Original Article
Prognostic significance of calcified plaque among symptomatic patients with nonobstructive coronary artery disease

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Abstract

Background

Coronary artery calcium (CAC) is a well-established predictor of clinical outcomes for population screening. Limited evidence is available as to its predictive value in symptomatic patients without obstructive coronary artery disease (CAD). The aim of the current study was to assess the prognostic value of CAC scores among symptomatic patients with nonobstructive CAD.

Methods

From the COronary Computed Tomographic Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter (CONFIRM) registry, 7,200 symptomatic patients with nonobstructive CAD (<50% coronary stenosis) on coronary-computed tomographic angiography were prospectively enrolled and followed for a median of 2.1 years. Patients were categorized as without (0% stenosis) or with (>0% but <50% coronary stenosis) a luminal stenosis. CAC scores were calculated using the Agatston method. Univariable and multivariable Cox proportional hazard models were employed to estimate all-cause mortality and/or myocardial infarction (MI). Four-year death and death or MI rates were 1.9% and 3.3%.

Results

Of the 4,380 patients with no luminal stenosis, 86% had CAC scores of <10 while those with a luminal stenosis had more prevalent and extensive CAC with 31.9% having a CAC score of ≥100. Among patients with no luminal stenosis, CAC was not predictive of all-cause mortality (P = .44). However, among patients with a luminal stenosis, 4-year mortality rates ranged from 0.8% to 9.8% for CAC scores of 0 to ≥400 (P < .0001). The mortality hazard was 6.0 (P = .004) and 13.3 (P < .0001) for patients with a CAC score of 100-399 and ≥400. In patients with a luminal stenosis, CAC remained independently predictive in all-cause mortality (P < .0001) and death or MI (P < .0001) in multivariable models containing CAD risk factors and presenting symptoms.

Conclusions

CAC allows for the identification of those at an increased hazard for death or MI in symptomatic patients with nonobstructive disease. From the CONFIRM registry, the extent of CAC was an independent estimator of long-term prognosis among symptomatic patients with luminal stenosis and may further define risk and guide preventive strategies in patients with nonobstructive CAD.

Introduction

The presence and extent of coronary artery calcium (CAC) is well-established predictor of clinical outcomes in asymptomatic individuals.1, 2, 3, 4 Several large population registries and clinical trials have been published which confirm a role for CAC scanning in the detection of risk among intermediate Framingham risk, asymptomatic patients.1, 2, 3, 4 A consistent message within this evidence is that the rate of cardiovascular events increases proportionally with the extent of CAC and is predictive across diverse populations.4, 5, 6, 7, 8

However, a modicum of evidence has been put forth on the prognostic value of CAC in symptomatic patients.9, 10, 11, 12 Among patients evaluated with suspected cardiac symptoms, management is largely based on defining the extent and severity of obstructive coronary artery disease (CAD).13 A large proportion of patients undergoing a diagnostic evaluation will not have any significant obstructive lesions (i.e., ≥50%)14,15 and additional tools may prove useful to further risk stratify this subset of patients. It remains unclear whether the extent to which patients without obstructive CAD have an identifiable burden of atherosclerosis that elevates their long-term risk. Recent evidence is supportive that coronary-computed tomographic angiography (CCTA) may prove useful to define atherosclerotic plaque in those without obstructive CAD.14 Specifically, the quantification of CAC is a reliable and easily quantifiable measure of the burden of atherosclerotic plaque extent.16 Preliminary work in relatively small patient series suggests that patients without obstructive CAD have an elevated mortality risk.7,14,17 The aim of the current study was to assess the independent contribution of CAC extent among symptomatic patients without obstructive CAD from a multinational registry of patients referred for CCTA.

Section snippets

Eligibility Criteria

The design of the COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter (CONFIRM) registry is described in detail elsewhere.11 As a prospective, observational, multicenter registry, adults ≥18 years were prospectively enrolled at each of the 12 centers between 2005 and 2009 (Capital Cardiology Associates, Albany, NY; Cedars Sinai Medical Center, Los Angeles, CA; Harbor UCLA Medical Center, Los Angeles, CA; Henry Ford Medical Center, Detroit, MI; Tennessee Heart

Clinical Characteristics of the Study Cohort

Table 1 provides clinical characteristics of the study cohort with nonobstructive CAD by their CAC scores. In general, patients with more extensive CAC were older, less often female, and had a greater prevalence of cardiac risk factors. Patients with higher CAC scores more often had luminal stenosis in the proximal segments of the right, left anterior descending, and circumflex coronary arteries (all P < .0001 when compared to lower CAC scores). Additionally, nearly one-fourth of patients with

Discussion

In patients without obstructive CAD, the current analysis revealed that CAC was highly and independently predictive of all-cause mortality and death or MI; particularly among patients with evidence of a luminal stenosis. This data contributes to our unfolding knowledge with regards to the adverse event risk associated in patients without obstructive CAD.14,17 Heretofore, nonobstructive atherosclerosis was largely defined as the absence of obstructive CAD or by visual estimation of luminal

New Knowledge Gained

For patients that undergo an angiographic evaluation, the vast majority of patients have nonobstructive coronary artery disease (CAD). Clinically, many of these patients are considered to be low risk. Recent evidence suggests that atherosclerotic plaque in patients without any obstructive lesions are at elevated prognostic risk. The current evaluation examined the prognostic utility of the extent of CAC provide important clues as to a patient’s risk of death or MI, particularly for patients

Conclusion

There is unfolding evidence as to the prognostic significance of atherosclerotic plaque absent of any obstructive lesions. Data from the CONFIRM registry validates prior findings in asymptomatic individuals that the extent of CAC can provide important clues as to a patient’s risk of death or MI, particularly for patients with a luminal stenosis on CCTA. Importantly, CAC scoring was not helpful for risk stratification purposes in the setting of no identifiable luminal stenosis. For patients with

Disclosures

The following authors declared conflicts of interest: Stephan Achenbach: (Grant Support: Siemens and Bayer Schering Pharma; Consultant: Servier); Mouaz Al-Mallah (Consultant: Astellas); Matthew Budoff (Consultant: GE Healthcare); Filippo Cademartiri (Speaker’s Bureau: Bracco Diagnostics; Consultant: Guerbet); Kavitha Chinnaiyan (Grant Support: Bayer Phama, Blue Cross Blue Shield of Michigan); Benjamin Chow (Grant Support and Consultant: GE Healthcare; Grant Support: Servier; Educational

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This registry was performed independently by the participating institutions and without any grant or in-kind support from any equipment or pharmaceutical manufacturer.

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