EDITORIAL COMMENT
A Zero Coronary Artery Calcium ScorePriceless*
Harvey S. Hecht, MD*
Lenox Hill Heart and Vascular Institute, New York, New York
* Reprint requests and correspondence: Dr. Harvey S. Hecht, Lenox Hill Heart and Vascular Institute, 130 East 77th Street, New York, New York 10021 (Email: hhecht{at}aol.com).
Key Words: coronary artery calcium • computed tomography • coronary artery disease
The data supporting the prognostic superiority of coronary artery calcium (CAC) to risk-factor-based paradigms is on the verge of achieving the critical mass necessary for widespread implementation in the asymptomatic population. The Texas State legislature has mandated insurance coverage for CAC for the intermediate-risk population (1), and it is now a covered service by United Healthcare (2). Forthcoming scientific statements from the major professional organizations are expected to further strengthen the existing recommendations.
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Randomized Controlled Trials
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The sole remaining counterargument is the absence of outcome data demonstrating that the use of CAC saves lives. This underlines the misconception that CAC is a treatment modality and typifies the erroneous application of the demand for randomized controlled trials to arenas that should not require this sort of validation. Randomized controlled trial outcome studies have never been required for any of the cardiac diagnostic modalities or for the Framingham risk score. The selective demand for their application to CAC has delayed its use, with a resultant loss of life that very likely could have been mitigated by appropriate reclassification of patients to higher-risk categories, with subsequent aggressive lifesaving medical treatment. Randomized controlled trials are not necessary to prove that treatment of high-risk patients saves lives. If a randomized controlled trial were performed and failed to show that treatment of CAC-identified high-risk patients saved more lives, the fault would lie with the treatment rather than the test.
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Zero CAC Score Patients
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The flip side of the equation is the reclassification of patients with a CAC = 0 to the lowest-risk category and the resultant change in the level of treatment. It is worthwhile to review the comments of Greenland et al. (3) in 2001: Consider a 50-year-old asymptomatic man who does not smoke, who has a blood pressure level of 140/85, total cholesterol of 210 mg/dl, LDL [low-density lipoprotein] cholesterol of 137 mg/dl, HDL [high-density lipoprotein] cholesterol of 32 mg/dl, a negative family history of vascular disease, and a normal fasting blood glucose. On the basis of Framingham risk assessment scoring, this man's risk falls into the "intermediate" zone with a 9% estimated 10-year risk of hard CHD [coronary heart disease]. Although he does not fall into the high-risk category requiring intensive intervention, his LDL cholesterol level is not optimal, and blood pressure is also not optimal. If further testing were done in this person, for example EBT [electron beam tomography], and a coronary calcium score of >80 were found, the physician would be able to reassign him to a higher risk category (at least 20% in 10 years) and justifiably proceed more aggressively to reduce his risk factors that are present. Specifically, given that this hypothetical patient's estimated risk is equivalent to that of a typical coronary patient, we propose the need for intensive intervention. If the calcium score were zero (as it would be in 35% of men his age), the physician should still counsel the patient about trying to control his risk factors for the long term, but one would not be justified to intervene with costly lipid-lowering or blood pressure–lowering drugs at this time, based on a revised (post-test) risk estimate of approximately 1.9% in 10 years.
In fact, the 10-year risk of a CAC = 0 is closer to 1% (4–8) (Table 1). In this instance, invocation of the need for randomized controlled trials to justify drug therapy is appropriate. There are simply no data showing that lipid-lowering drug treatment of patients with a 0 CAC score can reduce 10-year risk below 1%, and the burden of proof is on those who wish to administer a potentially harmful and costly drug without evidence-based demonstrable benefit, rather than on those who would withhold it.
Major changes in clinical treatment will follow implementation of the paradigm of Greenland et al. (3) quoted above and that expressed in 2004 in Risk Factors Revisited (9): The value of risk factors may reside more in determining the targets of intensive therapy in those with increased risk, rather than in factoring them into an equation that performs suboptimally in determining that risk. Once risk is established, either by clinical disease in secondary prevention or by CAC-defined subclinical disease in primary prevention, aggressive attention should be directed to modifying those factors that are modifiable.
Recommendations have been published by Hecht et al. (10), and by the SHAPE (Screening for Heart Attack Prevention and Education) guidelines (11), on which the Texas legislation was based.
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The Warranty Period
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Assuming that downgrading the intensity of or withholding drug therapy in CAC = 0 patients becomes the standard of care, the critical issue is the interval at which CAC evaluation should be repeated. The important paper by Min et al. (12) in this issue of the Journal is the first to provide the answer. The investigators assessed the frequency of progression, time to progression, and proportional increase of CAC in 422 patients, 66.4% of whom were on statin therapy, with a baseline CAC = 0 by annual CAC scanning for 5 consecutive years or until scan conversion. They compared the results to those from a referent cohort of 621 individuals with baseline score of CAC >0. Of the CAC = 0 patients, 25.1% developed CAC in a nonlinear fashion during follow-up, at a mean time to conversion of 4.1 ± 0.9 years. Conversion from a CAC = 0 to a CAC >0 score occurred in 2 (0.5%), 5 (1.2%), 24 (5.7%), 26 (6.2%), and 49 (11.6%) in years 1, 2, 3, 4, and 5, respectively. Progression to a score of CAC >0 was associated with age >40 years, diabetes, and smoking in multivariable analysis; time to conversion was not related to any risk factor. The CAC score on conversion was 19 ± 19.
Among the 621 individuals with baseline score of CAC >0, only the presence and extent of CAC itself, rather than any traditional coronary artery disease risk factors, was predictive of CAC progression over time. Among propensity score-matched patients with a score of CAC >0 versus CAC = 0, a baseline score of CAC >0 emerged as the strongest predictor of CAC progression (hazard ratio [HR]: 12.50, 95% confidence interval [CI]: 9.31 to 16.77), followed by diabetes (HR: 2.07, 95% CI: 1.47 to 2.90), and smoking (HR: 1.29, 95% CI: 1.02 to 1.63, p < 0.05 for all). They concluded that the rate of conversion to an abnormal CAC scan was nonlinear and occurred at a low frequency before 4 years of follow-up. No clinical factor, including age, seemed to mandate an earlier temporal window for repeat CAC scanning among such patients.
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Study Implications
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Thus, it seems reasonable to repeat CAC scanning at a 4-year interval in patients whose CAC = 0 have resulted in withholding drug therapy that might have been implemented on the basis of their Framingham risk score. The nonlinear conversion is reassuring and supports a 4-year rather than a shorter interval. Concerns regarding the confounding effect of statin treatment on conversion are very likely unfounded because 3 prospective randomized trials have shown no effect of statin treatment on CAC score progression (13–15).
The magnitude of this issue is highlighted in Table 1; the percentage of patients who would be candidates for the least aggressive therapy by virtue of a CAC = 0 score is 41% (Table 1). The percentage of these originally assigned to the Framingham high-, intermediate-, and low-risk groups is not available. However, in the Heinz Nixdorf Recall study (16), CAC-based reassignment of Framingham intermediate-risk patients included 62.9% to the low-risk category (CAC <100) and 14.1% to the high-risk category (CAC  400). Only 23.1% remained in the intermediate-risk category (CAC 100 to 399). Of course, clinical events may occur in the conversion period, but their frequency will be quite low ( 0.1%/year); conversion to a score of CAC >0 is not a clinical event. As discussed earlier, there are no data showing that treating these lowest-risk patients would have any impact on events or would have decreased conversion.
The cost savings implicit in the decreased prescription drug use during the 4-year warranty period are relatively straightforward and of great magnitude. In addition, there would be significant savings by eliminating stress testing for risk evaluation in asymptomatic patients with multiple risk factors, currently an American College of Cardiology/American Heart Association Class IIb indication (17), in the asymptomatic CAC = 0 population for a 4-year period.
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Conclusions
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The report by Min et al. (12) paves the way for a fresh approach to a large segment of the primary prevention population. Although additional confirmatory data would be helpful, it is unlikely that the annual CAC scans that were critical in establishing the nonlinear pattern of conversion can be incorporated into future protocols. The projected exponential increase in CAC scanning that will follow insurance, legislative, and professional society endorsement will offer an opportunity for implementing a safe, cost-saving paradigm that is supported by a large prospective and retrospective database. The cost of overtreatment in this lowest-risk asymptomatic population is quite high; CAC = 0 is priceless.
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Footnotes
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Dr. Hecht is on the Speakers' Bureau for Philips Medical Systems.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Texas Legistlature Online. Bill: HB 1290. Legistlative session: 81(R). http://www.capitol.state.tx.us/BillLookup/History.aspx?LegSess=81R&Bill=HB1290Accessed February 2010.2. United Health Group Incorporated. Medical Technology Assessment Committee http://www.unitedhealthcareonline.comAccessed April 16, 2009. 3. Greenland P, Smith SC, Grundy SM. Improving coronary heart disease risk assessment in asymptomatic people. Role of traditional risk factors and noninvasive cardiovascular tests. Circulation 2001;104:1863-1867.[Free Full Text] 4. Arad Y, Goodman KJ, Roth M, et al. Coronary calcification, coronary risk factors, and atherosclerotic cardiovascular disease events. The St. Francis Heart Study. J Am Coll Cardiol 2005;46:158-165.[Abstract/Free Full Text] 5. Becker A, Leber A, Becker C, Knez A. Predictive value of coronary calcifications for future cardiac events in asymptomatic individuals Am Heart J 2008;155:154-160.[CrossRef][Web of Science][Medline] 6. 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;358:1336-1345.[CrossRef][Medline] 7. Sarwar A, Shaw LJ, Shapiro, MD, et al. Diagnostic and prognostic value of absence of coronary artery calcification J Am Coll Cardiol Img 2009;2:675-688.[Abstract/Free Full Text] 8. Blaha M, Budoff MJ, Shaw LJ, et al. Absence of coronary artery calcification and all-cause mortality J Am Coll Cardiol Img 2009;2:692-700.[Abstract/Free Full Text] 9. Hecht HS. Risk factors revisited Am J Cardiol 2003;93:73-75.[Web of Science] 10. Hecht HS, Budoff M, Ehrlich J, Rumberger J. Coronary artery calcium scanning: clinical recommendations for cardiac risk assessment and treatment Am Heart J 2006;151:1139-1146.[CrossRef][Web of Science][Medline] 11. Naghavi M, Falk E, Hecht HS, et al. From vulnerable plaque to vulnerable patient—part III: executive summary of the Screening for Heart Attack Prevention and Education (SHAPE) task force report Am J Cardiol 2006;98(Suppl):2H-15H.[Web of Science][Medline] 12. Min JK, Lin FY, Gidseg DS, et al. Determinants of coronary calcium conversion among patients with a normal coronary calcium scan. What is the "warranty period" for remaining normal?. J Am Coll Cardiol 2010;55:1110-1117.[Abstract/Free Full Text] 13. Raggi P, Davidson M, Callister TQ, et al. Aggressive versus moderate lipid-lowering therapy in hypercholesterolemic post-menopausal women: beyond endorsed lipid lowering with EBT scanning (BELLES) Circulation 2005;112:563-571.[Abstract/Free Full Text] 14. Arad Y, Spadaro LA, Roth M, et al. Treatment of asymptomatic adults with elevated coronary calcium scores with atorvastatin, vitamin C, and vitamin E. The St. Francis heart study randomized clinical trial. J Am Coll Cardiol 2005;46:166-172.[Abstract/Free Full Text] 15. Schmermund A, Achenbach S, Budde T, et al. Effect of intensive versus standard lipid-lowering treatment with atorvastatin on the progression of calcified coronary atherosclerosis over 12 months. A multicenter, randomized, double-blind trial. Circulation 2006;113:427-437.[Abstract/Free Full Text] 16. Erbel R, Möhlenkamp S, Moebus S, et al. Signs of subclinical coronary atherosclerosis measured as coronary artery calcification improve risk prediction of hard events beyond traditional risk factors in an unselected general population. The Heinz Nixdorf Recall Study five-year outcome data. J Am Coll Cardiol 2010In press. 17. Gibbons RJ, Balady GJ, Bricker JT, et al. ACC/AHA 2002 guideline update for exercise testing: summary article. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines). J Am Coll Cardiol 2002;40:1531-1540.[Free Full Text]
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Randomized Controlled Trials
Zero CAC Score Patients