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Atherosclerosis of the coronary arteries is the underlying pathophysiology leading to a significant portion of clinical coronary heart disease events, but it is silent before the occurrence of a clinical coronary heart disease (CHD) event. Coronary artery calcium (CAC), which can be detected and quantified by noninvasive computed tomography (CT) scanning, is an indicator of the atherosclerosis burden.¹ As one might expect, the CAC score is a strong independent predictor of CHD events: in comparison with persons who have no detectable CAC (score = 0), persons with very high CAC scores (e.g., Agatston score >300) are at 7- to 10-fold risk of events; and even persons with modest CAC scores (1-100) are at 3- to 4-fold risk.² Measuring CAC (and quantifying it using a CAC score), is therefore potentially valuable as a marker of risk for CHD events.

Unlike measurement of traditional risk factors like blood pressure and lipids, however, CAC measurement has significant downsides; in particular, cost (from the test itself and from workup of incidental findings) and exposure to radiation from the CT scan. When is it most useful to measure the CAC score? When is it worth the cost and the radiation exposure? When does the net health benefit from CAC testing (accounting for the health risks of radiation) justify the cost of the test; i.e., when is it cost-effective?

To answer these questions, one has to carefully examine the mechanisms by which CAC testing might actually lead to improvements in health. Simply knowing the results of a CAC test does not improve health directly, but that knowledge can help clinicians and their patients make better decisions together about therapies for primary prevention of CHD. Any prevention strategy will provide higher absolute risk reduction to patients who are at higher baseline risk (all other things being equal). The 2013 American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults now recommends use of statin medications when 10-year atherosclerotic cardiovascular disease risk exceeds 7.5% in individuals without established cardiovascular disease or diabetes and low-density lipoprotein cholesterol (LDL-C) levels of 70-189 mg/dL.³ No other prevention decisions (with the possible exception of those associated with aspirin) are so highly dependent on estimating cardiovascular risk; treatment of elevated blood pressure and management of lifestyle risk factors like poor diet, low levels of physical activity, and smoking, for example, are recommended for all persons regardless of absolute cardiovascular risk. Since the purpose of using CAC testing is to accurately reclassify patients with moderate risk (such as using the atherosclerotic cardiovascular disease [ASCVD] risk estimation) into low or higher risk levels to direct therapy at those patients who will most benefit from aggressive preventive strategy, the cost-effectiveness of CAC testing is highly dependent on the benefits accruing from better and more accurate targeting, in particular, to statin therapy.

How valuable is it to further refine the way we target statin therapy? Statins are broadly effective at lowering risk, even in persons at moderately low risk.⁴ Although muscle pain is a common symptom reported by statin users, it is not appreciably different in patients randomized to placebo versus statins in blinded studies,⁵ and true myopathy rates are quite low. Development of diabetes does appear to be slightly more common in statin users,⁶ but cardiovascular risk and all-cause mortality are still lower in statin users than non-users despite slightly increased diabetes risk. And most statins, even high-dose atorvastatin, are now off-patent and available at relatively low prices. Recent analyses of statin therapy demonstrate cost effectiveness of statins at even lower-risk thresholds than are recommended in current guidelines.⁷ Then why should we spend money on CAC testing to better target statin therapy when we could spend it instead on increasing statin adherence or some other way to prevent disease and improve health?

Two critical factors reduce the cost effectiveness of statin therapy and thereby increase the potential value and cost effectiveness of targeting statin therapy with CAC testing. The first is the inefficiency in the pharmaceutical marketplace. Although the $4/month programs available at discount pharmacy outlets should provide access to low-cost statins, most Americans do not avail themselves of these programs,⁸ and the costs of even generic statins are substantially higher at retail pharmacies. Second, and perhaps more important, is the resistance of many patients to take statins. Adherence rates are not high,⁹ and a significant proportion of patients say they would literally trade away healthy days (17% would trade 1-364 days) or even years (13% would trade ≥365 days) of their life to not have to take statins or other preventive medications on a daily basis, even if the medication is free and has no side effects.¹⁰ It seems reasonable to account for this "disutility" (e.g., reduced quality of life) as a potential adverse health effect of statins.

In our prior attempts at modeling the cost-effectiveness of CAC testing, we found these aspects of statin therapy (cost and disutility) to be critical determinants.¹¹ When statins are inexpensive and do not reduce quality of life, they are very cost effective across a wide range of patients, even down to a 10-year CHD risk of 5%; and there is, therefore, little reason to order a CAC test. In contrast, when statins are assumed to be moderately expensive ($1 per pill/day) and to reduce quality of life (disutility score of 0.00384, such that a person might trade away up to 2 weeks of perfect health to avoid 10 years of statin therapy), we found that the CAC testing can be cost effective depending on level of risk (10-year coronary heart disease risk of about 5-10% is a sweet spot), age, and sex, all of which are strong determinants of the likelihood of actually finding a non-zero CAC score. The actual cost of the CAC scan and assumptions about its predictiveness were also determining factors, but they were, surprisingly, less important than assumptions about statin therapy. A Microsoft Excel-based calculator published with our article can provide quantitative estimates of cost effectiveness for specific clinical scenarios and under differing assumptions about statins and CAC testing. Another recent modeling effort used different assumptions (e.g., that CAC testing increases adherence and would trigger higher-dose statins compared to individuals who would otherwise not receive CAC testing) found a more liberal role for CAC testing overall, but the basic conclusion was qualitatively similar: that CAC testing can be cost effective if there are significant downsides of statin therapy.¹²

As we think about how to use novel biomarkers and especially CAC testing in clinical practice, a new term has entered the lexicon of prevention: "de-risking."¹³ Authors of a recent analysis of theMulti-Ethnic Study of Atherosclerosis (MESA) study have shown that nearly half of patients who would otherwise be eligible for statin therapy (10-year ASCVD risk 7.5%-20%) can be "de-risked" if their CAC score is 0 (e.g., their revised risk level is <5%).¹⁴ Our prior analyses demonstrate that this strategy (measuring CAC and abstaining from statin medications if CAC is absent) can be cost effective, increases coronary heart disease events only slightly, reduces the number of patients exposed to statins (and their side effects), and can save money, if applied judiciously among patients at intermediate risk for coronary heart disease. And it is clearly concordant with many patients' preferences, especially if they are averse to taking statins but are also willing to take them if their scan shows evidence of atherosclerosis.

References

1. Blankenhorn, DH. Coronary arterial calcification: a review. Am J Med Sci 1961;24:1-49.
2. Detrano R, Guerci AD, Carr JJ, et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med 2008;358:1336-45.
3. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2889-934.
4. Cholesterol Treatment Trialists' (CTT) Collaborators, Mihaylova B, Emberson J, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;380:581-90.
5. Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol 2006;97:52C-60C.
6. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010;375:735-42.
7. Pandya A, Sy S, Cho S, Weinstein MC, Gaziano TA. Cost-effectiveness of 10-year risk thresholds for initiation of statin therapy for primary prevention of cardiovascular disease. JAMA 2015;314:142-50.
8. Zhang Y, Gellad WF, Zhou L, Lin YJ, Lave JR. Access to and use of $4 generic programs in Medicare. J Gen Intern Med 2012;27:1251-7.
9. Lemstra M, Blackburn D, Crawley A, Fung R. Proportion and risk indicators of nonadherence to statin therapy: a meta-analysis. Can J Cardiol 2012;28:574-80.
10. Hutchins R, Viera AJ, Sheridan SL, Pignone MP. Quantifying the utility of taking pills for cardiovascular prevention. Circ Cardiovasc Qual Outcomes 2015;8:155-63.
11. Pletcher MJ, Pignone M, Earnshaw S, et al. Using the coronary artery calcium score to guide statin therapy: a cost-effectiveness analysis. Circ Cardiovasc Qual Outcomes 2014;7:276-84.
12. Roberts ET, Horne A, Martin SS, et al. Cost-effectiveness of coronary artery calcium testing for coronary heart and cardiovascular disease risk prediction to guide statin allocation: the Multi-Ethnic Study of Atherosclerosis (MESA). PLoS One 2015;10:e0116377.
13. Kolata G. Heart Scan Can Fine-Tune Risk Estimate for Patients Considering Statins (New York Times website) Oct 5, 2015. Available at: http://www.nytimes.com/2015/10/06/health/heart-scan-can-fine-tune-risk-estimate-for-patients-considering-statins.html. Accessed on 10/12/2015.
14. Nasir K, Bittencourt MS, Blaha MJ, et al. Implications of coronary artery calcium testing among statin candidates according to American College of Cardiology/American Heart Association cholesterol management guidelines: MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol 2015;66:1657-68.

Keywords: Aspirin, Atherosclerosis, Biomarkers, Blood Pressure, Calcium, Cardiovascular Diseases, Cholesterol, Coronary Artery Disease, Diabetes Mellitus, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypertension, Life Style, Lipids, Lipoproteins, LDL, Myalgia, Pharmacies, Primary Prevention, Risk Factors, Smoking, Tomography, Tomography, X-Ray Computed

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