Clinical Guidelines17 March 2009

Aspirin for the Prevention of Cardiovascular Disease: U.S. Preventive Services Task Force Recommendation Statement

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    Abstract

    Description:

    Update of the 2002 U.S. Preventive Services Task Force (USPSTF) recommendation about the use of aspirin for the prevention of coronary heart disease.

    Methods:

    Review of the literature since 2002, focusing on new evidence on the benefits and harms of aspirin for the primary prevention of cardiovascular disease, including myocardial infarction and stroke. The new evidence was reviewed and synthesized according to sex.

    Recommendations:

    Encourage men age 45 to 79 years to use aspirin when the potential benefit of a reduction in myocardial infarctions outweighs the potential harm of an increase in gastrointestinal hemorrhage. (A recommendation)

    Encourage women age 55 to 79 years to use aspirin when the potential benefit of a reduction in ischemic strokes outweighs the potential harm of an increase in gastrointestinal hemorrhage. (A recommendation)

    Evidence is insufficient to assess the balance of benefits and harms of aspirin for cardiovascular disease prevention in men and women 80 years or older. (I statement)

    Do not encourage aspirin use for cardiovascular disease prevention in women younger than 55 years and in men younger than 45 years. (D recommendation)

    The U.S. Preventive Services Task Force (USPSTF) makes recommendations about preventive care services for patients without recognized signs or symptoms of the target condition.

    It bases its recommendations on a systematic review of the evidence of the benefits and harms and an assessment of the net benefit of the service.

    The USPSTF recognizes that clinical or policy decisions involve more considerations than this body of evidence alone. Clinicians and policymakers should understand the evidence but individualize decision making to the specific patient or situation.

    Summary of Recommendation and Evidence

    The USPSTF recommends the use of aspirin for men age 45 to 79 years when the potential benefit due to a reduction in myocardial infarctions outweighs the potential harm due to an increase in gastrointestinal hemorrhage. See the Clinical Considerations section for discussion of benefits and harms. This is an A recommendation.

    The USPSTF recommends the use of aspirin for women age 55 to 79 years when the potential benefit of a reduction in ischemic strokes outweighs the potential harm of an increase in gastrointestinal hemorrhage. See the Clinical Considerations section for discussion of benefits and harms. This is an A recommendation.

    The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of aspirin for cardiovascular disease prevention in men and women 80 years or older. This is an I statement.

    See the Clinical Considerations section for suggestions for practice regarding the I statement.

    The USPSTF recommends against the use of aspirin for stroke prevention in women younger than 55 years and for myocardial infarction prevention in men younger than 45 years. This is a D recommendation.

    Figure 1 (page 403) shows a summary of the recommendations and suggestions for clinical practice.

    Figure 1. Aspirin for the prevention of cardiovascular disease: clinical summary of a U.S. Preventive Services Task Force recommendation statement.

    CHD = coronary heart disease; CVD = cardiovascular disease; GI = gastrointestinal; HDL = high-density lipoprotein; MI = myocardial infarction; NSAID = nonsteroidal anti-inflammatory drug; USPSTF = U.S. Preventive Services Task Force.

    Table 1 describes the USPSTF grades, and Table 2 describes the USPSTF classification of levels of certainty of net benefit.

    Table 1. What the USPSTF Grades Mean and Suggestions for Practice

    Table 1.

    Table 2. U.S. Preventive Services Task Force Levels of Certainty Regarding Net Benefit

    Table 2.
    Rationale
    Importance

    Cardiovascular disease, including heart attack and stroke, is the leading cause of death in the United States.

    Recognition of Risk Status

    For many groups, available risk calculators can provide an accurate estimate of the risk for coronary heart disease events and strokes based on information about cardiovascular risk factors that include sex. See the Clinical Considerations section.

    Benefits of Preventive Medication

    The USPSTF found good evidence that aspirin decreases the incidence of myocardial infarction in men and ischemic strokes in women.

    Harms of Preventive Medication

    The USPSTF found good evidence that aspirin increases the incidence of gastrointestinal bleeding and fair evidence that aspirin increases the incidence of hemorrhagic strokes.

    USPSTF Assessment

    The USPSTF concludes that, for men age 45 to 79 years whose benefit due to a reduction in myocardial infarctions exceeds the harm because of an increase in gastrointestinal bleeding, there is high certainty that the net benefit is substantial.

    The USPSTF concludes that, for women age 55 to 79 years whose benefit due to a reduction in ischemic stroke exceeds the harm because of gastrointestinal bleeding, there is high certainty that the net benefit is substantial.

    The USPSTF concludes that, for men and women 80 years or older, the evidence is insufficient to assess the balance of benefits and harms.

    The USPSTF concludes that, for men 44 years or younger and women 54 years or younger, the potential benefits of reducing myocardial infarction in men or ischemic stroke in women are small, and there is moderate certainty that the benefits do not outweigh harms.

    Clinical Considerations
    Patient Population Under Consideration

    These recommendations apply to adult men and women without a history of coronary heart disease or stroke.

    Assessment of Risk for Cardiovascular Disease
    Men

    The net benefit of aspirin depends on the initial risk for coronary heart disease events and gastrointestinal bleeding (1). Thus, decisions about aspirin therapy should consider the overall risks for coronary heart disease and gastrointestinal bleeding.

    Risk assessment for coronary heart disease should include ascertainment of risk factors: age, diabetes, total cholesterol levels, high-density lipoprotein cholesterol levels, blood pressure, and smoking. Available tools provide estimations of coronary heart disease risk (such as the calculator available at healthlink.mcw.edu/article/923521437.html).

    Figure 2(2, 3) shows the estimated number of myocardial infarctions prevented according to coronary heart disease risk level for men age 45 to 79 years—the age range with the potential for substantial net benefit from the use of aspirin. It also shows that the coronary heart disease risk level at which the absolute number of myocardial infarctions prevented by the use of aspirin is greater than the absolute number of gastrointestinal bleeding episodes and hemorrhagic strokes caused by aspirin therapy increases with age. The estimates in Figure 2 were developed assuming that the men are not currently taking nonsteroidal anti-inflammatory drugs (NSAIDs) and are without other conditions that increase the risk for gastrointestinal bleeding (see below). Furthermore, the decision about the exact level of risk at which the potential benefits outweigh potential harms is an individual one. Some men may decide that avoiding a myocardial infarction is of great value and that having a gastrointestinal bleeding event is not a major problem. This group would probably decide to take aspirin at a lower coronary heart disease risk level than men who are more afraid of gastrointestinal bleeding. Men who have a high likelihood of benefiting with little potential for harm should be encouraged to consider aspirin. Conversely, aspirin use should be discouraged among men who have little potential of benefiting from the therapy or have a high risk for gastrointestinal bleeding.

    Figure 2. Estimated MIs prevented and estimated harms of using aspirin for 10 years in a hypothetical cohort of 1000 men.

    Estimates are based on age and 10-year CHD risk. CHD = coronary heart disease; GI = gastrointestinal; MI = myocardial infarction.

    Shared decision making should be encouraged with men for whom the potential benefits and risks for serious bleeding are more closely balanced (Figure 3). This discussion should explore the potential benefits and harms and patient preferences. As the potential benefit increases above potential harms, the recommendation to take aspirin should become stronger.

    Figure 3. 10-year CHD risk levels at which the number of cardiovascular disease events prevented is closely balanced to the number of serious bleeding events.

    CHD = coronary heart disease.

    Evidence on the benefits in men younger than 45 years is limited, and the potential benefit in this age group is probably low because the risk for myocardial infarction is very low.

    Women

    The net benefit of aspirin depends on the initial risks for stroke and gastrointestinal bleeding. Thus, decisions about aspirin therapy should consider the overall risk for stroke and gastrointestinal bleeding.

    Risk factors for stroke include age, high blood pressure, diabetes, smoking, a history of cardiovascular disease, atrial fibrillation, and left ventricular hypertrophy. Tools for estimation of stroke risk are available (such as the calculator available at www.westernstroke.org/PersonalStrokeRisk1.xls).

    Figure 4 shows the estimated number of strokes prevented according to stroke risk level in women age 55 to 79 years—the age range for which evidence shows that there could be substantial potential net benefit of aspirin use. It also shows that the stroke risk level at which the absolute number of strokes prevented is greater than the absolute number of gastrointestinal bleeding events caused increases with age. The estimates in Figure 4 were developed assuming that women are not currently taking NSAIDs and are without other conditions that increase the risk for gastrointestinal bleeding (see the Risk for Gastrointestinal Bleeding section). Furthermore, the decision about the exact stroke risk level at which the potential benefits outweigh harms is an individual one. Some women may decide that avoiding a stroke is of great value but experiencing a gastrointestinal bleeding event is not a major problem. These women would probably decide to take aspirin at a lower stroke risk level than those who are more afraid of a bleeding event. Women who have little potential of benefiting from aspirin therapy or have a high risk for gastrointestinal bleeding should be discouraged from taking aspirin.

    Figure 4. Estimated number of strokes prevented and estimated harms of using aspirin for 10 years in a hypothetical cohort of 1000 women on the basis of age and 10-year stroke risk.

    GI = gastrointestinal.

    Shared decision making should be encouraged with women for whom the potential benefits and risks for serious bleeding are more closely balanced (Figure 3). This discussion should explore potential benefits and harms and patient preferences. As the potential stroke reduction benefit increases above the potential harms, the recommendation to take aspirin should become stronger.

    Evidence on benefits in women younger than 55 years is limited, and the potential benefit in this age group is probably low because the risk for stroke is very low.

    Assessment of Risk for Gastrointestinal Bleeding

    Evidence shows that the risk for gastrointestinal bleeding with and without aspirin use increases with age (2, 4). For the purposes of making this recommendation, the USPSTF considered age and sex to be the most important risk factors for gastrointestinal bleeding. Other risk factors for bleeding include upper gastrointestinal tract pain, gastrointestinal ulcers, and NSAID use. Nonsteroidal anti-inflammatory drug therapy combined with aspirin approximately quadruples the risk for serious gastrointestinal bleeding compared with the risk with aspirin alone. The rate of serious bleeding in aspirin users is approximately 2 to 3 times greater in patients with a history of a gastrointestinal ulcer. Men have twice the risk for serious gastrointestinal bleeding than women (2, 4). These risk factors increase the risk for bleeding substantially and should be considered in the overall decision about the balance of benefits and harms of aspirin therapy. Enteric-coated or buffered preparations do not clearly reduce the adverse gastrointestinal effects of aspirin. Uncontrolled hypertension and concomitant use of anticoagulants also increase the risk for serious bleeding.

    Treatment

    The optimum dose of aspirin for preventing cardiovascular disease events is not known. Primary prevention trials have demonstrated benefits with various regimens, including dosages of 75 and 100 mg/d and 100 and 325 mg every other day. A dosage of approximately 75 mg/d seems as effective as higher dosages. The risk for gastrointestinal bleeding may increase with dose.

    Intervention Intervals

    Although the optimal timing and frequency of discussions related to aspirin therapy are unknown, a reasonable option might be every 5 years in middle age and later and also whenever other cardiovascular risk factors are detected.

    Suggestions for Practice Regarding the I Statement

    The incidence of myocardial infarction and stroke is high in persons 80 years or older, and thus the potential benefit of aspirin is large. The relationship between increasing age and gastrointestinal bleeding is also well established, and thus the potential harms are also large. The net benefit of aspirin use in persons older than 80 years is probably best in those without risk factors for gastrointestinal bleeding (other than older age) and in those who could tolerate a gastrointestinal bleeding episode (for example, those with normal hemoglobin levels, good kidney function, and easy access to emergency care). Clinicians should inform patients about the adverse consequences of gastrointestinal bleeding because they might be mitigated by a patient's early recognition of the signs and symptoms of bleeding (dark stools, vomiting blood, bright red blood per rectum, syncope, and lightheadedness). If clinicians decide to prescribe aspirin in adults older than 80 years, they should do so only after a discussion with the patient that includes the potential harms and uncertain benefits.

    Useful Resources

    The USPSTF made recommendations on other interventions for the primary and secondary prevention of cardiovascular disease, including recommendations on screening for abdominal aortic aneurysm, carotid artery stenosis, coronary heart disease, high blood pressure, lipid disorders, and peripheral arterial disease. These are available at www.preventiveservices.ahrq.gov.

    Discussion
    Burden of Disease

    Cardiovascular disease 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 of every 3 adults had some form of cardiovascular disease. In adults older than 40 years, the lifetime risk is 2 in 3 for men and more than 1 in 2 for women.

    Scope of Review

    In 2002, the USPSTF strongly recommended that clinicians discuss the use of aspirin with adults who have an increased risk for coronary heart disease (5). In ensuing years, the results of the WHS (Women's Health Study) were published. The current USPSTF review focused on new evidence on the benefits and harms of aspirin for the primary prevention of cardiovascular disease. The evidence was reviewed and synthesized according to sex, because available evidence suggested that aspirin may have differential benefits and harms in men and women.

    Effectiveness of Risk Assessment and Preventive Medication

    A tool for predicting coronary heart disease events has been developed on the basis of Framingham Heart Study data. This tool uses sex, age, smoking, diabetes, blood pressure, and cholesterol levels as risk factors for coronary heart disease (6). A tool to calculate the risk for stroke has also been developed on the basis of Framingham data. Hypertension was shown to be the major risk factor for stroke in the Framingham study. Other risk factors that were shown to be associated with an increased risk for stroke and are included in the tool are age, sex, diabetes, smoking, known cardiovascular disease, atrial fibrillation, and left ventricular hypertrophy (7).

    Several randomized, controlled trials (RCTs) reviewed for the 2002 USPSTF recommendation showed a reduction in myocardial infarctions in men. Most of the participants in the trials were white men. Only 2 of these studies included women, and no substantial reduction in coronary heart disease events occurred in women in these studies. Since the last USPSTF review, new evidence from the WHS and a meta-analysis suggests differential effects of aspirin by sex: Men derive benefit in the reduction of myocardial infarctions, and women derive benefit in the reduction of ischemic strokes (3, 8).

    The WHS was a double-blind RCT that evaluated the risks and benefits of aspirin in the primary prevention of cardiovascular disease (8). The WHS randomly assigned 39 876 female health professionals to aspirin, 100 mg every other day, or placebo. The mean follow-up was 10.1 years. The WHS reported benefit with aspirin use in stroke reduction (relative risk [RR], 0.83 [95% CI, 0.69 to 0.99]). Specifically, investigators reported reduction in ischemic strokes (RR, 0.76 [CI, 0.63 to 0.93]) and found no significant benefit in reduction of combined cardiovascular events (strokes, myocardial infarctions, or death from either cause), myocardial infarctions, death from cardiovascular disease, or all-cause mortality.

    A recent meta-analysis reported on the sex-specific benefits of aspirin in 51 342 women and 44 114 men enrolled in 6 primary prevention trials, including the WHS (3). The number of participants in the studies ranged from 2540 to 39 876. Mean age was 53 to 61.5 years, and the dosage of aspirin ranged from 100 mg every other day to 500 mg/d; 3 trials had a placebo control group, 3 studied health professionals, and 3 included participants with 1 or more risk factor for cardiovascular disease. In the meta-analysis, aspirin use in women was associated with significant reductions in cardiovascular events (strokes, myocardial infarctions, or death from either cause) (odds ratio [OR], 0.88 [CI, 0.79 to 0.99]) and ischemic strokes (OR, 0.76 [CI, 0.63 to 0.93]); there was no significant benefit in the reduction of myocardial infarctions or cardiovascular disease mortality. In men, aspirin use was associated with a significant reduction in cardiovascular events (OR, 0.86 [0.78 to 0.94]) and myocardial infarctions (OR, 0.68 [0.54 to 0.86]); there was no significant benefit in the reduction of ischemic stroke or cardiovascular disease mortality. There was no significant reduction in total mortality with aspirin use either in men or in women.

    Potential Harms of Risk Assessment and Preventive Medication

    Using aspirin for the primary prevention of cardiovascular disease events increases the risk for major bleeding events in men and women. In the meta-analysis discussed earlier, hemorrhagic strokes were statistically significantly increased in men but not in women.

    The WHS reported harms of aspirin use in the primary prevention of cardiovascular events (8). Gastrointestinal bleeding, peptic ulcers, self-reported hematuria (blood in the urine), easy bruising, and epistaxis (nosebleeds) were significantly more common in women assigned to aspirin therapy than in women assigned to placebo. In each group, approximately equal numbers reported any gastrointestinal symptom. Serious gastrointestinal bleeding (requiring transfusion) were more common in the aspirin group: 127 in the aspirin group and 91 in the placebo group (RR, 1.40 [CI, 1.07 to 1.83]). Five deaths due to gastrointestinal bleeding occurred in the study. Of these, 3 were in the placebo group and 2 were in the aspirin group. Hemorrhagic strokes were not statistically significantly increased in the aspirin group (RR, 1.24 [CI, 0.82 to 1.87]).

    The sex-specific meta-analysis of RCTs described above reported adverse events with aspirin use in the primary prevention of cardiovascular events in 51 342 women and 44 114 men (3). Major bleeding events were increased in persons taking aspirin compared with persons not taking aspirin (OR, 1.68 [CI, 1.13 to 2.52] in women and 1.72 [CI, 1.35 to 2.20] in men). The odds of hemorrhagic strokes were not significantly increased in women (OR, 1.07 [CI, 0.42 to 2.69]) but were significantly increased in men (OR, 1.69 [CI, 1.04 to 2.73]).

    A study of very large databases of users and nonusers of aspirin and NSAIDs reported higher rates of excess serious gastrointestinal bleeding with aspirin use in people with the following factors: male sex, upper gastrointestinal pain, and a history of a gastrointestinal ulcer (2, 4). In women younger than 60 years without these risk factors, the excess number of serious gastrointestinal bleeding episodes associated with aspirin use is 0.4 per 1000 person-years. The rate is 0.8 per 1000 person-years for women with a history of upper gastrointestinal pain and 2.4 to 4.0 per 1000 person-years for women with a history of a gastrointestinal ulcer. In men younger than 60 years without these risk factors, the excess number of serious gastrointestinal bleeding episodes associated with aspirin use is 0.8 per 1000 person-years. The rate is 1.6 per 1000 person-years for men with a history of upper gastrointestinal pain and 4.8 to 8.0 per 1000 person-years for men with a history of gastrointestinal ulcer. As discussed above, gastrointestinal bleeding risk increases with age. In women without risk factors for gastrointestinal bleeding, the rate of excess serious bleeding associated with aspirin is 1.2 per 1000 person-years at 60 to 69 years, 1.8 per 1000 person-years at 70 to 79 years, and 3 per 1000 person-years at 79 years or older. In men, these numbers are 2.4, 3.6, and 6 per 1000 person-years, respectively. The use of NSAIDs approximately triples or quadruples these rates (2).

    Estimate of Magnitude of Net Benefit

    Aspirin use for the primary prevention of cardiovascular disease provides more benefits than harms in men or women whose risk for myocardial infarction or ischemic stroke, respectively, is high enough to outweigh the risk for gastrointestinal hemorrhage. In men similar to those enrolled in the RCTs, the number needed to treat to prevent 1 myocardial infarction over 5 years of aspirin use is 118, whereas the number needed to treat to cause 1 major bleeding event is 303 over 5 years of aspirin use and 769 to cause 1 hemorrhagic stroke. The balance of benefits and harms varies by coronary heart disease risk and risk for gastrointestinal bleeding. For a hypothetical group of 1000 men younger than 60 years with a 6% 10-year baseline risk for myocardial infarction, aspirin use will prevent approximately 19 myocardial infarctions and cause approximately 1 hemorrhagic stroke and 8 major bleeding events (Figure 2). The USPSTF concluded with high certainty that the net benefit is substantial in men at increased risk for myocardial infarctions and not at increased risk for serious bleeding.

    In women similar to those enrolled in the RCTs, the number needed to treat to prevent 1 ischemic stroke with 5 years of aspirin use is 417, and the number needed to treat to cause 1 major bleeding event is 392 over 5 years of aspirin use. The balance of benefits and harms varies by stroke risk and risk for a bleeding event. In a hypothetical group of 1000 women younger than 60 years with a 6% 10-year risk for stroke, aspirin use will prevent approximately 10 strokes and cause approximately 4 major bleeding events (Figure 4). The estimates of the number of major bleeding events were assumed to be stable within age strata with respect to increases in baseline stroke risk. The USPSTF concluded with high certainty that the net benefit is substantial for women at increased risk for stroke and not at increased risk for serious bleeding.

    How Evidence Fits With Biological Understanding

    Platelet adhesion and activation is part of the complex process of arterial thrombosis that may lead to vascular occlusion and subsequent myocardial infarctions and strokes. Aspirin is thought to be useful for the primary and secondary prevention of cardiovascular events because of its inhibition of platelet aggregation mediated through the permanent inactivation of cyclooxygenases (9).

    The epidemiology of cardiovascular disease events differs 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. After age 40 years, men have a 49% lifetime risk for a coronary heart disease event. Women older than 40 years have a 32% risk. The median age of first myocardial infarction is 65.8 years in men and 70.4 years in women. However, women are more likely to die of a myocardial infarction; 38% of women die within 1 year of a first event versus 25% of men. This is probably partly because of the older age in women at first event (7, 10).

    Although incidence rates of stroke are higher in men than in women, more women die of stroke than men because of their longer life expectancy. According to Framingham data, 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% in women and 5.8% in men. The lifetime risk for ischemic stroke is greater in women than in men from age 55 to 75 years (approximately 17% to 18% in women and 13% to 14% in men). After age 75 years, the lifetime risk decreases to 14% in women and 8% in men.

    The underlying biological reasons for these differences in epidemiology and aspirin effect are not understood.

    Recommendations of Others

    In 2006, the American Diabetes Association and the American Heart Association jointly recommended aspirin therapy (75 to 162 mg/d) for primary prevention of heart disease for persons with diabetes who are older than 40 years or who have additional risk factors for cardiovascular disease and no contraindications to aspirin therapy (11). Along with the American Stroke Association, the American Heart Association further recommended the use of aspirin for cardiovascular prophylaxis among persons whose risk is sufficiently high for the benefits to outweigh the risks associated with treatment (a 10-year risk for cardiovascular events of 6% to 10%). For the primary prevention of stroke, they recommended against aspirin in men and stated that aspirin can be useful for primary prevention of stroke in women whose risk is sufficiently high for the benefits to outweigh the harms of treatment (12).

    References

    • 1. Wolff T Miller T Ko S Aspirin for the primary prevention of cardiovascular events: an update of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med2009;150:405-10. LinkGoogle Scholar
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    • 3. Berger JS Roncaglioni MC Avanzini F Pangrazzi I Tognoni G Brown DL Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA2006;295:306-13. [PMID: 16418466] CrossrefMedlineGoogle Scholar
    • 4. Hernández-Díaz S Rodríguez LA Incidence of serious upper gastrointestinal bleeding/perforation in the general population: review of epidemiologic studies. J Clin Epidemiol2002;55:157-63. [PMID: 11809354] CrossrefMedlineGoogle Scholar
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    • 6. Wilson PW D'Agostino RB Levy D Belanger AM Silbershatz H Kannel WB Prediction of coronary heart disease using risk factor categories. Circulation1998;97:1837-47. [PMID: 9603539] CrossrefMedlineGoogle Scholar
    • 7. Wolf PA D'Agostino RB Belanger AJ Kannel WB Probability of stroke: a risk profile from the Framingham Study. Stroke1991;22:312-8. [PMID: 2003301] CrossrefMedlineGoogle Scholar
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    Appendix: U.S. Preventive Services Task Force

    Members of the U.S. Preventive Services Task Force† are Ned Calonge, MD, MPH, Chair (Colorado Department of Public Health and Environment, Denver, Colorado); Diana B. Petitti, MD, MPH, Vice Chair (Arizona State University, Phoenix, Arizona); Thomas G. DeWitt, MD (Children's Hospital Medical Center, Cincinnati, Ohio); Leon Gordis, MD, MPH, DrPH (Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland); Kimberly D. Gregory, MD, MPH (Cedars-Sinai Medical Center, Los Angeles, California); Russell Harris, MD, MPH (University of North Carolina School of Medicine, Chapel Hill, North Carolina); George Isham, MD, MS (HealthPartners, Minneapolis, Minnesota, Michael L. LeFevre, MD, MSPH (University of Missouri School of Medicine, Columbia, Missouri); Carol Loveland-Cherry, PhD, RN (University of Michigan School of Nursing, Ann Arbor, Michigan); Lucy N. Marion, PhD, RN (Medical College of Georgia, Augusta, Georgia); Virginia A. Moyer, MD, MPH (Baylor College of Medicine, Houston, Texas); Judith K. Ockene, PhD (University of Massachusetts Medical School, Worcester, Massachusetts); George F. Sawaya, MD (University of California, San Francisco, San Francisco, California); Albert L. Siu, MD, MSPH (Mount Sinai Medical Center, New York, New York); Steven M. Teutsch, MD, MPH (Merck & Company, West Point, Pennsylvania); and Barbara P. Yawn, MD, MSPH, MSc (Olmsted Medical Center, Rochester, Minnesota).

    †This list includes members of the Task Force at the time this recommendation was finalized. For a list of current Task Force members, go to www.ahrq.gov/clinic/uspstfab.htm.

    Comments

    Carlos Tornero20 July 2009
    INDICATIONS OF ASPIRIN IN PRIMARY PREVENTION AMONG HIV-INFECTED PATIENTS

    The recommendations on aspirin (A) use for the primary prevention of cardiovascular events (1), based on cardiovascular risk (CVR) calculation according to the Framingham scale, have recently been published (2). Despite the growing interest in CVR among HIV-infected patients (3, 4), the use of A in these subjects has received scant attention to date. However, the gradual aging of these patients means that we are reaching a point where A for primary prevention may be indicated according to the above mentioned recommendations. We have reviewed the indication of A in a group of HIV-infected patients based on the criteria of these recommendations, with calculation of CVR using the Framingham tables

    A total of 120 consecutive HIV-infected adults were included in a cross-sectional observational study. Demographic data were recorded, along with information on smoking or diabetes, total cholesterol, HDL-c, LDL-c and blood glucose. Blood pressure was recorded following the consensus recommendations, with confirmation of the new diagnoses based on Holter blood pressure monitoring to rule out white-coat hypertension. The Framingham tables were used to calculate CVR. The indication of A was based on the published criteria for males > 45 years of age and females > 55 years of age. Calculation was also made of the variation in percentage indication over the coming years as the patients gradually exceed this age limit without changes in the risk factors. In our experience primary prevention with A would be indicated in 30,8% of the patients, according to the assessment of the Framingham study. Only two patients were taking the medication. Among the males, the percentage would reach 40 %. Without modification of the CVR factors, over the next 5 years the indication would be expanded to another 15 % as a result of the aging of the group.

    Therefore, application of the recently published recommendations on the use of A in HIV-infected patients could help reduce the rise in cardiovascular events described in some studies. Aspirin would be indicated in a large proportion of patients, particularly in males, and this indication moreover may be expected to increase over the coming years.

    In the management of CVR among HIV-infected patients it is therefore necessary to also consider aspirin as primary prevention treatment.

    References

    (1) US preventive Services Task Force. Aspirin for the prevention of cardiovascular disease: US preventive services task force recommendation statement. Ann Intern Med 2009; 150 (6) 396-404

    (2) Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97:1837-47.

    (3) Friis-Moller N, Sabin CA, Weber R, et al. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl JMed 2003;349:1993-2003.

    (4) D:A:D Study group. Class of antiretroviral drugs and the risk of myocardial infarction in HIV infected patients. N Engl. J Med 2007; 356: 1723-1735

    Conflict of Interest:

    None declared

    Ned Calonge2 June 2009
    The USPSTF Recommendation on Aspirin for the Prevention of Cardiovascular Disease

    RE: L09-0238 and L09-0239: Aspirin for the Prevention of Cardiovascular Disease: U.S. Preventive Services Task Force Recommendation Statement

    To the Editors:

    We appreciate the thoughtful letters from Dr. Budhraja and Dr. Mohan regarding the U.S. Preventive Services Task Force (USPSTF) recommendation on aspirin prophylaxis for the prevention of cardiovascular disease (1). Dr. Budhraja calls attention to subgroups of women in whom the effect of aspirin in preventing cardiovascular disease may differ from the general population. In general, the USPSTF is cautious when considering unplanned subgroup analyses of randomized trials, which are the basis for Dr. Budhraja's comment. The authors of the original report from the Women's Health Study (2) mention multiple comparisons as an additional caution in interpreting this subgroup analysis. All sub-group analyses should be considered hypothesis-generating rather than independently persuasive.

    The possibility suggested by Dr. Budhraja that the higher risk of peptic ulcer disease in smokers might place them at higher risk of hemorrhage when taking aspirin is deserving of further research.

    Dr. Mohan raises a number of valuable points. The inadequate and contradictory information derived from web-enabled coronary and cardiovascular disease risk calculators has been a matter of great concern for the USPSTF. The calculator referenced in the recommendation was selected primarily because it is easy to use; also, it does not require information about high-density-lipoprotein cholesterol concentration. As of this writing, the calculator has been removed from the Medical College of Wisconsin's Website, and reportedly is being revised.

    The USPSTF felt that making a recommendation meant to be tailored to estimation of cardiovascular disease risk without making any suggestions to help clinicians use the recommendation would be worse than mentioning an imperfect calculator. Research in this field is sorely needed. The development of a "gold standard" cardiovascular disease risk calculator that would aid in predicting contemporary rates of cardiovascular disease in the United States should be a pressing priority for analysis of data derived from large cohort studies done in the last decade, perhaps pooling individual level-data across studies. AHRQ has funded a project to evaluate the models currently available for use for risk calculation for cardiovascular disease. The results will be available soon. The use of risk prediction models and the tools based these models to guide decisions about use of preventive and therapeutic medications, as well as decisions about screening, will become increasingly important in the emerging era of personalized medicine.

    References

    (1) U.S. Preventive Services Task Force. Aspirin for the Prevention of Cardiovascular Disease: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2009;150:396-404.

    (2) Ridker PM, Cook NR, Lee IM, Gordon D, Gaziano JM, Manson JE, Hennekens CH, Buring JE. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. : N Engl J Med. 2005 Mar 31;352(13):1293-304. Epub 2005 Mar 7.

    Conflict of Interest:

    None declared

    William Simon5 May 2009
    Should Aspirin be Discontinued at Age 80?

    To the Editor:

    A recent article by the U.S. Preventive Services Task Force in the Annals of Internal Medicine (1) compared the benefits of aspirin in reducing the risk of heart disease to the possible increased incidence of GI bleeding caused by the aspirin. The authors came to the conclusion that before the age of 79 there was a clear advantage due to the aspirin. They left open the issue of ages 80 and above on the basis of insufficient data.

    The reader may be tempted to infer that 80 years reprents a break even point between the two different risks, i.e. omitting the aspriin or accepting the risk of GI bleeding due to the aspirin.

    But these are not the only options. The addition of a Proton Pump Inhibitor (PPI) heavily biases the decision in favor of continuing the aspirin.

    Although there seems to be relatively little data beyond age 80, there is good reason to trust extrapolation, at least for a few years, in the absence of contradictory evidence. One can build considerable safety into this logic by comparing the least likely benefit situation from the aspirin-PPI combination to the maximum risk situation for GI bleeding and showing that even in this worst case, the break even piont is far above 80 and therefore the combination PPI-aspirin therapy is superior to discontinuing the aspirin.

    Assume for the moment that 80 is the break even age where the part of the GI risk due to aspirin alone equals or exceeds the reduction of CV risk expected of the aspirin.

    Data exists for patients below the age of 80 that indicates about a factor of three reduction in GI risk can be realized by the use of PPI and this number appears roughly independent of age (2).

    To be conservative let us assume, for reasons possibly unknown, that the factor of three is overly optimistic. Reduce it to a factor of two. Let us further assume that the CV risk does not increase beyond its value at age 80. This is of course not true but this assuption further penalizes the aspirin-PPI combination. Then the lowest break even age is that for which the GI risk curve without PPI increases by a factor of two from its value at 80. Unless there is some dramatic change occurring in the risk mechanism, one's best estimate is that the GI risk curve continues to tilt up or bend up beyond 80 about the way it does before 80. This moves the break even point up to about 90 years of age. Considering the very conservative assunptions above the estimate of 90 is itself conservative.

    In any case, if there exists an age at which the aspirin-PPI GI risk exceeds the reduction in CV risk, it certainly is not 80.

    References

    1. U.S. Preventive Services Task Force. Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2009; 150: 396-404.

    2. Sameer D. Saini, et al; Cost-effectiveness of Proton Pump Inhibitor Cotherapy in Patients Taking Long-term, Low-Dose Aspirin for Secondary Cardiovascular Prevention. Arch Intern Med. 2008; 168 (15): 1684 -1690.

    Conflict of Interest:

    None declared

    Bob van Kempen24 April 2009
    USPSTF Guideline on Aspirin

    To the Editor.

    We were pleased to see an attempt to translate current evidence for aspirin therapy into a clinically useful risk chart in the U.S. Preventive Services Task Force's (USPSTF) guideline update in the Annals of Internal Medicine March 17 issue (1). Whereas we concur with the guideline's conservative estimate of the value of aspirin therapy and agree with the need for shared decision making, we think the USPSTF's approach could be improved.

    For their guideline, the authors chose to value Harms and Benefits in terms of the cumulative probability of events over a period of 10 years without consideration of the timing, the severity, and the consequences of these events. Few people would consider a severely disabling stroke within the next year and a mild gastrointestinal bleeding episode 9 years from now as equal, which is in essence the assumption underlying the guideline. Shared decision making is advocated in the guideline to resolve the tough decisions. Although we are strongly in favor of shared decision making it does, however, require information not only about the cumulative probabilities of events but also on competing risks, timing of fatal and non-fatal events, and quality-of-life. This information is missing from the guideline and, if known, is difficult for patients and physicians to combine mentally without decision support. Furthermore, the USPSTF article only covered Myocardial Infarction (MI) in males, and Ischemic Stroke in females, while in females aged 65 or older the effect of aspirin on MI is also relevant (2).

    Greving et al.(3) developed a decision analytic simulation model based on a meta analysis by Berger (4), which takes all of these aspects into account. Interestingly, there seems to be a discrepancy between their results and the USPSTF approach. For example, based on Greving's model, a woman aged 75 and older, not at increased risk for serious bleeding, and with an average cardiovascular risk has a significant net benefit from aspirin use, whereas according to the USPSTF guideline additional risk factors are needed to outweigh potential harm. This example illustrates that omitting both the consequences of events and the effect of aspirin on MI in elderly women, could lead to suboptimal decisions.

    Since USPSTF recommendations are regarded as the "reference standard" for allocating preventive services to the general population we believe that primary care physicians and patients should be aware of the limitations of the recommended approach in this guideline.

    References

    1. Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2009; 150:396-404.

    2. Ridker PM, Cook NR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med. 2005; 352:1293-1304. Epub 2005 Mar 1297.

    3. Greving JP, Buskens E, Koffijberg H, Algra A. Cost-effectiveness of aspirin treatment in the primary prevention of cardiovascular disease events in subgroups based on age, gender, and varying cardiovascular risk. Circulation 2008; 117:2875-2883.

    4. Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi I, Tognoni G, Brown DL. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. Jama 2006; 295:306-313.

    Conflict of Interest:

    None declared

    Vikram Budhraja21 April 2009
    Aspirin for primary prevention: The evidence in women smokers

    The recently updated USPSTF guidelines on aspirin for primary prevention of cardiovascular disease are an ideal example evidence-based medicine in action (1). Although we can't fully explain why aspirin effects differ by gender, the evidence strongly suggests that it does, and now our guidelines, and practices, can reflect that. The concept makes intuitive sense: target aspirin use to those who are most at risk of cardiovascular disease. As cigarette smoking is a major risk factor for stroke and MI, the updated guidelines imply that smokers are more likely to be given aspirin.

    However, if we are willing to accept differential effects of aspirin in men and women, we should also accept the possibility of differential effects in other physiologically distinct subgroups. The WHS showed a significant interaction with smoking status (p<0.0001), and somewhat unexpectedly, aspirin use was associated with increased harm in currently smoking women (Relative risk = 1.3 for major CV event) (2).

    The question as to weather other studies have shown similar results is complicated by the established gender gap. The Thrombosis Prevention Trial (TPT) employed high risk patients, 44% of whom were smokers, and although a subgroup analysis was not published, benefits of aspirin were consistent with other trials (3). However, the TPT was performed solely in men. Other trials involving women had much fewer patients than WHS, and subgroup analyses from them were not published.

    Since smoking is also a risk factor for peptic ulcer (4), and the bulk of the data available suggest harm rather than benefit in smoking women, I believe it may be prudent to take a more cautious approach to aspirin use in this group until further data can clarify the issue.

    References

    1. US Preventive Services Task Force. Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2009 Mar 17;150(6):396-404.

    2. Ridker PM, Cook NR, Lee IM, Gordon D, Gaziano JM, Manson JE, Hennekens CH, Buring JE. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med. 2005 Mar 31;352(13):1293-304. Epub 2005 Mar 7.

    3. Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Medical Research Council's General Practice Research Framework. Lancet. 1998 Jan 24;351(9098):233-41.

    4. Kurata, JH, Nogawa, AN. Meta-analysis of risk factors for peptic ulcer. Nonsteroidal antiinflammatory drugs, Helicobacter pylori, and smoking. J Clin Gastroenterol 1997; 24:2.

    Conflict of Interest:

    None declared

    Ildikó Kriszbacher31 March 2009
    Time of Taking Aspirin Can Have an Effect on the Frequency of Occurence of Coronary Heart Disease

    We read the article by Calonge et al.(1) with great interest, in which they recommend aspirin for the prevention of coronary heart disease. The incidence of acute myocardial infarction and stroke assessed by onset of clinical symptoms exhibits a marked circadian variation with a peak period during the morning. Acute myocardial infarction usually occurs unexpectedly or more frequently in the morning hours, between 8-11 a.m. In this morning period there is a higher aggregability of thrombocytes. Patients usually take aspirin for prevention in the morning as the treatment regimen is one tablet per day to be swallowed without chewing at least 30 min before breakfast. It is obvious that highest plasma level of the drug occurs after the morning peak-incidene of the thromboembolic event, suggesting lower profilactic effect of Aspirin. Furthermore, this treatment regimen has its highest protective effect during the day, when synergistically, normal physical activity exerts a protective action on thromboembolic processes. However, this method of daily Aspirin administration has its lowest protective value against cardiovascular events during the night and early morning, when the lack of physical activity further augment the cascade of haemorheological events favoring platelet aggregation and subsequent ischemia. In contrast, highest plasma level of Aspirin taken late evening (10:00 pm) would be reached prior to the peak-incidence of thromboembolic disorders (2). We are confident that this time shift in the administration of Aspirin would better fit in the circadian scheme of the occurrence of cardiovascular events, thus resulting in a significantly more effective prevention.

    References:

    1.Calonge, N., Petitti D. B., DeWitt T. G., et al. Aspirin for the Prevention of Cardiovascular Disease:U.S. Preventive Services Task force Recommendation Statement. Ann Intern Med. 2009;150:396-404.

    2.Kriszbacher I., Koppan M., Bodis J. Aspirin for stroke prevention taken in the evening? Stroke. 2004;35:2760-1.

    Conflict of Interest:

    None declared

    Arun V Mohan20 March 2009
    CHD Risk-Assessment Tools May Lead to Inappropriate Use of Aspirin for Primary Prevention

    TO THE EDITOR: Although we agree with the expanded role of aspirin for primary prevention of coronary heart disease (CHD) recommended by the U.S. Preventive Services Task Force (USPSTF)(1), we are concerned that their designated risk-assessment tool (http://healthlink. mcw.edu/article/923521437.html) - one of many they suggest would be useful - may lead to the inappropriate overuse of aspirin for primary prevention.

    Using this calculator, based on Framingham data (2), a 45-year old low-risk male (normotensive, non-diabetic, non-smoker, total cholesterol=160 mg/dL, HDL=50 mg/dL) is assigned a 10-year risk of 4%. This low-risk patient, according to USPSTF would be placed on preventive aspirin. However, calculating the same patient's risk using the online tool (http://hp2010.nhlbi hin.net/atpiii/calculator.asp) accompanying the National Cholesterol Education Program guidelines(3)"“ also based on Framingham data "“generates a risk of 1%.

    Clinicians often exhort patients to be wary of online information, yet medical professionals apparently need to exercise the same caution. The USPSTF committee writes, "Available tools provide estimations of coronary heart disease risk . . ." suggesting that all tools are equivalent and accurate. However, previous research has shown wide variability of equation-based prediction tools (4,5). The Table demonstrates such inconsistency using three readily available risk-assessment tools. Without more specific guidance from the USPSTF, use of any online tool may lead to inappropriate overuse or underuse of aspirin depending on the specific tool chosen.

    We encourage the USPSTF to reissue their most recent recommendations with a specific risk- assessment tool that has been thoroughly studied to ensure the clinically appropriate application of these important guidelines.

    Table. Predicted 10-year CHD risk of 3 hypothetical patients using 3 different online risk calculators

     HealthLink, %*NCEP, %" PROCAM, %"¡
    Low- risk§
    4
    1
    1
    Moderate-risk||
    13
    7
    5
    High-risk ¶
    37
    19
    69

    * Risk assessment tool can be found at http://healthlink.mcw.edu/article/923521437.html
    "  Risk assessment tool can be found at http://hp2010.nhlbihin.net/atpiii/calculator.asp
    "¡ Risk assessment tool can be found at http://www.chd- taskforce.com/
    § Low-risk (45 year-old male, non-smoker, untreated BP = 120/80 mm Hg, total cholesterol = 160 mg/dL, LDL = 90 mg/dL, HDL = 50 mg/dL, triglyceride = 100 mg/dL, no family history of CHD)
    ||Moderate-risk (55 year-old male, non-smoker, untreated BP = 130/90 mm Hg, total cholesterol = 200 mg/dL, LDL = 140 mg/dL, HDL = 50 mg/dL, triglyceride = 150 mg/dL, no family history of CHD)
    ¶High-risk (65 year-old male, smoker, treated BP = 120/80 mm Hg, total cholesterol = 240 mg/dL, LDL = 200 mg/dL, HDL = 30 mg/dL, triglyceride = 200 mg/dL, no family history of CHD)

     

    REFERENCES
    1. U.S. Preventive Task Force. Aspirin for the Prevention of Cardiovascular Disease: U.S. Preventive Task Force Recommendation Statement. Ann Intern Med. 2009; 150:396-404.
    2. Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation 1998;97:1837"“1847.
    3. National Cholesterol Education Program. 10-year CVD Risk Calculator. 19 March 2009. National Heart Lung and Blood Institute. <http://hp2010.nhlbihin.net/atpiii/calculator.asp>
    4. Lenz M, Mühlhauser I. [Cardiovascular risk assessment for informed decision making. Validity of prediction tools]. Med Klin (Munich) 2004;99:651- 61.
    5. Brindle P et al. Accuracy and impact of risk assessment in the primary prevention of cardiovascular disease: a systematic review. Heart. 2006 Dec;92(12):1752-9

    Conflict of Interest:

    None declared