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Diagnostic and Prognostic Value of Absence of Coronary Artery Calcification

Ammar Sarwar, MD^_*, Leslee J. Shaw, PhD, Michael D. Shapiro, DO^_*, Ron Blankstein, MD^_*, Udo Hoffman, MD, MPH^_*, Ricardo C. Cury, MD^_*, Suhny Abbara, MD^_*, Thomas J. Brady, MD^_*, Matthew J. Budoff, MD, Roger S. Blumenthal, MD, Khurram Nasir, MD, MPH^_*,_*,,||

^_* Cardiac PET CT MRI Program, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
Department of Cardiology, Emory University, Atlanta, Georgia
Los Angeles Biomedical Research Institute at Harbor—University of California Los Angeles, Los Angeles, California
Ciccarone Preventive Cardiology Center, Johns Hopkins University, School of Medicine, Baltimore, Maryland
^|| Department of Internal Medicine, Boston Medical Center, Boston, Massachusetts

	Abstract

Top Abstract Methods Results Discussion Conclusions Appendix REFERENCES

 
Objectives: In this study, we systematically assessed the diagnostic and prognostic value of absence of coronary artery calcification (CAC) in asymptomatic and symptomatic individuals.

Background: Presence of CAC is a well-established marker of coronary plaque burden and is associated with a higher risk of adverse cardiovascular outcomes. Absence of CAC has been suggested to be associated with a very low risk of significant coronary artery disease, as well as minimal risk of future events.

Methods: We searched online databases (e.g., PubMed and MEDLINE) for original research articles published in English between January 1990 and March 2008 examining the diagnostic and prognostic utility of CAC.

Results: A systematic review of published articles revealed 49 studies that fulfilled our criteria for inclusion. These included 13 studies assessing the relationship of CAC with adverse cardiovascular outcomes in 64,873 asymptomatic patients. In this cohort, 146 of 25,903 patients without CAC (0.56%) had a cardiovascular event during a mean follow-up period of 51 months. In the 7 studies assessing the prognostic value of CAC in a symptomatic population, 1.80% of patients without CAC had a cardiovascular event. Overall, 18 studies demonstrated that the presence of any CAC had a pooled sensitivity and negative predictive value of 98% and 93%, respectively, for detection of significant coronary artery disease on invasive coronary angiography. In 4,870 individuals undergoing myocardial perfusion and CAC testing, in the absence of CAC, only 6% demonstrated any sign of ischemia. Finally, 3 studies demonstrated that absence of CAC had a negative predictive value of 99% for ruling out acute coronary syndrome.

Conclusions: On the basis of our review of more than 85,000 patients, we conclude that the absence of CAC is associated with a very low risk of future cardiovascular events, with modest incremental value of other diagnostic tests in this very low-risk group.

Key Words: computed tomography • coronary calcification • outcomes • meta-analysis

Abbreviations and Acronyms   ACC = American College of Cardiology   ACS = acute coronary syndromes   AHA = American Heart Association   CAC = coronary artery calcium   CAD = coronary artery disease   CI = confidence interval   CT = computed tomography   ICA = invasive coronary angiography   LDL = low-density lipoprotein   MPS = myocardial perfusion scans

Therefore, the purpose of this review was to provide a "back to the basics" approach examining the clinical, diagnostic, and prognostic significance of the absence of CAC. We examined published reports for the relevance of the absence of CAC in the context of 3 major categories: 1) its prognostic utility in categorizing both asymptomatic and symptomatic patients according to their risk for adverse events; 2) its relationship with the presence or absence of significant coronary artery stenosis by invasive coronary angiography; and 3) the degree of myocardial ischemia detected in those with the absence of CAC.

	Methods

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We searched the MEDLINE database for studies published in the English language between January 1990 and March 2008, assessing CAC using either multidetector computed tomography or electron beam computed tomography in adult populations of both sexes. The search was performed using various permutations of the following search terms: "electron beam computed tomography," "multidetector computed tomography," "coronary artery calcium," "coronary artery calcification," "invasive coronary angiography," and "myocardial perfusion imaging." Additional references were found by reviewing bibliographies from identified articles. Individual articles had to meet the following criteria to be included: 1) articles examining the relationship between CAC and adverse cardiovascular events in asymptomatic individuals; only studies that prospectively enrolled asymptomatic patients and had a follow-up >1 year for cardiovascular events were included. Authors of articles that did not contain data on patients without CAC were contacted for more information. 2) Articles examining the relationship between CAC and adverse cardiovascular events in symptomatic individuals. 3) Articles examining the relationship between CAC and invasive coronary angiography (ICA) and defining a significant stenosis as >50% coronary luminal narrowing. 4) Articles comparing the incidence of myocardial perfusion abnormalities with the extent of CAC. 5) Articles reporting the ability of CAC to predict acute coronary syndromes. We contacted authors of studies in which the incidence of coronary artery disease (CAD) in patients without CAC was not reported or could not be calculated.

Statistical analysis.   Based on the 2 x 2 event data for patients with no CAC and CAC >0, individual and summary Mantel-Haenszel relative risk ratios and 95% confidence intervals (CIs) were calculated (Comprehensive Meta-Analysis, version 2.2, Biostat, Englewood, New Jersey). For this analysis, a cumulative relative risk ratio was displayed in a Forest plot. Although duplicate series were included in the plot, the summary risk ratio was calculated using only the latter series. For reports showing no events in patients with 0 CAC, 1 event was added so that the relative risk ratio could be calculated. The test for heterogeneity for asymptomatic patients was significant (Q statistic = 26, p = 0.001); however, inclusion of studies published after 2004 revealed greater homogeneity in study results (Q statistic = 6, p = 0.19). Presentation of the data with and without publications before 2004, however, did not change the results noted herein. A funnel plot was created to estimate publication bias and is included in the online version of this article. For asymptomatic individuals, a review of this plot reveals that 4 series with results outside the precision lines may suggest publication bias, including Greenland (17), Shemesh (16), Raggi (11), and Wong (13), all with sample sizes <1,030. For asymptomatic individuals, the classic fail-safe number of missing studies that would bring the p value to >alpha = 0.05 was 1,354; if the alpha is changed to 0.01, the number of studies missing that would bring the p value >alpha was 779. The test for heterogeneity in symptomatic patients was nonsignificant (Q statistic = 4, p = 0.50), suggesting that pooling of these reports was appropriate. A funnel plot was also created for symptomatic patient reports. Noted in this plot, there was 1 study exhibiting an extreme measure, possibly reflecting publication bias (5). For the symptomatic series, the classic fail-safe number of missing studies that would bring the p value to >alpha = 0.01 was only 26.

The positive and negative predictive value and 95% CI for significant CAD were calculated for each study and for a summary weighted (proportional to the sample size) measure.

Individual and summary odds ratios and 95% CIs were calculated for the frequency of ischemia in patients with no CAC and CAC >0. For patients with no ischemia in the zero-CAC group, a single case was added to allow for calculation of the odds ratio. The test for heterogeneity was significant (Q statistic = 54, p < 0.0001), with exclusion of the He and Rozanski series suggesting more homogeneous results (Q statistic = 5, p = 0.18).

	Results

Top Abstract Methods Results Discussion Conclusions Appendix REFERENCES

 
Prognosis in asymptomatic adults.   Table 1 compares 13 studies assessing the relationship of CAC with adverse cardiovascular outcomes consisting of 71,595 asymptomatic patients (65% men) (11–23). In this cohort, 29,312 patients (41%) did not have any evidence of CAC (range 22% to 80% of total patients per study). These patients were followed for 32 to 102 months (mean 50 months) for the occurrence of cardiovascular events. Overall, 154 of 29,312 patients (0.47%) without CAC had a cardiovascular event during follow-up, as compared with 1,749 of 42,283 patients (4.14%) with CAC. The cumulative relative risk ratio was 0.15 (95% CI: 0.11 to 0.21, p < 0.001) (Fig. 1).

View larger version (20K): [in this window] [in a new window] [Download PPT slide]   Figure 1 Forest Plot of the Cumulative Relative Risk Ratio for Events in No CAC Versus CAC Asymptomatic Patients The relative risk ratio is calculated using a Mantel-Haenszel relative risk ratio (95% confidence interval [CI]). The individual study relative risks are reported, but the Forest plot details a cumulative relative risk ratio. All p < 0.0001. CAC = coronary artery calcium.

View larger version (14K): [in this window] [in a new window] [Download PPT slide]   Figure 2 Forest Plot of the Cumulative Relative Risk Ratio for Events in the No CAC Versus CAC Symptomatic Patients The relative risk ratio is calculated using a Mantel-Haenszel relative risk ratio (95% confidence interval [CI]). CAC = coronary artery calcium.

View larger version (20K): [in this window] [in a new window] [Download PPT slide]   Figure 3 Negative and Positive Predictive Value of No CAC and CAC >0 Negative and positive predictive value of absence of detectable no CAC and CAC >0 for detection of significant coronary artery disease detected on invasive angiography, with summary statistics of 92% and 68%, respectively. CAC = coronary artery calcium; CAD = coronary artery disease; CI = confidence interval.

View larger version (18K): [in this window] [in a new window] [Download PPT slide]   Figure 4 Forest Plot of the Cumulative Odds Ratio for Ischemia in Patients With No CAC Versus CAC Patients The relative risk ratio is calculated using a Peto odds ratio (95% confidence interval [CI]), random effects model.

	Discussion

Top Abstract Methods Results Discussion Conclusions Appendix REFERENCES

Prognostic significance.   Asymptomatic patients
A total of 13 studies examining the prognostic significance of CAC in asymptomatic individuals fit our criteria for inclusion. There were adverse cardiac events in an average of 0.47% (range 0 to 4.43%) of the total 29,312 individuals without evidence of CAC. Although 11 studies had event rates 1.01%, there were 2 studies that had extremely high event rates (3.95 and 4.43%) (16,17). When we examined these studies more carefully, the study with the highest event rates (4.43%) (17) applied an unconventional scanning protocol that employed a 6-mm slice thickness rather than the standard 3-mm collimation. It has been well established (57) that use of a larger slice thickness misses approximately one-third of calcified lesions. The effect of missing these lesions can result in misclassifying individuals as having no evidence of CAC. The other study with a higher event rate (3.95%) assessed 446 high-risk hypertensive patients from the INSIGHT (International Nifedipine Study Intervention as Goal for Hypertension Therapy) trial (16). Nearly one-third of the events in this study were strokes. Hemorrhagic strokes related to hypertension might have elevated the number of events seen in individuals without CAC. Neither the nature of the strokes nor the number of patients with/without CAC who suffered a stroke was reported in the article.

Overall, despite the results of these 3 studies, our review indicates that the absence of CAC is associated with a very low overall risk of any event in asymptomatic individuals. Budoff et al. (21) demonstrated a similarly low risk for mortality (0.4%) in a follow-up extending up to 12 years, confirming the minimal long-term risk associated with absence of CAC in long-term follow-up.

Another key question is how CAC compares with other noninvasive tests for subclinical atherosclerosis such as carotid intimal medial thickness, ankle-arm pressure index, and C-reactive protein. This question was examined recently (58) in a comparative review of subclinical atherosclerosis tests. The authors found that negative testing for subclinical atherosclerosis conveyed a low risk (<10%) regardless of the test considered. However, with respect to prognostic value in asymptomatic patients, the data on CAC seem to be the most robust in sheer size, diversity of populations, and duration of follow-up. Although other tests for subclinical atherosclerosis have the benefit of low cost, higher reproducibility, and a better safety profile owing to the absence of radiation, none have shown any added benefit in prognostic value over traditional risk factors.

Despite its utility, it is important to assess whether the result of a negative CAC score would lead asymptomatic individuals to engage in less stringent adherence to preventive and therapeutic strategies. The results of a randomized controlled trial looking at this question suggest otherwise. O'Malley et al. (59) followed 459 young men for 1 year and found no difference in projected risk, and, more importantly, no change in behavior in those who were informed that they did not have evidence of CAC versus those who were found to have CAC. They concluded that the knowledge of a negative CAC score scan did not convey false reassurance resulting in adverse behavioral outcomes.

Another issue that must be closely examined is how often individuals without CAC should be assessed for development of atherosclerosis and who among these individuals may need early follow-up. A study examining progression rates of coronary calcification in 710 patients without CAC (60) reported that 62% of the cohort did not develop CAC in a period extending up to 5 years. In fact, only 2% developed a CAC score >50 (60). The investigators concluded that after an initial negative CAC scan, an individual can safely receive a follow-up scan up to 5 years later. Similarly, Kronmal et al. (61) reported from the MESA (Multiethnic Study on Atherosclerosis) study that only 16% of individuals without CAC developed CAC in a median follow-up of 41 months. This indicates that a negative CAC scan could save a patient from costly therapy over the course of 3 to 5 years and that these patients can be followed simply with regular outpatient visits without the need for costly diagnostic imaging.

Although current guidelines do not recommend that preventive therapies such as lipid-lowering medications can be down-regulated in the absence of CAC (62), our data suggest that aggressive management in this cohort is not warranted if patients do not qualify according to National Cholesterol Education Program guidelines. For example, among individuals who are considered as intermediate Framingham risk, lipid-lowering medications are recommended only for low-density lipoprotein (LDL) cholesterol >160 mg/dl. In these scenarios, patients with LDL <160 mg/dl can be reassured of their risk without initiation of further pharmacotherapy. The results of our review provide an opportunity to introduce a robust model for providing treatment to deserving individuals in societies with finite resources. This would allow those with the absence of CAC to follow healthy lifestyle modifications with little or no medical therapy while focusing intense therapy on a smaller population of patients with an actual higher risk of events as demonstrated by increasing atherosclerotic burden.

Symptomatic patients
Along with the comprehensive literature on the prognostic utility of CAC in asymptomatic patients, a number of studies looked at similar parameters in a symptomatic population (Table 2). Although the prevalence of a CAC score of 0 was lower in symptomatic versus asymptomatic patients (23% vs. 40%), symptomatic patients without CAC also had a significantly lower event rate than those with CAC (1.8% vs. 8.99%). Although the prognostic data available on symptomatic patients are not as large as those on asymptomatic individuals, there is evidence that an absence of CAC translates into a reduced risk for adverse events in this population. Further studies are needed to identify the true role of CAC in symptomatic individuals and how best to incorporate CAC information into the overall risk stratification algorithm in combination with other diagnostic tests, such as contrast-enhanced coronary computed tomography (CT) angiography and/or stress myocardial perfusion imaging.

Utility of CAC in ruling out significant CAD.   Aside from the long-term prognostic value, our review reveals the potential of CAC scanning to serve as a gatekeeper for further diagnostic imaging for evaluation of coronary luminal patency. There were 18 studies comparing the diagnostic accuracy of Agatston scores with ICA to detect a significant (>50%) stenosis of the coronary lumen (Table 3).

The presence of CAC was highly sensitive (98%) in predicting a luminal stenosis >50% in any coronary artery, although the specificity was low (40%). In fact, recent American College of Cardiology (ACC)/American Heart Association (AHA) guidelines also consider that "for the symptomatic patient, exclusion of measurable coronary calcium may be an effective filter before undertaking invasive diagnostic procedures or hospital admission" (62,63). Although absence of CAC is associated with a very low likelihood of significant CAD, approximately 2% of symptomatic individuals with significant CAD do not have evidence of CAC. These individuals (i.e., significant CAD without CAC) tend to be younger than 50 years of age (32,33,39,40,43,46). As a result, one must exercise caution when evaluating patients for potential CAD in the absence of CAC.

Recent advances in contrast-enhanced coronary CT angiography have allowed for higher accuracy in detection and exclusion of significant CAD, and thus the role of absence of CAC in this setting needs further assessment. Although the pooled sensitivity and specificity of CAC for detecting a significant stenosis are 98% and 40%, respectively, the sensitivity and specificity of contrast-enhanced 64-slice CT are 97% and 90%, respectively (64). The most practical application would be using CT angiography in improving on the limited specificity of CAC for obstructive disease. Because the presence of CAC is often associated with nonobstructive disease, specificity for obstructive disease is reduced. The determination of significant stenotic disease with CT angiography in those with the presence of CAC will undoubtedly be useful to the clinician and patient.

However, it is important to keep in mind that approximately 2% of symptomatic patients with CAC may have underlying significant obstructive epicardial CAD, the significance of which is not entirely clear. As suggested by current ACC/AHA guidelines, absence of CAC can serve as a possible exclusion criterion for further cardiovascular risk testing, as the long-term prognosis of these patients is excellent.

Prevalence of myocardial ischemia in individuals without CAC.   Although the absence of CAC shows exceptional ability for predicting the absence of a significant stenosis, its ability to predict myocardial ischemia by myocardial perfusion scans (MPS) is also encouraging, although somewhat more modest. The negative predictive value of CAC for a perfusion abnormality was an average of 93% in 8 studies. More importantly, the 1 prognostic study simultaneously evaluating the prognostic value of both MPS and CAC scores (28) conclusively showed that the event risk of a person without CAC was extremely low regardless of whether they had ischemia. In fact none of the patients without CAC who had an abnormal MPS had an event, whereas a very low percentage of those without CAC and a normal MPS had an adverse outcome (0% vs. 0.2%, respectively). The recent ACC/American Society of Nuclear Cardiology appropriateness criteria state that a low calcium score (especially in the absence of CAC) precludes the need for MPS assessment (65).

However, in 3 studies, a significantly higher prevalence of ischemia in patients without CAC was reported. One of these studies (52) showed that 11% of individuals without CAC had an abnormal MPS. This study was exclusively performed in siblings of those with premature CAD. Another study by Budoff et al. (53) examined a cohort of 30 individuals, with 70% of the subjects demonstrating a clinically significant stenosis. The investigators found 2 of 6 individuals (33%) without CAC to have ischemia on MPS. The results of this study are remarkably discordant with other studies, not only because of the study's small sample size but also because of the high prevalence of disease in this cohort.

ACS in individuals without CAC.   The 3 studies evaluating the relationship between CAC and ACS reported a 99% sensitivity and 99% negative predictive value, which is comparable to that of contrast-enhanced coronary CT angiography (66,67). On the other hand, the specificity and positive predictive value was modest (57% and 24%, respectively). The total number of patients in each of these studies was too small to conclusively establish the role of CAC evaluation in the emergency department. The current state of published reports is certainly small and inconclusive with respect to this important clinical entity. Although CAC can serve as a useful marker for excluding ACS in patients presenting to the emergency department, further studies in larger cohorts need to be done to establish CAC's role in a clinical paradigm, especially in lieu of excellent depiction of not only coronary anatomy but also of left ventricular function with contrast-enhanced coronary CT angiography.

Study limitations.   This is a systematic review of a large number of studies consisting of heterogeneous populations. Although the results of the vast majority of these studies are concordant, the results might not be generalizable to populations that were not examined by any of the preceding studies. It is also important to keep in mind that no information was available in a majority of the studies on the effect of the absence of CAC in various pre-test CHD risk settings. However, when we extrapolate the data over a range of asymptomatic and symptomatic patients, absence of CAC has generally demonstrated favorable prognostic value. This key question will need to be addressed in large population-based cohorts such as MESA. In addition, for studies examining the diagnostic accuracy of CAC to predict a significant stenosis by ICA, caregivers were blinded to CAC results in a majority of cases. However in 4 studies, the results of the ICA could have been driven by CAC scores (33,34,37,46).

	Conclusions

Top Abstract Methods Results Discussion Conclusions Appendix REFERENCES

 
On the basis of extensive evidence in published reports (in more than 85,000 patients), the absence of CAC identifies a group of asymptomatic and symptomatic individuals at a very low cardiovascular risk. As endorsed by current guidelines, these results should be considered strongly in current management algorithms for better utilization of health care resources.

	Appendix

Top Abstract Methods Results Discussion Conclusions Appendix REFERENCES

 
For supplementary figures, please see the online version of this article.

	Footnotes

 
Drs. Shapiro, Blankstein, and Nasir have received support from National Institutes of Health grant 1T32 HL076136-02. Dr. H. William Strauss served as Guest Editor.

^_* Reprint requests and correspondence: Dr. Khurram Nasir, Division of Cardiology, Johns Hopkins University, Baltimore, Maryland 21287 (Email: knasir1{at}jhmi.edu).

Manuscript received September 30, 2008; revised manuscript received December 1, 2008, accepted December 1, 2008.

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Top Abstract Methods Results Discussion Conclusions Appendix REFERENCES

 

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