"Readers wishing to see the figures and/or tables for this paper should consult the print version of this paper."

Studies have proven that both aspirin and HMG-CoA reductase inhibitors (statins) are effective in preventing first coronary artery disease (CAD) events in men.¹ Each drug has been separately recommended by national treatment guidelines as primary prevention for some men at greater risk for CAD events.^2,3 Previous guidelines have not, however, jointly and rigorously defined which patients should receive aspirin or statins, both drugs, or neither drug at different levels of heart disease risk. We recently developed a heart disease prevention model that assesses the effectiveness and cost effectiveness of aspirin, statins, or both drugs in cohorts of men with different underlying CAD risk levels.

Patients and methods
In the model, we assessed the cost utility of treatment with aspirin, statins, both aspirin and statins, or neither drug in groups of healthy, moderate-risk (10-year CAD risk, 7.5%) 45-year-old men. The model tracked individuals’ experiences on a yearly basis. They could continue in a healthy state; die; progress to having an initial cardiovascular event, such as myocardial infarction (MI), stroke, or angina; or have adverse effects related to treatment, such as myopathy from statins or gastrointestinal bleeding from aspirin. The model presumed full adherence to therapy. Patients who experienced adverse effects discontinued the drug causing the reaction. Estimates of the effectiveness of medications, risk of adverse events, costs, and patients’ average values (“utilities”) for the outcomes considered were taken from the medical literature. The model was designed to consider different scenarios in which all the basic values were varied to test their independent and joint effects.

Results
In our main analysis of 45-year-old men at moderate risk (7.5% chance of a CAD event over 10 years), we found that mean quality-adjusted life-years (QALYs) was increased among patients treated with aspirin for 10 years (17.20) versus patients who received no treatment (17.16). The cost of treatment was also lower for patients treated with aspirin ($6694) compared with those who received no treatment ($6909). When a statin drug was added to aspirin treatment, QALYs increased, but so did the cost. The total cost was about $56 200 for each QALY gained over 10 years of treatment.⁴ Table 1 shows the clinical outcomes that would be expected in hypothetical cohorts of 45-year-old men undergoing treatment over 10 years.

The cost effectiveness of adding statins improved with higher CAD risk. The principal benefit of aspirin came from the prevention of nonfatal MI; statins also reduced new-onset angina. The main adverse effects were myopathy from statins and increased gastrointestinal bleeding and hemorrhagic strokes from aspirin. If hemorrhagic strokes were considered separately as an adverse event, treatment with aspirin appeared harmful (less effective and more costly than no therapy) for patients at low risk (10-year CAD risk of 5%).

The model’s results depended on the price of statins, which in the base case was assumed to be just over $700 per year according to average wholesale prices of prescription statins. When the cost was lower, as with generic lovastatin, the cost-effectiveness ratio improved; if the cost was higher (as with some branded statins), the cost-effectiveness ratio was less favorable. The results for aspirin also depended on the excess rate of gastrointestinal bleeding, the risk of hemorrhagic stroke, and the “hassle” that a patient attributed to taking medication daily. Even the small decrease in quality of life associated with taking a pill each day makes aspirin less effective than no treatment. Other factors, such as treatment efficacy, other costs, risk of myopathy with statins, other utilities, and risk of death after an initial CAD event had little effect on the overall results. When we used simulation to examine the combined effect of the different sources of uncertainty, we found that our results were not likely to be altered by the net amount of uncertainty.⁴

Discussion
So what should you do for the patient described in the Case Report, who had an estimated 10-year CAD risk of 8%? National guideline-issuing organizations, such as the US Preventive Services Task Force⁵ and the American Heart Association,³ recommend consideration of aspirin for patients with 10-year CAD risks more than 6% and 10%, respectively. Our results provide additional support for recommending aspirin for patients with moderate (7.5%) 10-year risk and suggest that we should support its use for the patient described in the Case Report, assuming there are no contraindications to therapy. Statin use would save more life-years, but at a relatively high cost per QALY gained, given our assumptions about cost. Table 2 shows how our results can be translated into clinical practice.

Despite their proven efficacy, utilization of aspirin and statins for primary prevention is currently far below optimal levels.^6,7 Clinicians should assess CAD risk in all middle-aged and older adults, and investigate ways to promote the appropriate use of aspirin and statins among men with moderate or higher risk, as well as among younger adults with additional CAD risk factors. The threshold for adding statins will be reduced when the price of statins decreases.

How should CAD risk be calculated? Several risk calculators are available with paper, PDA, or Web-based interfaces.⁸ Risk estimates based on the Framingham Heart Study have been well validated for use in US populations and appear to give accurate results for whites and African Americans.⁹ They do not perform as well for other ethnic populations.¹⁰ Framingham-based calculators require information on the patient’s age, sex, systolic blood pressure, total and HDL cholesterol levels, the presence or absence of diabetes, and smoking status.⁸ Some versions incorporate information about electrocardiographic evidence of left ventricular hypertrophy, but calculating risk in the absence of an electrocardiogram does not frequently affect the results. Some Framingham risk tools use equations that predict total CAD events (angina, MI, and sudden death), whereas others give only “hard” events (MI and sudden death). The risk levels we used in this model were for total CAD events. An example of a CAD risk calculator for total events that we developed can be found at www.med-decisions.com.¹¹ A version developed for the National Heart, Lung, and Blood Institute that calculates hard events only is available at www.hp2010.nhlbihin.net/atpiii/calculator.asp.

Conclusion
Our cost-utility analysis of treatment with aspirin, statins, and a combination of aspirin and statins among 45-year-old men showed that treatment with aspirin cost less and was more effective than no treatment for patients with a 10-year risk of CAD of 7.5% before treatment. For those with more than a 10% 10-year risk of CAD, the addition of a statin to aspirin therapy was cost effective. Although aspirin and statins have been shown to be effective for the primary prevention of CAD events, they are underused. Clinicians should consider prescribing these treatments for their patients with moderate to high risk of CAD.

References
1. Hayden M, Pignone M, Phillips C, et al. Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the US Preventive Services Task Force. Ann Intern Med. 2002;136(2):161-172.

2. Grundy SM, Cleeman JI, Merz CN, et al; National Heart, Lung, and Blood Institute; American College of Cardiology Foundation; American Heart Association. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110(2):227-239.

3. Pearson TA, Blair SN, Daniels SR, et al. AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke: 2002 Update: Consensus Panel Guide to Comprehensive Risk Reduction for Adult Patients Without Coronary or Other Atherosclerotic Vascular Diseases. American Heart Association Science Advisory and Coordinating Committee. Circulation. 2002;106(3):388-391.

4. Pignone M, Earnshaw S, Tice JA, et al. Aspirin, statins, or both drugs for the primary prevention of coronary heart disease events in men: a cost-utility analysis.Ann Intern Med. 2006;144(5):326-336.

5. US Preventive Services Task Force. Aspirin for the primary prevention of cardiovascular events: recommendation and rationale. Ann Intern Med. 2002;136(2): 157-160.

6. Ajani UA, Ford ES, Greenland KJ, et al. Aspirin use among US adults behavioral risk factor surveillance system. Am J Prev Med. 2006;30(1):74-77.

7. Stafford RS, Monti V, Ma J. Underutilization of aspirin persists in US ambulatory care for the secondary and primary prevention of cardiovascular disease.PLoS Med. 2005;2(12):e353.

8. Sheridan S, Pignone M, Mulrow C. Framingham-based tools to calculate the global risk of coronary heart disease: a systematic review of tools for clinicians.J Gen Intern Med. 2003;18(12): 1039-1052.

9. Wilson PW, D’Agostino RB, Levy D, et al. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97(18): 1837-1847.

10. D’Agostino RB Sr, Grundy S, Sullivan LM, et al; CHD Risk Prediction Group. Validation of the Framingham coronary heart disease prediction scores: results of a multiple ethnic groups investigation. JAMA. 2001;286(2):180-187.

11. Pignone M, Sheridan SL, Lee YZ, et al. Heart to Heart: a computerized decision aid for assessment of coronary heart disease risk and the impact of risk-reduction interventions for primary prevention. Prev Cardiol. 2004;7(1): 26-33.

A more detailed discussion of this topic can be found in Pignone M, Earnshaw S, Tice JA, et al. Aspirin, statins, or both drugs for the primary prevention of coronary heart disease events in men: a cost-utility analysis. Ann Intern Med. 2006;144(5):326-336.