Primary prevention of coronary artery disease

Application of coronary risk scores: pros and cons Primary prevention of coronary artery disease (CAD) is of utmost importance in public health policies of industrialized nations. The adoption of the Framingham risk score1 (FRS) was waived many years ago as an innovative population-based method to assess the median risk of developing CAD. Cohort studies and randomized trials led to multivariate risk functions and enabled the development of risk scores and the application of simplified charts, with the FRS being considered the reference standard.2 Although such scores, solely based on the assessment of demographic and clinical risk factors, have been extensively applied in the last decades,3 there are inherent limitations in their application. In a systematic review of 27 studies using the Framingham risk equation, the predicted-to-observed ratios ranged from an underprediction of 0.43 in a high-risk population to an overprediction of 2.87 in a low-risk population.4 In other words, risk score may tend to overestimate risk in low-risk populations and underestimate it in high-risk populations. Furthermore, the increased risk of developing cardiovascular events in patient categories is small (three-fold to five-fold),5 and does not satisfy the requirement for the new concepts of personalized medicine. In fact, the FRS can predict the risk of the general population but does not allow discernment of the individual's risk. For instance, even when more liberal treatment criteria are applied, as suggested in the recent Air Force/Texas Coronary Atherosclerosis Prevention Study trial,6 only 37% of the acute myocardial infarctions (MIs) are prevented. Brindle et al.4 addressed in a meta-analysis the accuracy of cardiovascular disease risk according to FRS in primary prevention. The analysis of 27 nonrandomized controlled trials showed a 0.43 underprediction in a high-risk population, and an overprediction of 2.87 in a lower-risk population. In a second review including four randomized controlled trials, confined to people with hypertension or diabetes, there was no clear evidence that a cardiovascular risk assessment can improve clinical outcomes. The search for subclinical atherosclerosis Indicators of subclinical atherosclerosis have been incorporated to improve prediction of risk charts as they serve as a direct measure of the cumulative effect of known and unknown risk factors on the vasculature with respect to atherosclerosis.7–9 Coronary artery calcium (CAC), carotid-intima-media thickness (CIMT), and the ankle brachial index are markers of atherosclerosis that proved to be a reasonable solution to improve prediction of cardiovascular events. Carotid-intima-media thickness CIMT is a surrogate measure of atherosclerosis8 that is widely used to predict cardiovascular outcomes. However, measurement of CIMT seems to add little value to risk prediction obtained with Framingham risk factors score. The intima-media thickness is the distance from the lumen–intima interface to the media–adventitia interface of the artery wall. Although the mean intima-media thickness of the common carotid artery is a more reproducible measure than the intima-media thickness of the internal carotid artery, data on its capability to predict clinical outcome are not fully convincing. Polak et al.10 explored the incremental predictive value of the intima-media thickness of either the common carotid artery or the internal carotid artery, over and above the value of traditional cardiovascular risk factors assessed by means of FRS. The authors measured CIMT in 2965 members of the Framingham Offspring Study cohort and addressed clinical outcomes at an average follow-up of 7.2 years. Only the maximum intima-media thickness of the internal carotid artery (and presence of plaque) significantly (albeit modestly) improved the classification of risk of cardiovascular disease over the Framingham. These data are in line with those from other studies9 showing an improved predictive power for CAD and stroke/transient ischemic attacks10 when plaque was included in CIMT measurement. It should be noted that the sole assessment of increased sonographic CIMT is not necessarily indicative of atherosclerosis and can occur in patients without atherosclerosis. It is because atherosclerosis exclusively involves the intimal layer, whereas thickened CIMT may be due to medial hypertrophy as a result of adaptive arterial wall remodeling or aging.8 Another reason limiting the widespread application of CIMT measurement for stratification of CAD resides in the complexity and modest reproducibility of the technique. As a consequence, CIMT image acquisition differs in the number of segments. Some studies examined CIMT at the distal common carotid artery that is easily accessible.8 The success rate of acquiring CIMT at the bulb and internal carotid artery, in which plaque tends to grow, is unfortunately less than that obtained at the common carotid. The presence of different reading methods of CIMT, considering the number of imaging angles and the cardiac cycle, is an additional variable to be taken into account. Electron beam computed tomography calcium score CAC has long been identified as a marker of underlying CAD.1 EBCT (electron beam computed tomography) is a well tolerated, low-cost modality that proved to be extremely sensitive for the detection and quantification of the extent of coronary artery calcification. Measures of CAC which are commonly expressed as calcium scores showed a close correlation with the atherosclerotic plaque burden.11 Furthermore, the presence of CAC on a screening EBCT test was found to be associated with high odds ratios (ORs) for developing cardiovascular events.12 Patients without evidence of CAC were shown to have a very low risk of coronary events. This finding is of importance as absence of CAC on imaging is common, with a 50% prevalence in asymptomatic patients13 and a 33% prevalence in patients with more than three atherosclerotic cardiovascular disease (ASCVD) risk factors.13–15 According to published studies,11,12,16 the annual rate of cardiovascular events comprises between 0.06 and 0.11% in absence of detectable CAC by EBCT. Furthermore, in a cohort of approximately 900 diabetic patients, 5-year survival was 98.8% in the absence of CAC.17 Lastly, no differences in survival were found between diabetic and nondiabetic patients with no CAC (98.8 and 99.4%, respectively, P = 0.5). A prospective study of type-2 diabetic patients showed that no cardiac events or perfusion abnormalities occurred in patients with a CAC score less than 100 through 2 years of follow-up.18 There is only one study that reported a higher event rate for 0 score. However, the authors used a typical image acquisition and quantification of CAC, relying on thick slices (6 mm) and large areas of calcification which has been shown to result in data loss.1 On the other hand, presence of calcium at EBCT helps in identifying patients at risk of coronary events. Coronary calcifications are frequently found in patients who suffer a coronary event,19,20 indicating that this is a true marker of CAD. However, although patients with high calcium scores were shown to be at high risk of hard events, only a small portion of the population would show high calcium score.21 In the effort to identify a calcium scores threshold to identify patients at risk of coronary events, Raggi et al.1 explored the impact of CAC score on long-term clinical outcome in a mixed population including patients with and without CAD. They conducted two analyses: a first group (group A) comprised 172 patients who suffered an unheralded MI within 60 days from EBCT scan; a second group (group B) included 632 patients without CAD history. Patients were followed up for a mean of 33 months. Authors then compared group A patients vs. group B patients who developed a cardiac event during follow-up (n = 27). The prevalence of coronary calcification was similar in these two groups (96% each), and high degree of calcium score (>75th percentile) was found in 70% of cases in both groups. Furthermore, ORs of 21.5 for future hard cardiovascular events were found for patients in the highest quartile of calcium scores. Budoff et al.22 reported data from an observational outcome study of 25 253 consecutive, asymptomatic individuals referred by their primary physician for CAC scanning to assess cardiovascular risk. Risk-adjusted models incorporated traditional risk factors for coronary disease and CAC scores. The frequency of CAC scores was 44, 14, 20, 13, 6, and 4% for scores of 0, 1–10, 11–100, 101–400, 401–1000, and more than 1000, respectively. During a mean follow-up of over 6 years, the death rate was 2% (510 deaths). The CAC was an independent predictor of mortality in a multivariable model adjusted for age, sex ethnicity, and cardiac risk factors (P = 0.0001). The addition of CAC to traditional risk factors increased the concordance index significantly (0.61 for risk factors vs. 0.81 for the CAC score, P = 0.0001). Risk-adjusted relative risk ratios for CAC were 2.2-fold, 4.5-fold, 6.4-fold, 9.2-fold, 10.4-fold, and 12.5-fold for scores of 11–100, 101–299, 300–399, 400–699, 700–999, and more than 1000, respectively (P = 0.0001), when compared with a score of 0. A period of 10-year survival (after adjustment for risk factors, including age) was 99.4% for a CAC score of 0 and worsened to 87.8% for a score of less than 1000 (P = 0.0001). Importantly, in several risk-adjusted models, CAC scores remained independently predictive of all-cause mortality even after adjusting for age, sex, ethnicity, hypertension, hyperlipidemia, diabetes, smoking, and family history of premature CAD.22,23 How to incorporate calcium score grading to reduce patient's cardiovascular risk Calcium score grading by means of EBCT represents a valid solution to reduce the individual risk of cardiovascular events. For instance, the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III)24 suggested that a score higher than 100 might lead to the recommendation of continued aspirin use and more aggressive lipid control. The third report of the NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults suggested that, in presence of multiple risk factors, high coronary calcium scores (i.e., >75th percentile for age and sex, indicative of advanced coronary atherosclerosis), an intensified LDL-lowering therapy should be started.24 Based on more recent recommendations, cardiac computed tomography should be adopted for measuring CAC in individuals determined to be at intermediate clinical risk according to the NCEP-ATP III criteria. Such preventive strategy seems rational, in the attempt to improve individual risk of cardiovascular disease in the large group of Framingham intermediate risk score, in which the individual risk identification needs to be improved.22 CAC imaging was endorsed in the 2013 Risk Assessment Guideline from the American College of Cardiology and the American Heart Association to enhance ASCVD risk estimation and facilitate statin allocation.25 However, only a tepid IIb recommendation (may be considered) for statin therapy was given, due to absence of any adequately powered, prospective, randomized trials of CAC-guided ASCVD prevention.25 To date, the only CAC trial assessing clinical outcomes was the single-center St. Francis Heart study.16 All participants had CAC screening, and those with CAC more than 80th percentile for age and sex were randomized to receive placebo or atorvastatin 20 mg daily. Over 4.3 years mean follow-up, a trend for a lower incidence of major cardiovascular events was found in the treated group (6.9 vs. 9.9%, respectively; P = 0.08). The trial was underpowered to show a clinical benefit; however, in a post-hoc analysis, patients with CAC scores more than 400 appeared to derive benefit. In Europe, the ROBINSCA trial, a large, under way, randomized study is being conducted in 33 000 patients. Based on study design, usual care is suggested for CAC less than 100, statin for CAC 100–399, and statin with angiotensin-converting enzyme inhibitor for CAC more than 400.26 Conclusion Despite the efforts carried on decades ago to identify the median risk of a certain population to develop cardiovascular disease, there is still much to do to measure the individual risk, in the attempt to embrace the concept of personalized medicine. The adoption of a strategy that adds assessment of EBCT calcium score in individuals with intermediate FRS seems a reasonable solution. This is the effort to prescribe aspirin and statins to reduce the individual risk. Dedicated clinical follow-up is needed to prove that a tailored prevention based on calcium score evaluation decreases cardiovascular events. Acknowledgements Conflict of interest There are no conflicts of interest.