For patients without known cardiovascular disease who are similar to those enrolled in the five large primary prevention trials, our systematic review suggests that aspirin chemoprevention reduces myocardial infarction but has no effect on ischemic stroke or all-cause mortality over 5 years. Aspirin therapy also increases the risk for gastrointestinal bleeding and hemorrhagic stroke. Aspirin chemoprevention is probably beneficial for patients who have no previous diagnosis of CVD but are at high risk for developing CHD in the next 5 years. Conversely, patients at low risk for CHD probably do not benefit from and may even be harmed by aspirin because the risk for adverse events may exceed the benefits of chemoprevention.6,28
To aid in applying these general results to individual patients, we have attempted to define quantitatively the benefits and harms of aspirin at various levels of risk for CHD. The advantage of such an approach is that it allows a more specific and accurate discussion and consideration of the potential consequences of using or not using aspirin for each individual patient.
Utilization of our results from our review in shared decisionmaking with patients requires an estimation of a given patient's absolute risk for CHD as well as his or her willingness to accept the risks of low-dose aspirin to avoid CHD events. Risk for future CHD events can be predicted from coronary risk algorithms.29 Factors used to estimate risk include sex, age, blood pressure, serum total cholesterol level (or low-density lipoprotein cholesterol level), high-density lipoprotein cholesterol level, diabetes mellitus, cigarette smoking, and left ventricular hypertrophy (LVH).
Several easy-to-use risk assessment tools, most based on risk equations derived from the Framingham Heart Study, are available on the Internet (for example, at www.intmed.mcw.edu/clincalc/heartrisk.html) or in printed form.29 For tools that calculate only 10-year risk estimates, halving the 10-year estimate is a reasonable approximation of the 5-year risk for which we project our potential outcomes. Framingham data have recently been shown to generalize adequately to other populations.30 We have also provided a risk calculator at www.med-decisions.com to facilitate risk calculation.
Estimates of benefits and harms should be interpreted and compared cautiously. The principal beneficial effect of aspirin, a reduction in nonfatal myocardial infarction, cannot be directly equated to an adverse event, such as a stroke or gastrointestinal bleeding. We modeled outcomes over a period of 5 years because the trials included in our review ranged from 3 to 7 years in duration. However, outcomes from the use of aspirin chemoprevention will affect not only patients' current health status but also their future risk for CHD. For example, a nonfatal myocardial infarction may produce a relatively small decrement in the patient's current health status but may also increase the future risk for a more disabling condition, such as recurrent myocardial infarction or congestive heart failure, and may lead to premature death.
The value that individual patients place on the outcomes affected by aspirin will vary. Decision analysts have measured mean values in representative populations. Augustovski et al.31 used existing studies to estimate utility values as follows: nonfatal myocardial infarction, 0.88; disabling stroke, 0.50; nondisabling stroke, 0.75; and gastrointestinal bleeding, 0.97. Our estimates of expected event rates and these mean utility values can provide an initial framework for discussion with individual patients, who may weigh or value outcomes differently.
Others have attempted to quantitate the benefits and harms of aspirin therapy.19,32 Sanmuganathan et al.33 performed a meta-analysis of the first four primary prevention trials and reached similar estimates of the beneficial effects of aspirin. They chose to combine data on harms into a single category of "major bleeding events" induced and calculated that the number of bleeding events induced equaled the number of cardiovascular events averted when the cardiovascular event rate was 0.22 percent per year. They further estimated that the upper end of the 95 percent confidence interval for this point estimate occurred at an event rate of 0.8 percent per year for CVD; this is equivalent to an event rate of 0.6 percent per year for CHD. Sanmuganathan et al. concluded that aspirin was "safe and worthwhile" for people whose risk for CHD events exceeded 1.5 percent per year and was "unsafe" for people whose risk was less than 0.5 percent per year. However, their analysis treated the beneficial and harmful outcomes as equal in magnitude, an assumption that oversimplifies the clinical dilemma.
Augustovski et al.31 used a Markov decision analysis model to consider the effect of low-dose aspirin for primary prevention in patients with different risk factor profiles. Effect estimates were based on the evidence available at the time of the analysis, which was before publication of the three most recent trials. Outcomes were measured as changes in quality-adjusted life days. For 55-year-old patients, those at low risk (no risk factors in men; 0 or 1 risk factor in women) were harmed by aspirin therapy, whereas those at moderate to high risk (2 or more risk factors) seemed to benefit. However, because outcomes were presented in mean life-days gained or lost, it is difficult to translate their findings for use in counseling of individual patients.
Based on our review, we conclude that aspirin appears to reduce myocardial infarction but increases gastrointestinal and intracranial bleeding. The net effect of aspirin improves with increasing CHD risk. Consideration of underlying CHD risk, as well as the relative values patients attach to the main outcomes, can help patients and providers decide whether aspirin chemoprevention is warranted.
Select for Analytic Framework (4 KB; Text Version).
Search Strategy
We used the following MESH® headings: for the beneficial effects of aspirin: aspirin AND cardiovascular disease AND (randomized controlled trial or controlled clinical trial or randomized controlled trials or random allocation or double blind method or single blind method); for the adverse effects of aspirin: aspirin AND (gastrointestinal bleeding or cerebral hemorrhage). We supplemented our basic search strategies by examining bibliographies from other relevant articles, systematic reviews, and by seeking the advice of content experts.
Inclusion Criteria
For studies examining the benefits of aspirin chemoprevention, we included randomized trials of at least 1 year's duration that met the following criteria:
For harms data, we examined case-control studies, randomized trials, and systematic reviews or meta-analyses of randomized trials that examined rates of hemorrhagic stroke or gastrointestinal bleeding from aspirin use.
Data Extraction and Definition of Outcomes
Two reviewers examined all abstracts and excluded those that they agreed were clearly outside the scope of the review. The same reviewers then examined the full articles for the remaining studies and determined final eligibility by consensus. Two independent reviewers abstracted the included studies. Disagreements were resolved by consensus. Potentially beneficial outcomes examined were the efficacy of aspirin versus placebo in reducing the following events:
Major harms examined were hemorrhagic stroke and major gastrointestinal bleeding.
Select for Flow Chart (16 KB) of Beneficial Effects (Text Version).
Select for Flow Chart (17 KB) of Harmful Effects (Text Version).
This study was developed by the RTI-UNC Evidence-based Practice Center under contract to the Agency for Healthcare Research and Quality (Contract No. 290-97-0011), Rockville, MD. We acknowledge the assistance of Kathleen Lohr, Ph.D., Sonya Sutton, BSPH, and Sheila White, of Research Triangle Institute and Carol Krasnov of the University of North Carolina at Chapel Hill.
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a Hayden: Department of Internal Medicine, School of Medicine, University of North Carolina at Chapel Hill and Robert Wood Johnson Clinical Scholars Program.
b Pignone: Department of Internal Medicine, University of North Carolina at Chapel Hill School of Medicine, Cecil Sheps Center for Health Services Research, and RTI-UNC Evidence-based Practice Center.
c Phillips: Office for Prevention and Health Services Assessment, Air Force Medical Operations Agency, San Antonio, TX.
d Mulrow: Department of Medicine, Audie Murphy VA Hospital, University of Texas Health Sciences Center, San Antonio, TX.
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Source: U.S. Preventive Services Task Force. Aspirin for the primary prevention of cardiovascular events: summary of the evidence. Ann Int Med 2002;136(2):161-72.
Disclaimer: The authors of this article are responsible for its contents, including any clinical or treatment recommendations. No statement in this article should be construed as an official position of the U.S. Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
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Aspirin for the Primary Prevention of Cardiovascular Events: Summary of the Evidence. Article originally in Annals of Internal Medicine 2002. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/3rduspstf/aspirin/aspsum1.htm
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