovascular events in 118445 participants; trials ranged from 1276 to 39876 participants (24, 3039) (Appendix Table) Follow up durations ranged from 3.6 to 10.1 years; most trials lasted 4 to 6 years. Eight of 11 trials studied aspirin doses of 100 mg or less per day or 100 mg or less every other day (24, 31, 3335, 3739) Older trials used higher doses (325 to 650 mg/d) (30, 32, 36) Three of 11 trials were conducted exclusively in men (24, 30, 36) and 1 was conducted exclusively in women (37) Where reported, the mean age of participants was 55 to 70.5 years, and the oldest participants recruited were aged 84 and 85 years (30, 35, 39) Appendix Table. Methodological and Intervention Characteristics of Included Trials for Primary Prevention of Cardiovascular Events Four trials (31, 33, 35, 39) published since the previous review for the USPSTF (17) focused on populations with cardiovascular risk factors, including diabetes and abnormal anklebrachial index. The level of baseline cardiovascular risk in included populations, which was estimated by the annualized CVD event rate in control groups, varied widelyfrom 0.26% in the WHS (Women's Health Study) (37) to 4.09% in the ETDRS (Early Treatment Diabetic Retinopathy Study) (32) Effect of Aspirin on Nonfatal MI Ten trials (24, 30, 31, 3339) reported the effect of aspirin for the primary prevention of nonfatal MI. Meta analysis showed a statistically significant 22% reduction in nonfatal MI, although heterogeneity was high (RR, 0.78 [95% CI, 0.71 to 0.87] I 2= 61.9% (Figure 1, top) Three of the 4 largest trials (30, 34, 39) showed a statistically significant benefit despite being conducted in considerably different populations. The fourth large trial (WHS) showed an MI benefit in the older age group but not overall. One smaller trial conducted in high risk men (40% were smokers) also showed an MI benefit, with additional smaller trials trending in this direction (33, 38) Two point estimates were near 1 (31, 36, 37) and 1 trial (35) that included few events showed a trend toward favoring the control group. Qualitative exploration of heterogeneity by aspirin dose, publication date, and cardiovascular risk as estimated by control group event rates did not clearly explain heterogeneity. Figure 1. Benefits of aspirin for nonfatal MI and nonfatal stroke. AAA= Aspirin for Asymptomatic Atherosclerosis; ABI= ankle brachial index; BMD= British Male Doctors Trial; CG= control group; CVD= cardiovascular disease; ETDRS= Early Treatment Diabetic Retinopathy; HOT= Hypertension Optimal Treatment; IG= intervention group; JPAD= Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes; JPPP= Japanese Primary Prevention Project; MI= myocardial infarction; PHS= Physicians' Health Study; POPADAD= Prevention of Progression of Arterial Disease and Diabetes; PPP= Primary Prevention Project; RR= relative risk; TPT= Thrombosis Prevention Trial; WHS= Women's Health Study. Effect of Aspirin on Nonfatal Stroke Ten trials that reported nonfatal stroke (all types) yielded mixed results, with RR estimates ranging from 0.64 to 1.26 (Figure 1, bottom) A pooled analysis from these 10 trials showed no difference in nonfatal stroke in the aspirin group compared with the control group, and heterogeneity was relatively low (RR, 0.95 [CI, 0.85 to 1.06] I 2= 25.1% Only the WHS (37) showed a statistically significant benefit for aspirin (RR, 0.81 [CI, 0.67 to 0.97] This good quality trial of 100 mg of aspirin every other day was conducted in a large sample of generally younger female health professionals (mean age was 55 years, with only 10% aged 65 or older) Other trials showed mixed results (24, 3033, 35, 36, 38, 39) Effect of Aspirin on CVD Mortality Eleven trials contributed to our composite CVD mortality analysis. Pooled analysis showed no statistically significant effect (RR, 0.94 [CI, 0.86 to 1.03] I 2= 8.8% (Figure 2, top) Two trials showed a statistically significant ben
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