Medical Policy: 06.01.06
Original Effective Date: September 2000
Reviewed: July 2019
Revised: July 2017
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This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
Coronary artery calcium (CAC) scoring is a noninvasive test that has been reported to detect the presence of coronary artery disease (CAD) by measuring the location and extent of calcium in the coronary arteries. The role of CAC as an independent predictor of risk in the cardiovascular assessment, either alone or in combination with conventional risk factors, of both asymptomatic and symptomatic individuals have been studied.
The development of fast computed tomography (CT) scanners has allowed the measurement of CAC in clinical practice. Coronary artery calcium has been evaluated in several clinical settings. The most widely studied indication is for the use of CAC in the prediction of future risk for CAD in patients with subclinical disease, with the goal of instituting appropriate risk reducing therapy (e.g. statin therapy, lifestyle modifications) to improve outcomes. In addition, CAC has been evaluated in patients with symptoms potentially consistent with CAD, but in whom a diagnosis is unclear.
Electron beam computed tomography (ECBT; also known as ultrafast CT) and spiral CT (or helical CT) may be used as an alternative to conventional CT scanning due to their faster throughput. In both methods, speed of image acquisition gives them unique value for imaging of the moving heart. The rapid image acquisition time virtually eliminates motion artifact related to cardiac contraction, permitting visualization of the calcium in the epicardial coronary arteries. ECBT software permits quantification of calcium area and density, which are translated into calcium scores. Calcium scores have been investigated as a technique for detecting CAC, both as a diagnostic technique in symptomatic patients to rule out an atherosclerotic etiology of symptoms or, in asymptomatic patients, as an adjunctive method for risk stratification for CAD.
EBCT and multi-detector computed tomography were initially the primary fast CT methods for measurement of CAC. A fast CT study for CAC measurement generally takes 10 to 15 minutes and requires only a few seconds of scanning time. However, more recently computed tomography angiography (CTA) has been used to assess coronary calcium. Because of the basic similarity between EBCT and CTA in measuring coronary calcium, it is expected that CTA provides information on coronary calcium that is similar to EBCT.
Computed tomography (CT) scan measures have been used to evaluate coronary atherosclerosis. Coronary calcium is present in coronary atherosclerosis, but the atherosclerosis detected may or may not be causing ischemia or symptoms. Coronary calcium measures may be correlated with the presence of critical coronary stenosis or serve as a measure of the patient’s proclivity toward atherosclerosis and future coronary disease. Thus, coronary calcium could serve as a variable to be used in a risk assessment calculation to determine appropriate preventative treatment in asymptomatic patients. Alternatively, in other clinical scenarios, coronary calcium scores might help determine whether there is an atherosclerotic etiology or component to the presenting clinical problem in symptomatic patients, therefore, helping to direct further workup for the clinical problems. In this second scenario, a calcium score of 0 usually indicates that the patient’s clinical problem is unlikely to be due to atherosclerosis and that other etiologies should be more strongly considered. In neither case does the test determine a specific diagnosis. Most clinical studies have examined the use of coronary calcium for its potential use in estimating the risk of future coronary heart disease (CAD) events.
Coronary calcium levels can be expressed in many ways. The most widely used is the Agatston score, which is a weighted summed total of calcified coronary artery area observed on computed tomography (CT). This value can be expressed as an absolute number, commonly ranging from 0 to 400. These values can be translated into age and sex-specific percentile values.
The purpose of coronary artery calcium (CAC) scoring using computed tomography (CT) in asymptomatic patients is to assess who may benefit from preventative interventions targeted to minimize the risk of atherosclerotic cardiovascular disease (CVD).
The population of interest is individuals who are asymptomatic with risk of CAD.
The intervention of interest is CAC scoring using fast CT imaging, including electron-beam computed tomography (EBCT) and spiral CT.
The comparator of interest is CAD risk factor stratification based on standard risk, such as Framingham risk scores (FRS).
The outcomes of interest include survival, test accuracy, test validity, morbid events (e.g. major adverse cardiac events (MACEs), need for invasive coronary angiography (ICA), and revascularization. Additional intermediate or surrogate outcomes of interest are changes in cardiac risk profile indicators such as smoking, hyperlipidemia, or hypertension.
CAC scoring is usually initiated or used to modify risk-reduction interventions in individuals asymptomatic for CAD.
The setting is a primary care or general cardiology practice to assess the risk of CAD.
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).
The Multi-Ethnic Study of Atherosclerosis (MESA) Trial is an ongoing, multi-center, prospective longitudinal study of asymptomatic individuals across four racial/ethnic groups to evaluate the long-term cardiovascular outcomes with a 10-year follow-up of 6772 asymptomatic participants after baseline risk assessment (including CAC measurement). The MESA study was launched in 2000. In 2008 interim results were published (median follow-up 3.9 years) that suggest that the CAC score is a predictor of subsequent clinically significant coronary heart disease (CHD) and may provide predictive information beyond that provided by standard risk factors, (that is, the Framingham Risk Score [FRS]). The authors reported that after adjustment for standard risk factors, a doubling of the CAC score resulted in a 20% increase in the risk of a major coronary event (myocardial infarction/death from CHD) and a 25% increase in the risk of any coronary event. A limitation of this study was variation in CT acquisition and reading methods across the six study centers. The authors also caution against using the absolute calcium scores cited in the study and note that ethnic-specific calibrations of CAC scores are needed to adjust for baseline differences between different ethnic groups. Another limitation of this interim report is the small number of measured clinical events (72 non-fatal MI, 17 fatal coronary events, and 73 events of angina pectoris).
The data, collected thus far, from the MESA Trial have been studied and reported in multiple published studies.
Polonsky et. al. (2010) used data from MESA to determine whether incorporation of calcium score into a risk model based on traditional risk factors improve classification of risk. During a median of 5.8 years of follow-up among a final cohort of 5878, 209 cardiovascular heart disease (CHD) events occurred, of which 122 were myocardial infarction, death from CHD, or resuscitated cardiac arrest. Addition of coronary artery calcium (CAC) score in the model resulted in significant improvements in risk prediction compared with the model without CAC score (NRI=0.25; 95% CI, 0.16 to 0.34; p<0.001). Subjects reclassified to high risk had a similar risk of CHD events as those originally classified as high risk.
Elias-Smale et. al. (2011) conducted a study among 2153 asymptomatic participants (69.6 years) who underwent an MDCT scan. During a median follow-up of 3.5 years, 58 coronary heart disease (CHD) events (myocardial infarction or death) occurred. Participants were classified into low (<5%), intermediate (5%-10%), and high (>10%) 5-year risk categories based on a refitted Framingham risk model. For the outcome of CHD, the C statistic improved from 0.693 for the Framingham refitted model to 0.743 by addition of coronary calcium. Reclassification of subjects occurred most substantially in the intermediate-risk group (5-year risk, 5%-10%) where 56% of persons were reclassified. Addition of coronary artery calcium (CAC) scoring reclassified 56% of persons: 36% moved to low risk while 20% moved to high risk, leading to a net gain in reclassification of 18% in persons with an event and a net decline in reclassification of 3% in persons without event, resulting in an NRI of 15% (p<0.01).
In 2012, Yeboah et. al. sought to improve the prediction accuracy and reclassification into high and low risk categories using six risk markers (CAC, carotid intima-media thickness, ankle-brachial index, brachial flow-mediate dilation, high-sensitivity C-reactive protein and family history of CHD) using 6814 asymptomatic intermediate risk participants from the MESA (Multi-Ethnic Study of Atherosclerosis) population. Of the 6814 MESA participants from 6 US field centers, 1330 were intermediate risk, without diabetes mellitus, and had complete data on all 6 markers. Recruitment spanned July 2000 to September 2002, with follow-up through May 2011. Probability-weighted Cox proportional hazard models were used to estimate hazard ratios (HRs). Area under the receiver operator characteristic curve (AUC) and net reclassification improvement were used to compare incremental contributions of each marker when added to the FRS, plus race/ethnicity. The main outcome measures included incident CHD defined as myocardial infarction, angina followed by revascularization, resuscitated cardiac arrest, or CHD death. Incident CVD additionally included stroke or CVD death. After 7.6-year median follow-up (IQR, 7.3-7.8), 94 CHD and 123 CVD events occurred. Coronary artery calcium, ankle-brachial index, high-sensitivity CRP, and family history were independently associated with incident CHD in multivariable analyses (HR, 2.60 [95% CI, 1.94-3.50]; HR, 0.79 [95% CI, 0.66-0.95]; HR, 1.28 [95% CI, 1.00-1.64]; and HR, 2.18 [95% CI, 1.38-3.42], respectively). Carotid intima-media thickness and brachial flow-mediated dilation were not associated with incident CHD in multivariable analyses (HR, 1.17 [95% CI, 0.95-1.45] and HR, 0.95 [95% CI, 0.78-1.14]). Although addition of the markers individually to the FRS plus race/ethnicity improved AUC, coronary artery calcium afforded the highest increment (0.623 vs 0.784), while brachial flow-mediated dilation had the least (0.623 vs 0.639). For incident CHD, the net reclassification improvement with coronary artery calcium was 0.659, brachial flow-mediated dilation was 0.024, ankle-brachial index was 0.036, carotid intima-media thickness was 0.102, family history was 0.160 and high-sensitivity CRP was 0.079. Similar results were obtained for incident CVD. The study has limitations. The analysis was limited to the subset of MESA participants with complete data on all six risk markers, which decreased the sample size. There were insufficient numbers of events to demonstrate clearly the superiority of CAC over the other measures in a head-head ROC and NRI analyses. In MESA, they did not specifically define family history of CHD as premature (i.e. before the age of 55 for men and 65 for women). This may have influenced the association of family history with CHD and CVD. The authors concluded, even though our study indicates considerable superiority of CAC over several risk markers for risk prediction of CHD and CVD, several other risk factors should be considered before making broad recommendations about incorporation of CAC into primary prevention screening strategies. One notable concern is that measurement of CAC exposes individuals to small but non-trivial amount of ionizing radiation. Even with the lowest possible radiation dose there remains an uncertainty about the magnitude of long term cancer risks. Similarly, the benefits and risk associated with incidental findings detected during CAC imaging remain unclear. These indirect costs, in addition to the direct financial costs of CAC imaging need to be weighed against the presumed benefits from better discrimination of subjects at high risk for CHD and CVD events to best determine the role of CAC screening of patients with an intermediate risk for a CHD/CVD event. The ultimate decision regarding the optimum test to order should not be based solely on improvement in risk prediction afforded by a test but also cost effectiveness, acceptability to patients and the potential risk and benefits associated with the test. Additional research is warranted to explore further both the costs and benefits for CAC screening in intermediate risk individuals.
Won et. al. (2015) conducted a single-center cross-sectional study among 328 consecutive asymptomatic patients with type 2 diabetes who underwent computed tomographic coronary angiography (CTCA) between 2008 and 2009 in a hospital in South Korea to evaluate the predictive value of the coronary artery calcium (CAC) score for obstructive coronary plaques (OCP) assessed by CTCA. On the basis of a CAC score of 0, 1 to 10, 11 to 100, or greater than 100, OCPs were found in 2%, 5%, 15%, and 36% of patients, respectively. On receiver operating characteristic curve analysis, the optimal cutoff CAC score for predicting OCPs was found to be 33, with 83% sensitivity and 81% specificity (AUC=0.853; 95% CI, 0.777 to 0.930; p<0.001). Positive and negative predictive values of a CAC score of 33 for OCPs were 30% and 98%, respectively. On multivariate logistic regression analysis, age (odds ratio [OR], 1.09), microalbuminuria levels (OR=3.43), current smoker (OR= 3.93), and a CAC score greater than 33 (OR=15.85) were found to be independently associated with an increased risk for OCPs (p<0.05).
Nakanishi et. al. (2016) conducted a study among 13,092 consecutive asymptomatic individuals without known coronary artery disease (CAD) (mean age, 58 years) clinically referred for a coronary artery calcium (CAC) scan between 1997 and 2011 at a university medical center; the study examined the predictive value of CAC for 5 and 15 year mortality rates among men and women. CAC showed an incremental prognostic value over traditional risk factors among men at 5 years (area under curve [AUC], 0.702 vs 0.655; p=0.002) as well as at 15 years (AUC, 0.723 vs 0.656; p<0.001). In women, the incremental prognostic value of CAC was not statistically significant at 5 years (AUC, 0.650 vs 0.612; p=0.065) but was statistically significant at 15 years (AUC, 0.690 vs 0.624; p<0.001).
Blaha et. al. (2016) conducted a study using data from MESA to compare the value of various negative risk markers. The authors evaluated the accuracy of change in risk classification by calculating the net reclassification improvement (NRI) for each of the 13 negative risk markers. During a median of 10.3 years of follow-up among a cohort of 6814, 710 cardiovascular disease (CVD) events occurred. Among all negative risk markers, a coronary artery calcium (CAC) score of 0 was the strongest, with an adjusted mean diagnostic likelihood ratio of 0.41 (SD=0.12) for all CHD. NRI for downward reclassification (10-year CVD risk, <7.5%) of CVD events with CAC scores of 0 in participants with a pretest 10-year CVD risk of 7.5% or higher (n=3833 [3227 participants without events and 606 with events]) was 0.14, higher than other negative risk markers included in the study.
Gepner et. al. (2017) prospectively evaluated cardiovascular disease (CVD), coronary heart disease (CHD), and stroke or transient ischemic attack (TIA) events to compare the use of coronary artery calcium (CAC) with carotid plaque scores to predict CVD events; the study used data from the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based cohort of individuals without known CVD. After 11.3 years of follow-up among 4955 participants (mean age, 61.6 years), 709 CVD, 498 CHD, and 262 stroke/TIA events had occurred. CAC score significantly reclassified non-CVD events (3%; 95% CI, 2% to 5%) and CHD events (13%; 95% CI, 5% to 18%). Carotid plaque score did not consistently reclassify CVD or CHD events or nonevents.
Multiple prospective cohort studies have consistently demonstrated the incremental prognostic value of coronary artery calcium (CAC) scoring in predicting coronary heart disease (CHD) and mortality over traditional risk factors among asymptomatic populations over the intermediate and long term. However, considering the heterogeneity of methods applied and inherent limitations of observational studies, there is a need for more evidence on diagnostic accuracy of CAC scoring in predicting CHD risk among the asymptomatic population, preferably from randomized controlled trials (RCTs).
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. The preferred evidence would be from randomized controlled trials (RCTS).
In 2012, Whelton et. al. published a meta-analysis of randomized controlled trials (RCTs) that evaluated the impact of coronary artery calcium (CAC) scores on cardiac risk profiles and cardiac procedures. Four trials were identified (total N=2490 participants); the individual trials ranged in size from 50 to 1934 patients. Reviewers pooled data from 4 trials on the impact of calcium scores on blood pressure, three to evaluate the impact on low-density lipoprotein, and from two to determine the impact on high-density lipoprotein. Pooled analysis did not show a significant change in any of these parameters when incorporating calcium scores. Similarly, in 4 studies that looked at the rates of smoking cessation following calcium scores, no significant change was found. Two studies included rates of coronary angiography and two included rates of revascularization. Pooled analysis of these studies did not show a significant change after measurement of coronary calcium.
Xie et al (2013) conducted a systematic review to evaluate the prognostic performance of the coronary artery calcium (CAC) score derived from non-triggered CT. In 5 studies, 34,028 cardiac asymptomatic patients were followed for a mean of 45 months (range, 0-72 months). No meta-analysis was performed on the studies because of large heterogeneity in calcium quantification methods, calcium score categorization, and outcomes. During follow-up, 207 cardiovascular deaths and 675 cardiovascular events were observed. Overall, increasing unadjusted and adjusted hazard ratios (HR) were observed with increasing calcium score categories.
Mamudu et. al. (2014) conducted a systematic review of studies evaluating the effects of coronary artery calcium (CAC) screening on behavioral modification, risk perception, and medication adherence in asymptomatic adults. Fifteen studies were selected (3 RCTs, 12 observational studies). The size of the study populations ranged from 56 to 6814 individuals. Reviewers primarily provided descriptive results of the studies given the lack of standardization across studies regarding CAC measures and outcome variables. CAC screening improved medication adherence. However, the impact of CAC screening on behavioral and lifestyle factors (BMI, diet, exercise, smoking), perception of CAD risk, and psychosocial effects was nonsignificant compared with baseline.
In 2018, the Agency for Healthcare Research and Quality (AHRQ) issued a systematic evidence report for the U.S. Preventative Services Task Force (USPSTF) for non-traditional risk factors in cardiovascular disease risk assessment. The review focuses on three of the most promising nontraditional risk factors: ankle-brachial index (ABI), high sensitivity C-reactive protein (hsCRP), and coronary artery calcium (CAC) score.
KQ2. Does Use of Nontraditional Risk Factors in Addition to Traditional Risk Factors to Predict CVD Risk Improve Measures of Calibration, Discrimination, and Risk Reclassification?
CAC has the smallest body of evidence, owing to the smaller sample sizes of included cohorts; no IPD meta-analysis presents results for the incremental predictive value of CAC. Nonetheless, CAC consistently appears to result in at least small, and often larger, improvements in discrimination in studies evaluating hard outcomes in all participants using published coefficients (0.02 to 0.102) and model development studies (0.02 to 0.05). Five studies report improvement in discrimination and reclassification from adding CAC to the PCE or models with PCE variables: three published coefficient studies evaluating just two cohorts and two model development studies. Categorical NRI from model development studies in all participants ranged from 0.14 to 0.319 (continuous NRI ranged from 0.20 to 0.28); evaluation of separate components of the NRI shows that improvements in NRI are consistently driven by event NRIs much larger than nonevent NRIs, which were commonly negative (when reported), and sometimes statistically significant. A limited number of studies report sex-stratified analyses; however, without IPD meta-analyses, it is unclear if there are any consistent sex differences in discrimination or reclassification. The bias-corrected NRI was not consistently reported or calculable. Based on limited data, the bias-corrected NRI is not consistently greater than the NRI for all participants.
Nine studies evaluate more than one nontraditional risk factor and therefore allow for more direct comparison across ABI, hsCRP, and CAC. Overall, CAC appears to be the most promising nontraditional risk factor to add to traditional cardiovascular risk factor assessment. Only two studies using published coefficients evaluated multiple nontraditional risk factors; one evaluated both the PCE and FRS. This study, using the Multi-Ethnic Study of Atherosclerosis (MESA) cohort, found no improvement in discrimination or reclassification for ABI and hsCRP, but the study was limited to lower-risk people because participants taking a statin were excluded from the analyses. However, in this study, CAC did improve both discrimination and reclassification. The other published coefficient analysis using the Heinz Nixdorf Recall cohort evaluated both ABI and CAC added to the FRS and similarly found greater improvement for CAC than ABI. Six model development studies evaluated more than one nontraditional risk factor in addition to the FRS to predict hard CHD or soft CVD events. Five of these six studies included CAC and found statistically significant improvements in discrimination and reclassification; these improvements were greater than effects seen for either ABI and/or hsCRP
No studies have evaluated the clinical impact of cardiovascular risk assessment with or without nontraditional risk factors on patient health outcomes. Clinical impact studies should be a priority if any of these nontraditional risk factors are implemented on a targeted population level. Largely speaking, the proliferation of cardiovascular risk assessment literature, particularly model development studies without external validation, will not provide the much-needed clinical answers on nontraditional risk factor assessment. However, there are some exceptions. Given that traditional risk tools can overestimate CVD risk, it is crucial to understand the incremental value of promising nontraditional risk factors on calibration, as well as discrimination and reclassification. More consistent reporting of calibration plots will allow for better understanding of what individuals will benefit from improved calibration and O:E ratios will facilitate comparison of calibration across studies. To understand the true net benefit of reclassification, robust reporting of event and nonevent NRI, and reporting of integrated measures that weight the erroneous misclassification for nonevent proportionally, are important. More studies in diverse populations will aid in understanding whether there are population segments for whom traditional risk factor assessment may underperform to a greater degree and thereby achieve greater benefit from nontraditional risk factor assessment. External validation studies of extended models with nontraditional risk factors are needed. Apart from the ABI Collaboration IPD meta-analysis, none of the extended models has been externally validated.
Given that CAC appears to be the most promising nontraditional risk factor, an IPD meta-analysis for CAC (including longer follow-up of included cohorts) would be informative in furthering understanding of reclassification in subpopulations (e.g., intermediate-risk groups, those for whom traditional risk factor assessment typically underperforms), and vet what impact a CAC score of 0 has on appropriate downward classification of people at intermediate or high risk by traditional risk assessment. Well-designed prospective studies that are reflective of real world practice are needed to evaluate the downstream effects of CAC on cardiac imaging and revascularization, as well as incidental findings, since these are common. These include studies that aid in determining whether the identification of incidental findings, and/or increased health care utilization, is a net benefit or net harm.
Based on this systematic evidence report it concluded the following: In the absence of true clinical impact studies reporting cardiovascular morbidity and/or mortality, we need to understand the incremental value of risk prediction with nontraditional risk factors, using calibration, discrimination and reclassification. Despite limitations in the reporting of these performance measures as well as limitations in the measures themselves, we can draw some conclusions. There remains scant information on the incremental value of nontraditional risk factors to help with the problem of miscalibration of traditional cardiovascular risk assessment. Evidence from one large IPD meta-analysis suggests that clinicians could use ABI in addition to the FRS to improve upon discrimination and reclassification in populations for whom the FRS model has poor discrimination. While CAC appears to be the most promising nontraditional risk factor to improve discrimination and reclassification, it is based on a smaller body of evidence which lacks IPD meta-analyses. CAC may also result in additional downstream testing/procedures, and it is unclear whether these sequelae represent a net benefit or harm to individuals. One large RCT shows that high-intensity statin therapy in individuals with elevated hsCRP and normal lipid levels can reduce CVD morbidity and mortality, but it is unclear whether these benefits would not also be applicable to individuals with normal hsCRP. The use of hsCRP-guided therapy has not been evaluated against therapy guided by multivariate cardiovascular risk assessment.
Rozanski et. al. (2011) conducted an RCT to evaluate the impact of computed tomography (CT) scanning for coronary artery calcium (CAC) on cardiac risk factors. A total of 2137 healthy volunteers were randomized in a 2:1 ratio to CT scanning (n=1424) or no CT scanning (n=713) and followed for 4 years. At baseline, both groups received 1 session of risk factor counseling by a nurse practitioner. The primary end point was 4 year change in cardiovascular disease (CAD) risk factors and Framingham Risk Score (FRS). At the 4 year follow-up, there was differential dropout among the groups, with 88.2% (1256/1424) of follow-up in the scan group versus 81.9% (584/713) in the no-scan group. Compared with the no-scan group, the scan group showed a net favorable change in systolic blood pressure (p=0.02), low-density lipoprotein cholesterol (p=0.04), and waist circumference for those with increased abdominal girth (p=0.01), and a tendency to weight loss among overweight subjects (p=0.07). While there was a mean rise in FRS in the no-scan group (0.7, SD=5.1), FRS remained static in the scan group (0.002, SD=4.9; p=0.003). Downstream medical testing and costs in the scan group were comparable with those of the no-scan group, balanced by lower and higher resource utilization for subjects with normal CAC scans and CAC scores of 400 or higher, respectively.
This trial highlights the potential benefit of CAC screening in modifying cardiac risk profile but is not definitive in demonstrating improved outcomes. Trial limitations included differing intensities of interventions between groups and differential dropout. It is possible that the small differences reported in the trial result from bias related to these methodologic limitations. Also, this trial did not compare the impact of other types of risk factor intervention, most notably more intensive risk factor counseling. Finally, the generalizability of the findings is uncertain, because this was a volunteer population that might have been highly motivated for change.
Budoff et. al. (2013) evaluated the association between coronary calcium scores and coronary heart disease (CHD) events during 5 year follow-up of 2232 adults from MESA (discussed above), and 3119 subjects from the Heinz Nixdorf RECALL (Risk factors, Evaluation of Coronary Calcium and Lifestyle Factors) study. Increasing Agatston scores were associated with increased risk of CHD. In MESA, compared with a CAC score of 0, having a score greater than 400 was associated with a hazard for CHD of 3.31 (95% CI, 1.12 to 9.8) after adjusting for CHD risk factors; a score ranging from 100 to 399 was associated with a hazard of 3.27 (95% CI, 1.19 to 8.95). In the RECALL study, compared with a CAC score of 0, having a score greater than 400 was associated with a hazard for CHD of 2.96 (95% CI, 1.22 to 7.19). Lower CAC scores were not significantly associated with CHD after adjusting for other risk factors.
Chang et. al. (2015) prospectively evaluated whether coronary artery calcium (CAC) scoring added incremental predictive value to exercise treadmill testing and stress myocardial perfusion single-photon emission computed tomography testing when used to assess risk of cardiac events (a composite of cardiac death, nonfatal myocardial infarction, and the need for coronary revascularization) in a cohort of 988 asymptomatic and symptomatic low-risk patients without known coronary heart disease (CHD). Over a median follow-up of 6.9 years, the cardiac event rate was 11.2% (1.6% per year). Annual event rates were higher in patients with CAC scores above 400 (3.7% per year) compared with those with CAC scores of 10 or less (0.6% per year; p<0.001). The addition of CAC score to risk stratification based on the FRS improved risk prediction.
Johnson et. al. (2015) assessed the association between coronary artery calcium (CAC) score and subsequent health behavior change. The study included a convenience sample of 174 adults with CHD risk factors who underwent CAC scoring. The authors found no significant between-group change in risk perception measured by Perception of Risk of Heart Disease Scale scores (CAC score range, 0, 1-10, 11-100, 101-400, >400), with the exception of a small increase in the moderate-risk group (CAC score, 101-400) from 55.5 to 58.7 (p=0.004). All groups demonstrated increases in health-promoting behavior over time.
Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.
While there is evidence CAC scoring has a degree of clinical validity, uncertainty remains in the magnitude of increased risk conferred by a given CAC score. For this reason, a chain of evidence supporting the clinical utility of CAC scoring in this population current cannot be constructed.
Multiple prospective studies have found that coronary artery calcium (CAC) scoring is associated with future risk of coronary heart disease (CHD) events. CAC scores likely add to the predictive ability of clinical risk prediction models. However, relevant studies enrolled different populations, assessed different traditional risk factors, and assessed different coronary disease outcomes. Different calcium score cutoffs were analyzed in these studies. Given the variation across studies, the magnitude of increased risk conferred by a given calcium score is still uncertain. Studies that evaluated use of CAC scoring in asymptomatic patients have reported mixed findings on whether the score led to improved cardiovascular risk profiles or improvements in other meaningful clinical outcomes. The meta-analysis of randomized controlled trials (RCTs) did not find significant improvements in cardiac risk profiles, smoking cessation, or incidence of subsequent cardiac procedures with the use of CAC scoring.
In certain clinical situations, such as patients presenting with chest pain, it is uncertain whether the symptoms are due to CAD. Coronary calcium measurement has been proposed as a method to rule out CAD in certain patients if their CAC score is 0. The presence of any coronary calcium can be a sensitive but not specific test for coronary disease because CAD rarely occurs in the absence of coronary calcium, False positives occur because the calcium may not be associated with an ischemic lesion. The absence of any coronary calcium can be a specific test for the absence of coronary disease and direct the diagnostic workup toward other causes of the patient’s symptoms. In this context, coronary calcium measurement is not used to make a positive diagnosis but as a diagnostic “filter” to rule out an atherosclerotic cause for the patient’s symptoms.
The use of coronary artery calcium (CAC) scoring with computed tomography (CT) in symptomatic patients can rule out the atherosclerotic etiology of CAD.
The population of interest includes individuals who have signs and/or symptoms suggested of CAD.
The intervention of interest isCC scoring using fast CT imaging, including EBCT and spiral CT.
The comparators of interest is standard diagnostic testing (functional testing, exercise electrocardiography [ECG])
The outcomes of interest include over survival, test accuracy, test validity, morbid events (e.g. major adverse cardiac events [MACEs], need for ICA (interventional coronary angiography) and revascularization)
The timing of use of CT CAC scoring is when individuals require evaluation for persistent stable angina or experience onset of acute chest pain.
The setting is a cardiology practice or emergent care setting for patients undergoing evaluation of chest pain.
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).
Chaikriangkrai et. al. (2016) conducted a systematic review and meta-analysis to examine the prognostic value and accuracy of a coronary artery calcium (CAC) score of 0 for identifying patients presenting with acute chest pain at acceptable low risk for future cardiovascular events. The systematic review included only prospective cohort studies that used multidetector computed tomography (MDCT) or electron beam computed tomography (EBCT) to calculate CAC scores using the Agatston method and reported major adverse cardiac events (MACEs) at 1 month and beyond the index emergency department visit. Eight studies evaluating 3556 patients with a median follow-up of 10.5 months were selected. Reviewers conducted a subgroup analysis of 6 studies at predominantly white patients (n=2432 patients) to estimate the prognostic accuracy indices of CAC scores (0, >0) for cardiovascular events (MACEs, all-cause deaths, nonfatal myocardial infarction). Pooled sensitivity, specificity, as well as positive and negative likelihood ratios were 96% (I2=0%), 60% (I2=15.1%), 2.36 (I2=0%), and 0.07 (I2=0%), respectively.
Lubbers et. al. (2016) conducted a multicenter RCT to compare the effectiveness and safety of a cardiac CT algorithm with functional testing in patients with symptoms (stable chest pain or angina equivalent symptoms) suggestive of coronary artery disease (CAD). A total of 350 patients with stable angina were prospectively randomized 2:1 to cardiac CT and functional testing, such as exercise ECG, myocardial perfusion imaging, or stress echocardiography. Patients in the cardiac CT arm (n=242) initially underwent calcium scanning followed by computed tomography angiography (CCTA) if the Agatston calcium score was between 1 and 400. CAD was ruled out if the patients had a CAC score of 0. The original primary end point of the trial was the proportion of patients undergoing catheter angiography followed by revascularization, but because of insufficient funding, authors could not assess that end point and chose clinical effectiveness as the alternative primary outcome, defined as the absence of chest pain complaints after 1 year. After 1 year, fewer patients randomized to CT reported angina symptoms that those in the functional testing group (39% vs 25%, p=0.012), although the proportion of patients with similar or worsened symptoms was comparable (26% vs 29%, p=0.595). The tiered protocol study design is a strength of this study, but the unplanned change in end points limits analysis and conclusions.
In 2014, Hulten et. al. published results from a retrospective cohort study among symptomatic patients without a history of coronary artery disease (CAD) to evaluate the accuracy of coronary artery calcium (CAC) scoring for excluding coronary stenosis, using computed tomography angiography (CTA) as the criterion standard. The study included 1145 patients who had symptoms possibly consistent with CAD who underwent non-contrast CAC scoring and contrast-enhanced CTA from 2004 to 2011. For detection of greater than 50% stenosis, CAC had a sensitivity, specificity, and negative predictive value of 98%, 55%, and 99%, respectively. For prediction of cardiovascular death or myocardial infarction, the addition of either or both CAC and CTA to a clinical prediction score did not significantly improve prognostic value.
Chaikriangkrai et. al. (2015) retrospectively evaluated whether coronary artery cacliums (CAC) added incremental value to computed tomography angiography (CTA) for predicting coronary artery stenosis in 805 symptomatic patients without known coronary heart disease (CHD). CAC score was significantly associated with the presence of coronary artery stenosis on CTA. Both CAC score and the presence of CTA stenosis were significantly associated with MACE (major adverse cardiac event) rates, including cardiac death, nonfatal myocardial infarction, and late coronary revascularization. Patients with more than 50% stenosis on CTA had higher MACE rates, compared with those who had a normal CTA (4.5% vs 0.1%, p<0.001) and with those who had less than 50% stenosis (4.5% vs 1.4%, p=0.002). Those with a CAC score of more than 400 had higher MACE rates than those with scores between 1 and 100 (4.2% vs 1.4%, p=0.014) and those with scores of 0 (4.2% vs 0% p<0.001). The addition of CAC score to a risk prediction model for MACE, which included clinical risk factors and CTA stenosis, significantly improved the model’s predictive performance (global X2 score, 108 vs 70, p=0.019).
In 2015, Pursnani et. al. published results from a subgroup analysis of the ROMICAT II trial. It evaluated the incremental diagnostic value of coronary artery calcium (CAC) scoring plus computed tomography angiography (CTA) in low- to intermediate-risk patients presenting to the emergency department with symptoms (chest pain or angina equivalent of ≥5 minutes duration within 24 hours) suggesting acute coronary syndrome (ACS). The ROMICAT II trial randomized patients with possible ACS to CTA as part of an initial evaluation or to the standard emergency department evaluation strategy, as directed by local caregivers. As part of the trial protocol, all patients undergoing CTA had a CAC scan; the present analysis included 473 patients who underwent both CTA and CAC scanning. Among these patients, the ACS rate (defined as unstable angina and myocardial infarction during the index hospitalization) was 8% (n=38). Patients with lower CAC scores were less likely to have a discharge diagnosis of ACS. Among 253 patients with a CAC score of 0, 2 (0.8%) patients were diagnosed with ACS (95% CI, 0.1% to 2.8%). Receiver operating characteristic curve analysis was used to predict the risk of ACS by CAC score greater than 0, continuous CAC score, CTA results, and combined CAC and CTA score. The optimal cut point of CAC for ACS detection was 22 (C statistic, 0.81), with 318 (67%) patients having a CAC score less than 22. All CTA strategies had high sensitivity for ACS detection, without significant differences in stenosis thresholds. CAC was inferior to CTA for predicting ACS (C range, 0.86 vs 0.92; p=0.03). The addition of CAC score to CTA (i.e., using selective CTA only for patients with CAC score >22 or >0) did not significantly improve the detection of ACS (CAC+CTA C=0.93 vs CTA C=0.92; p=0.88). Overall, this trial suggested that CAC scoring does not provide incremental value beyond CTA in predicting the likelihood of ACS in a low- to intermediate-risk population presenting to the emergency department.
Systematic reviews and meta-analyses have reported a very low negative likelihood ratio for coronary artery calcium (CAC) score in predicting major adverse cardiac events (MACEs) and significant coronary stenosis, suggesting the potential value of calcium score of 0 in ruling out an atherosclerotic etiology of disease. However, multiple observational studies with angiographic (computed tomography angiography [CTA] or interventional coronary angiography [ICA]) have suggested that a CAC score of 0 may not rule out the presence of significant atherosclerotic coronary artery disease (CAD) among symptomatic patients.
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy or avoid unnecessary testing.
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would from randomized controlled trials (RCTs).
The 2016 systematic review by Chaikriangkrai et. al. (discussed above) assessed studies of relevance to our analysis of clinical utility. Specifically, in 8 studies (total N=3556 patients), those with a coronary artery calcium (CAC) score of 0 had a significantly lower risk of MACEs (major adverse cardiac events) compared with patients with CAC scores greater than 0 (RR=0.06; 95% CI, 0.04 to 0.11; p<0.001; I2=0%). The risk difference was 0.19 (95% CI, 0.11 to 0.27).
Subgroup analyses in the 5 studies evaluating death or nonfatal myocardial infarction showed that the patients with a CAC score of 0 had a significantly lower risk of death or nonfatal myocardial infarction compared with patients with CAC scores greater than 0 (RR=0.19; 95% CI, 0.08 to 0.47; I2=0%). The risk difference was 0.03 (95% CI, 0 to 0.05). The pooled event rate for death or nonfatal myocardial infarction with a CAC score of 0 (0.5%/year [0.04 death/myocardial infarction per 100 patient-months, or 6 deaths/myocardial infarction in 13,656 patient-months]) was significantly lower than with a CAC scores greater than 0 (3.5%/year [0.29 death/myocardial infarction per 100 patient-months, or 33 deaths/myocardial infarction in 11,350 patient-months]).
Yerramasu et. al. (2014) prospectively assessed an evaluation algorithm including coronary artery calcium (CAC) scoring for patients presenting to a rapid access chest pain clinic with stable chest pain possibly consistent with coronary heart disease (CHD). Three hundred patients presenting with acute chest pain to 1 of 3 chest pain clinics underwent CAC scoring. If the CAC score was 1000 or more Agatston units, interventional coronary angiography (ICA) was performed; if the CAC score was less than 1000, (computed tomography coronary angiography) CTCA was performed. All patients with a CAC score of 0 and low pretest likelihood of CHD had no obstructive CHD on CTCA and were event-free during follow-up. Of the 18 patients with CAC scores from 400 to 1000, 17 (94%) had greater than 50% obstruction on subsequent CTCA and were referred for further evaluation, 14 (78%) of whom had obstructive CHD. Of 15 patients with CAC scores 1000 or more and who were referred for coronary angiography, obstructive CHD was present in 13 (87%). This study suggested that CAC scoring can be used in the acute chest pain setting to stratify decision making for further testing.
Ten Kate et. al. (2013) prospectively evaluated the accuracy of cardiac computed tomography (CT), including coronary artery calcium (CAC) scoring with or without computed tomography coronary angiography (CTCA), in distinguishing heart failure due to coronary artery disease (CAD) from heart failure due to non-CAD causes. Data on the predictive ability of a negative CAC score in ruling out CAD was also included. The study included 93 symptomatic patients with newly diagnosed heart failure of unknown etiology, all of whom underwent CAC scoring. Those with a CAC score greater than 0 underwent CTCA and, if the CTCA was positive for CAD (>20% luminal diameter narrowing), interventional coronary angiography (ICA) was recommended. Forty-six percent of patients had a CAC score of 0. At a mean follow-up of 20 months, no patient with a CAC score of 0 had a myocardial infarction, underwent percutaneous coronary intervention, had a coronary artery bypass graft, or had signs of CAD.
Currently, evidence from nonrandomized observational studies suggests very low short or long term risk of cardiovascular events or death in patients having calcium scores of 0 compared with those having positive (more than 0) calcium scores. However, considering the inconsistency in evidence regarding the diagnostic accuracy of calcium scoring and lack of evidence from randomized controlled trials (RCTs), further research is needed to examine the clinical utility of ruling out atherosclerotic coronary artery disease (CAD) based on coronary artery calcium (CAC) score of 0.
For individuals who are asymptomatic with risk of coronary artery disease (CAD) who receive coronary artery calcium (CAC) scoring, the evidence includes multiple systematic reviews, randomized controlled trials (RCTs) and nonrandomized observational studies. There is extensive evidence on the predictive value of CAC score screening for cardiovascular disease among asymptomatic patients, and this evidence has demonstrated that scanning has incremental predictive accuracy above traditional risk factor measurement. However, high-quality evidence demonstrating that the use of CAC scores in clinical practice leads to changes in patient management or in individual risk behaviors that improve cardiac outcomes is lacking. USPSTF 2018 recommendation for cardiovascular disease risk assessment with nontraditional risk factors that includes coronary artery calcium (CAC) score, found inadequate evidence to assess whether treatment decisions guided by coronary artery calcium (CAC) score results, when added to existing CVD risk assessment models, lead to reduced incidence of CVD events or mortality. The evidence is insufficient to determine the effects of the technology on net health outcomes.
For individuals with signs and/or symptoms suggested of coronary artery disease (CAD) who receive coronary artery calcium (CAC) scoring before other diagnostic testing, the evidence includes prospective and retrospective nonrandomized studies. CAC scoring has potential as a diagnostic test to rule out CAD in patients presenting with symptoms or as a “gatekeeper” test before invasive imaging is performed. Evidence from observational studies has suggested that negative results on CAC scoring rule out CAD with good reliability. However, the evidence has been inconsistent, with some studies reporting lack of value when using a zero calcium score to rule out CAD. Further prospective trials would be needed to demonstrate that such strategy is effective in practice and is at least as effective as alternative strategies for ruling out CAD. To demonstrate that use of calcium scores improves the efficiency or accuracy of the diagnostic workup of symptomatic patients, rigorous defining exactly how CAC scores are used in combination with other tests to triage patients would be necessary. The evidence is insufficient to determine the effects of technology on net health outcomes.
In 2010, the American College of Cardiology Foundation and the American Heart Association, issued a guideline for the assessment of cardiovascular risk in asymptomatic adults, which included the following recommendation regarding computed tomography for coronary artery calcium (CAC) scoring:
In 2012, the American College of Cardiology (ACC)/ American Heart Association (AHA) released guidelines for the diagnosis and management of patients with stable ischemic heart disease that include the same recommendation related to CAC scoring for Class IIb:
In 2014, ACC/AHA issued focused update to the 2012 guideline on the diagnosis and management of patients with stable ischemic heart disease with no additional recommendations related to CAC scoring.
In 2018 the U.S. Preventative Services Task Force (USPSTF) updated their 2009 recommendation regarding cariovascular disease: risk assessment with non-traditional risk factors. The USPSTF concludes that current evidence is insufficient to assess the balance of benefits and harms of adding ankle-brachial index (ABI), high-sensitivity C-reative protein (hsCRP) level, or coronary artery calcium (CAC) score to traditional risk assessment for cardiovascular disease (CVD) in asymptomatic adults to prevent CVD events.
Cardiovascular disease risk assessment in the United States has been generally based on the Framingham Risk Score and, more recently, the Pooled Cohort Equations (PCE). However, both have been documented to overestimate and underestimate risk in some persons. Therefore, identification of additional tests (for nontraditional risk factors) that could improve risk prediction, including the ABI, hsCRP level, and CAC score, is of interest
The USPSTF found only 1 study that directly assessed the potential benefit on clinical outcomes of adding 1 of these 3 nontraditional risk factors (ABI, hsCRP level, and CAC score) to traditional risk assessment models. This fair-quality randomized clinical trial (RCT) assigned asymptomatic volunteers (N = 2137) with no history of CVD to CAC scoring plus risk factor assessment counseling vs risk factor assessment counseling alone. At 4 years, there was no difference in CVD outcomes between the 2 groups; however, the study was not adequately powered to detect a difference in patient health outcomes. The USPSTF found no studies that assessed the incremental benefit on health outcomes of adding the ABI or hsCRP level to traditional risk factor assessment. The Viborg Vascular (VIVA) screening trial recently reported interim results; this trial randomized men aged 65 to 74 years to invitation for a triple screening (screening for high blood pressure, abdominal aortic aneurysm, and peripheral artery disease using the ABI) or no screening and found a decrease in mortality with screening; however, it was not possible to determine how much of the decrease was attributable to screening for peripheral artery disease and how much was attributable to screening for abdominal aortic aneurysm and high blood pressure, both of which are already recommended screenings.
The USPSTF found no trials evaluating the additional benefit of adding the ABI, hsCRP level, or CAC score to traditional risk assessment models for guiding decisions about specific interventions to prevent CVD. The USPSTF found a few studies evaluating the use of a nontraditional risk factor as a single intervention to guide decisions about specific preventive medications compared with usual care. Two RCTs (total N = 4626) compared using the ABI to guide decisions to start aspirin therapy vs usual care and found no benefit in CVD outcomes at 7 years of follow-up. However, both studies used atypical cutoff points for diagnosing peripheral artery disease, and the results may not be applicable to current practice. One RCT (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin [JUPITER]; N = 17,802) compared hsCRP screening vs usual care to guide high-intensity statin therapy and found benefit at 1.9 years of follow-up in the reduction of CVD events in the hsCRP group.9 However, because the study only randomized persons with elevated hsCRP levels, it is not known whether patients with lower hsCRP levels would also have benefited from high-intensity statin therapy. Further, many of these patients met criteria for statin therapy based on traditional CVD risk assessment and would already have been candidates for treatment. One study (n = 1005) of using CAC score to guide statin therapy found no benefit at 4 years in the reduction of CVD events.33
A systematic review that addressed the effect of screening with CAC score on risk perception, adherence to medication, and behavioral therapies found only 2 studies comparing traditional CVD risk assessment vs CAC score. Neither of these studies found that screening with CAC score was superior to traditional CVD risk assessment for preventive medication use or risk factor management
The USPSTF found adequate evidence that adding the ABI, hsCRP level, and CAC score to existing CVD risk assessment models results in small improvements in discrimination and reclassification. However, the clinical meaning of these changes is largely unknown. Evidence on adding the ABI, hsCRP level, and CAC score to the Pooled Cohort Equations is sparse, which makes it difficult to infer the clinical significance of these findings. The USPSTF found inadequate evidence to assess whether treatment decisions guided by the ABI, hsCRP level, or CAC score, in addition to risk factors in existing CVD risk assessment models, leads to reduced incidence of CVD events or mortality. Few studies were available and were either underpowered or used atypical test thresholds for intervention. The USPSTF found adequate evidence to bound the harms of early detection and interventions as small. The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of using the ABI, hsCRP level, or CAC score in risk assessment for CVD in asymptomatic adults to prevent CVD events.
Several comments noted that the addition of nontraditional risk factors, especially CAC score, is useful for patients whose risk stratification is unclear or for those who fall into intermediate-risk groups. The USPSTF did not find convincing evidence that adding nontraditional risk factors to traditional risk factors improves reclassification in intermediate-risk groups. As clinical practice moves toward a single threshold for treatment, this concern may no longer be relevant in clinical decision making. Some comments also expressed belief that CAC score testing leads to better adherence to preventive therapies (ie, medications and lifestyle changes). The USPSTF carefully reviewed the available evidence and concluded that CAC score testing showed no benefit over traditional CVD risk assessment in preventive medication use or risk factor control. The USPSTF added language to address this point.
In 2019, the American College of Cardiology (ACA)/American Heart Association (AHA) released guideline on the primary intervention of cardiovascular disease that included the following recommendations:
Coronary artery calcium (CAC) scoring by means of computed tomography (CT) is considered investigational for all indications.
Based on the peer reviewed medical literature to include a systematic review by AHRQ on behalf of the USPSTF for their updated 2018 insufficient recommendation regarding cardiovascular disease risk assessment with nontraditional risk factors that includes coronary artery calcium (CAC) score, because of the lack of high-quality evidence demonstrating improved clinical outcomes or impact to treatment management from the use of coronary artery calcium (CAC) score either as screening tests to risk stratify asymptomatic patients or as a diagnostic test in symptomatic patients the use of coronary artery calcium scoring by means of computed tomography (CT) is considered investigational.
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