doi: 10.1161/CIRCULATIONAHA.108.778407
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(Circulation. 2008;117:2844-2846.)
© 2008 American Heart Association, Inc.
Editorial |
Aspirin Chemoprevention
One Size Does Not Fit All
From Columbia University, New York, NY.
Correspondence to Dr Lori Mosca, Professor of Medicine, Director, Preventive Cardiology, New York–Presbyterian Hospital, Columbia University Medical Center, 601 W 168th St, Ste 43, New York, NY 10032. E-mail ljm10{at}columbia.edu (copy lmr2@columbia.edu).
Key Words: Editorials • aspirin • cardiovascular diseases • cost-benefit analysis • prevention • women
In 400 BC, Hippocrates prescribed the bark and leaves of the willow tree, which contain salicin, a natural compound similar to aspirin, to relieve pain and fever.1 In 1948, Dr Lawrence Craven noted that 400 men he prescribed aspirin to had not suffered any heart attacks.1 Forty years later, the Physician’s Health Study was terminated early because of a significant reduction in the incidence of myocardial infarction (MI) among men randomized to 325 mg aspirin every other day compared with placebo.2 Today, aspirin recommendations for chemoprevention of cardiovascular disease (CVD) are incorporated into numerous American Heart Association guidelines (the Table).3–12 The effectiveness of aspirin prophylaxis for patients with CVD has been well established13; however, the clinical utility of aspirin in the primary prevention of CVD has been debated, especially among women.14,15
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Article p 2875
In this issue of Circulation, Greving and colleagues,16 using Markov statistical models with simulated Danish cohorts, show that the cost-effectiveness of aspirin in the primary prevention of CVD varies according to gender, age, and baseline level of CVD risk. A threshold of baseline CVD risk >10% in men and >15% in women was shown to be cost-effective. The gender differential has important clinical implications because most women will not attain this level of CVD risk until their later years, and for many women, the risks of aspirin outweighs the benefits in the setting of primary prevention. The authors showed that costs associated with aspirin treatment were greater in women than men and that for most women aspirin resulted in worse health outcomes. Among women 
75 years of age with a 2-fold increase in CVD risk, aspirin was cost-effective; outcomes were favorable compared with risk in those 65 years of age with a 5-times-increased CVD baseline risk. In contrast, aspirin was cost-effective for a 55-year-old man with a 2-fold-increased CVD risk and in men 65 and 75 years of age regardless of baseline risk.
AHA guidelines recommend that aspirin be considered for primary prevention in persons with a Framingham risk of 10%, which still applies to men.4 However, updated guidelines suggest that for women <65 years of age, the usefulness of aspirin to prevent stroke is less well established, and it is not recommended to prevent MI.6 The present study documented the cost-effectiveness among women 65 years of age with elevated baseline risk and supports the AHA recommendations that the weight of evidence is in favor of aspirin therapy for primary prevention in this population, with the important caveats that blood pressure should be controlled and the risk of gastrointestinal bleeding and hemorrhagic stroke should be taken into consideration.6 The data also support a more conservative approach to aspirin for primary prevention in younger versus older women, consistent with current guidelines.6 Although AHA guidelines state not to use aspirin for the prevention of MI in women <65 years of age, a recent national survey documented that >80% of women in this age group perceive that aspirin will prevent heart disease.17 This discordance underscores the need for physicians to counsel most younger women that aspirin is associated with little proven preventive benefit and possible harm. As illustrated in the Table, there are nearly 2 dozen different AHA recommendations for aspirin chemoprevention. The complexity of these recommendations is a major public health challenge because aspirin is widely available without prescription. Moreover, aspirin is frequently marketed to women directly without the context of gender and age differences in benefits and risks. Therefore, individualized advice from a healthcare provider is essential in weighing the potential risks and benefits of aspirin for primary prevention.
The gender differential in aspirin utility in this study is biologically plausible and is congruent with our knowledge that the risk of CVD in women is delayed 10 years compared with men and thus the cost-effectiveness of CVD preventive interventions might also be delayed. In addition, as women age, stroke becomes a relatively more frequent outcome compared with MI, suggesting that aspirin will be more cost-effective as women age because of its greater impact on stroke than MI.18 In contrast, aspirin has been shown to have a significant benefit on the prevention of a first MI in men but not stroke2; therefore, the cost-effectiveness of aspirin in men is expected to occur at younger ages than in women when the relative incidence of MI to stroke is higher. Data from the Women’s Health Study showed that the ratio of stroke to MI was 1.4:1 among women in the placebo group, whereas the ratio was 0.4:1 among men of similar age in the Physician’s Health Study.2,18 The frequency distribution of various cardiovascular outcomes in gender subgroups may therefore affect the cost-effectiveness of aspirin.
As with any cost-effectiveness evaluation, the interpretation of the findings depends on the assumptions of the statistical models and the input parameters. The choice of outcomes may introduce bias when women are compared with men. For example, women are more likely to experience angina than MI as an initial manifestation of coronary disease, whereas men are more likely to have MI. The authors did not include angina as a predicted outcome in the Markov models, which may underestimate the cost-effectiveness of aspirin in older women, in whom it has been shown to have a modest effect on coronary disease.18 Differences in population CVD event rates and background rates of preventive therapy between the Dutch and other populations may affect the external validity of the findings. If the rate of uncontrolled hypertension is higher in a target population than the one studied, then the balance of benefits and risks may be less favorable than predicted owing to a higher-than-expected rate of hemorrhagic stroke, which may be worsened by aspirin treatment.
The authors showed that the results were sensitive to certain parameters, including drug treatment costs, utility of taking aspirin, and effectiveness of aspirin treatment. The last parameter is a potentially important limitation because the authors based the relative effects of aspirin on a meta-analysis that included 6 trials of aspirin for primary prevention, but the majority of data in women come from 1 trial.18,19 The Women’s Health Study included primarily healthy women, and 85% had a 10-year Framingham coronary risk score of <5%, so it is difficult to draw firm conclusions about the impact and cost-effectiveness of aspirin in women with higher levels of CVD risk.18 Other limitations of applying the results of this study to clinical practice include the possibility of aspirin resistance and the fact that the optimal dose for cardiovascular prophylaxis is not firmly established.
One of the most important take-home messages from this study is that when it comes to aspirin for the primary prevention of CVD, what is good for the goose may not be good for the gander. From these data and the totality of evidence, the use of aspirin in low-risk women <65 years of age is not cost-effective. The threshold to treat women at moderate risk should be higher than for men, and the risks of therapy should be carefully considered in all patients. This study has important implications for the application of other preventive interventions and guidelines that often are based on a "one size fits all" approach. It is imperative that scientists and clinicians take into consideration the guiding principles that sex-based differences in biology, population differences in baseline risk of disease, and subgroup variations in side effects of interventions may significantly influence the ratio of benefit to risk in individual patients and the cost-effectiveness of preventive interventions for a society.
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Acknowledgments |
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Disclosures
Dr Mosca has served as a consultant for McNeil Consumer Healthcare, Inc.
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Footnotes |
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The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
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