Identifying Likelihood of Obstructive Coronary Disease in Patients With a Calcium Score of Zero

HomeCirculation: Cardiovascular ImagingVol. 12, No. 9Identifying Likelihood of Obstructive Coronary Disease in Patients With a Calcium Score of Zero Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBIdentifying Likelihood of Obstructive Coronary Disease in Patients With a Calcium Score of ZeroSeparating the Wheat From the Chaff Jay Ramchand, BMedSci, MBBS, Wael Jaber, MD and Rory Hachamovitch, MD, MSc Jay RamchandJay Ramchand Section of Cardiovascular Imaging, Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, OH. , Wael JaberWael Jaber Section of Cardiovascular Imaging, Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, OH. and Rory HachamovitchRory Hachamovitch Rory Hachamovitch, MD, MSc, Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, 9500 Euclid Ave, Desk J1-5, Cleveland, OH 44195. Email E-mail Address: [email protected] Section of Cardiovascular Imaging, Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, OH. Originally published17 Sep 2019https://doi.org/10.1161/CIRCIMAGING.119.009649Circulation: Cardiovascular Imaging. 2019;12:e009649This article is a commentary on the followingPoint of Care Clinical Risk Score to Improve the Negative Diagnostic Utility of an Agatston Score of ZeroSee Article by Alshahrani et alThe lesson I've learned the most often in life is that you're always going to know more in the future than you know now.—Taylor SwiftDon't think, look!—Ludwig WittgensteinThe presence of coronary artery calcium (CAC)—a pathognomonic marker of atherosclerosis—has emerged as a factor strongly associated with the development of adverse cardiovascular events. It is established that a zero CAC score is a unique negative risk marker, aptly referred to as the power of zero given its association with an exceedingly low event rate.1 This result permits a reclassification of risk incremental to conventional risk markers alone. However, as noncalcified plaque can occur, the presence of a zero CAC score is not identical to the absence of atherosclerosis. Noncalcific plaque formation can be dynamic, with a preponderance to develop and bring about symptoms in younger patients.2 The optimal evaluative approach to the symptomatic individual with a CAC score of zero is undefined.In the current issue, Alshahrani et al3 report a new clinical score predicting the presence of coronary computed tomography angiography (CCTA)–defined obstructive coronary artery disease (CAD) in patients with zero CAC. The score was based on a derivation cohort from a computed tomography registry4 of predominantly symptomatic patients (82%) with a CAC score of zero (n=4903) and validated in an independent cohort of 4290 mostly symptomatic patients (73%) from the Coronary CT Angiography Evaluation for Clinical Outcomes: an International Multicenter Registry multinational registry.5 Logistic regression modeling was applied to patient characteristics—patient sex, age, typical chest pain, dyslipidemia, hypertension, family history of CAD, and diabetes mellitus—to identify CCTA-defined obstructive CAD (stenosis ≥50%; 3.5% of patients). Based on weights of the β-coefficients, a score of ≤6 was considered low risk (negative predictive value, 99%; negative likelihood ratio, 0.42), scores of 7 to 13 were intermediate risk, and scores >14 were high risk for obstructive CAD (specificity, 98%; positive likelihood ratio, >5). The prognostic characteristics were examined in an underpowered small subanalysis with all-cause mortality over a median 2-year follow-up was 0.51% and 0.58% in the low- and intermediate-risk groups, respectively, versus 2% in the high-risk group. The results of the current study potentially aid the decision-making process in symptomatic patients with zero CAC. Study findings suggest that in low-risk individuals (risk score, ≤6), CCTA-defined obstructive CAD can be excluded with a high degree of certainty, potentially avoiding further investigation.Study strengths include the large sample size, the well-phenotyped patient population, and validation of findings in an independent cohort. The study limitations include a 22% frequency of asymptomatic patients, possibly obfuscating the accuracy of the score. The prevalence of CAD was very low, 3.5% overall, and only 2.8% of patients were reclassified by the score as high likelihood of CAD. The use of a 50% CCTA stenosis threshold has been shown to be associated with a significant false positive rate6; thus, the low CAD prevalence may well be an overestimation. Finally, as many as 47% of patients from the validation cohort were excluded from analysis, which may have influenced the results of the study. Although there are currently no guideline recommendations to support the use of CAC in symptomatic individuals,7 it is unclear whether the current results sway the reader toward or away from its use given the extremely low risk of obstructive CAD even in the high-risk zero CAC patients.A basic axiom of noninvasive testing is that the utility of the test depends on the pretest probability of the population tested.8,9 The importance of conditional probability still holds true in a seemingly low-risk population with a zero CAC. A low pretest CAD probability combined with a zero CAC is associated with low CAD prevalence and risk.10 However, in the presence of symptoms, with increasing age and risk factors,11 a zero CAC is increasingly associated with myocardial ischemia on functional testing and a significantly higher risk of coronary-related adverse events. A zero CAC in this context does not rule out obstructive CAD and begs the question of the appropriateness and value of the CAC assessment in greater than low-risk, symptomatic patient groups. The PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain)12,13 and SCOT-HEART14 trials (CT Coronary Angiography in Patients with Suspected Angina due to Coronary Heart Disease) demonstrated the potential utility of CCTA to overcome shortcomings of CAC. In SCOT-HEART, the use of CCTA in addition to standard care in patients with stable chest pain resulted in a lower rate of death from coronary heart disease or nonfatal myocardial infarction at 5 years compared with standard care alone. Indeed, the 2016 update to the National Institute for Health and Care Excellence CG95 no longer recommends CAC scoring.15 Moreover, this document does not recommend CAC scoring in symptomatic individuals with low pretest probability, particularly given the risks of noncalcific plaques.Given the avalanche of available data, clinicians often rely on heuristics—an educated guess or rule of thumb. These cognitive shortcuts provide quick and efficient decision-making when faced with a complex cognitive problem, albeit imperfect and likely flawed. A solution for this frustrating challenge is the use of predictive instruments. There is a long history of scores for predicting CAD probability or risk of adverse outcomes.8,16 These scores, the original personalized medicine, permit patient-specific prediction via weighted combination of all available data. The prerequisites for a predictive instrument include calibration to an observed outcome, generalizability, portability to an outside population, and acceptability by clinicians with an impact on practice.17 Independently of the generalizability of CAC to symptomatic low-risk patients, is there a need for another clinical score? Indeed, the variables included in the model proposed by Alshahrani et al3 are similar to those used in more ubiquitous tools used to determine pretest probability.18 Although the CAD risk model proposed by Alshahrani et al3 was able to categorize risk for obstructive CAD and mortality, the patient population was dominated by younger individuals with atypical symptoms and otherwise low pretest CAD probability. Therefore, the applicability of this model in other patient populations such as the elderly or those without symptoms, or extension to other cohorts, requires further evaluation. Although the analysis of net reclassification or integrated discriminative value is not provided, most individuals (≈58%) were stratified into the intermediate-risk category, which does not suggest an improved predictive utility of the present model compared with already available risk scores. Nevertheless, the study represents an important step forward to develop an optimal approach in the assessment of patients with CAC score of zero.At present, routine use of CAC assessment cannot be recommended for the assessment of symptomatic individuals. That said, there is little doubt in our minds that words by Swift are true—we will know more in the future than the past. Future studies will refine our approaches to best select candidates for CAC versus CCTA testing. It will be particularly interesting to see what the role will be in the future for CAC in the era of modern day CCTA technology.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Rory Hachamovitch, MD, MSc, Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, 9500 Euclid Ave, Desk J1-5, Cleveland, OH 44195. Email [email protected]orgReferences1. Budoff MJ, Mayrhofer T, Ferencik M, Bittner D, Lee KL, Lu MT, Coles A, Jang J, Krishnam M, Douglas PS, Hoffmann U; PROMISE Investigators. Prognostic value of coronary artery calcium in the PROMISE Study (Prospective Multicenter Imaging Study for Evaluation of Chest Pain).Circulation. 2017; 136:1993–2005. doi: 10.1161/CIRCULATIONAHA.117.030578LinkGoogle Scholar2. Marwan M, Ropers D, Pflederer T, Daniel WG, Achenbach S. Clinical characteristics of patients with obstructive coronary lesions in the absence of coronary calcification: an evaluation by coronary CT angiography.Heart. 2009; 95:1056–1060. doi: 10.1136/hrt.2008.153353CrossrefMedlineGoogle Scholar3. Alshahrani AM, Mahmood H, Wells GA, Hossain A, Rybicki FJ, Achenbach S, Al-Mallah MH, Andreini D, Bax JJ, Berman DS, Budoff MJ, Cademartiri F, Callister TQ, Chang HJ, Chinnaiyan K, Cury RC, DeLago A, Feuchtner G, Hadamitzky M, Hausleiter J, Kaufmann PA, Kim Y-J, Leipsic JA, Maffei E, Marques H, Pontone G, Raff G, Rubinshtein R, Shaw LJ, Villines TC, Lin FY, Min JK, Chow BJ. Point of care clinical risk score to improve the negative diagnostic utility of an Agatston score of zero: averting the need for coronary computed tomography angiography.Circ Cardiovasc Imag. 2019; 12:e008737. doi: 10.1161/CIRCIMAGING.118.008737LinkGoogle Scholar4. Chow BJ, Wells GA, Chen L, Yam Y, Galiwango P, Abraham A, Sheth T, Dennie C, Beanlands RS, Ruddy TD. Prognostic value of 64-slice cardiac computed tomography severity of coronary artery disease, coronary atherosclerosis, and left ventricular ejection fraction.J Am Coll Cardiol. 2010; 55:1017–1028. doi: 10.1016/j.jacc.2009.10.039CrossrefMedlineGoogle Scholar5. Min JK, Dunning A, Lin FY, Achenbach S, Al-Mallah M, Budoff MJ, Cademartiri F, Callister TQ, Chang HJ, Cheng V, Chinnaiyan K, Chow BJ, Delago A, Hadamitzky M, Hausleiter J, Kaufmann P, Maffei E, Raff G, Shaw LJ, Villines T, Berman DS; CONFIRM Investigators. Age- and sex-related differences in all-cause mortality risk based on coronary computed tomography angiography findings results from the International Multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: an International Multicenter Registry) of 23,854 patients without known coronary artery disease.J Am Coll Cardiol. 2011; 58:849–860. doi: 10.1016/j.jacc.2011.02.074CrossrefMedlineGoogle Scholar6. Kim C, Hong SJ, Shin DH, Kim JS, Kim BK, Ko YG, Choi D, Jang Y, Hong MK. Limitations of coronary computed tomographic angiography for delineating the lumen and vessel contours of coronary arteries in patients with stable angina.Eur Heart J Cardiovasc Imaging. 2015; 16:1358–1365. doi: 10.1093/ehjci/jev100CrossrefMedlineGoogle Scholar7. Wolk MJ, Bailey SR, Doherty JU, Douglas PS, Hendel RC, Kramer CM, Min JK, Patel MR, Rosenbaum L, Shaw LJ, Stainback RF, Allen JM; American College of Cardiology Foundation Appropriate Use Criteria Task Force. ACCF/AHA/ASE/ASNC/HFSA/HRS/SCAI/SCCT/SCMR/STS 2013 multimodality appropriate use criteria for the detection and risk assessment of stable ischemic heart disease: a report of the American College of Cardiology Foundation appropriate use criteria task force, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, heart rhythm society, society for cardiovascular angiography and interventions, society of cardiovascular computed tomography, society for cardiovascular magnetic resonance, and society of thoracic surgeons.J Am Coll Cardiol. 2014; 63:380–406. doi: 10.1016/j.jacc.2013.11.009CrossrefMedlineGoogle Scholar8. Diamond GA, Forrester JS. Analysis of probability as an aid in the clinical diagnosis of coronary-artery disease.N Engl J Med. 1979; 300:1350–1358. doi: 10.1056/NEJM197906143002402CrossrefMedlineGoogle Scholar9. Greenland P, Bonow RO. How low-risk is a coronary calcium score of zero? The importance of conditional probability.Circulation. 2008; 117:1627–1629. doi: 10.1161/CIRCULATIONAHA.108.767665LinkGoogle Scholar10. 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. doi: 10.1016/j.ahj.2007.08.024CrossrefMedlineGoogle Scholar11. Schenker MP, Dorbala S, Hong EC, Rybicki FJ, Hachamovitch R, Kwong RY, Di Carli MF. Interrelation of coronary calcification, myocardial ischemia, and outcomes in patients with intermediate likelihood of coronary artery disease: a combined positron emission tomography/computed tomography study.Circulation. 2008; 117:1693–1700. doi: 10.1161/CIRCULATIONAHA.107.717512LinkGoogle Scholar12. Hoffmann U, Ferencik M, Udelson JE, Picard MH, Truong QA, Patel MR, Huang M, Pencina M, Mark DB, Heitner JF, Fordyce CB, Pellikka PA, Tardif JC, Budoff M, Nahhas G, Chow B, Kosinski AS, Lee KL, Douglas PS; PROMISE Investigators. Prognostic value of noninvasive cardiovascular testing in patients with stable chest pain: insights from the PROMISE Trial (Prospective Multicenter Imaging Study for Evaluation of Chest Pain).Circulation. 2017; 135:2320–2332. doi: 10.1161/CIRCULATIONAHA.116.024360LinkGoogle Scholar13. Douglas PS, Hoffmann U, Patel MR, Mark DB, Al-Khalidi HR, Cavanaugh B, Cole J, Dolor RJ, Fordyce CB, Huang M, Khan MA, Kosinski AS, Krucoff MW, Malhotra V, Picard MH, Udelson JE, Velazquez EJ, Yow E, Cooper LS, Lee KL; PROMISE Investigators. Outcomes of anatomical versus functional testing for coronary artery disease.N Engl J Med. 2015; 372:1291–1300. doi: 10.1056/NEJMoa1415516CrossrefMedlineGoogle Scholar14. SCOT-Heart Investigators. Coronary CT angiography and 5-year risk of myocardial infarction.N Engl J Med. 2018; 379:924–933. doi: 10.1056/NEJMoa180597CrossrefMedlineGoogle Scholar15. Moss AJ, Williams MC, Newby DE, Nicol ED. The updated NICE guidelines: cardiac CT as the first-line test for coronary artery disease.Curr Cardiovasc Imaging Rep. 2017; 10:15. doi:10.1007/s12410-017-9412-6CrossrefMedlineGoogle Scholar16. Mark DB, Hlatky MA, Harrell FE, Lee KL, Califf RM, Pryor DB. Exercise treadmill score for predicting prognosis in coronary artery disease.Ann Intern Med. 1987; 106:793–800. doi: 10.7326/0003-4819-106-6-793CrossrefMedlineGoogle Scholar17. Udelson JE, Selker HP. Quantitative instruments for predicting risk. and benefit.J Am Coll Cardiol. 2005; 45:730–732. doi: 10.1016/j.jacc.2004.12.017CrossrefMedlineGoogle Scholar18. Fihn SD, Gardin JM, Abrams J, Berra K, Blankenship JC, Dallas AP, Douglas PS, Foody JM, Gerber TC, Hinderliter AL, King SB, Kligfield PD, Krumholz HM, Kwong RY, Lim MJ, Linderbaum JA, Mack MJ, Munger MA, Prager RL, Sabik JF, Shaw LJ, Sikkema JD, Smith CR, Smith SC, Spertus JA, Williams SV; American College of Cardiology Foundation. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: executive summary: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.Circulation. 2012; 126:3097–3137. doi: 10.1161/CIR.0b013e3182776f83LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesPoint of Care Clinical Risk Score to Improve the Negative Diagnostic Utility of an Agatston Score of ZeroAli M. Alshahrani, et al. Circulation: Cardiovascular Imaging. 2019;12 September 2019Vol 12, Issue 9 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCIMAGING.119.009649PMID: 31526299 Originally publishedSeptember 17, 2019 Keywordscalcium, dietarycoronary artery diseaseEditorialsprognosishumansPDF download Advertisement SubjectsComputerized Tomography (CT)Imaging