Emerging Risk Factors for Coronary Heart Disease: A Summary of Systematic Reviews Conducted for the U.S. Preventive Services Task Force

Clinicians use the Framingham risk score to stratify persons according to their 10-year risk for coronary death or myocardial infarction, also known as major or hard coronary heart disease (CHD) events (1, 2). The Framingham risk score predicts major CHD events well in different demographic and ethnic groups (3). Guidelines recommend using the Framingham risk score, or a modified version of it, to identify high-risk persons (persons with a 10-year risk >20%), who benefit from aggressive risk-reduction measures (4, 5). In the United States, 23 million adults with no history of cardiovascular disease are classified as intermediate-risk by the Framingham score, meaning they have a 10-year risk for major CHD events of 10% to 20% (6). New or emerging risk factors, particularly inflammatory markers and markers of atherosclerotic burden, might identify those in this group who are actually at high risk and might benefit from more aggressive risk reduction. More than 100 emerging risk factors have been proposed for their potential to improve global risk assessment (7). However, consensus conferences held in 1998 (8) and 2002 (4, 9) recommended against using these factors in the absence of stronger data to support their ability to independently predict CHD events. These consensus groups also noted that assays for some markers were not sufficiently standardized for clinical use. Among the few tests proven to predict cardiovascular events, none had been demonstrated to reclassify as high-risk a subgroup of persons who were initially classified as intermediate-risk by using the Framingham risk score (9). Table 1 outlines the criteria a new risk factor must meet to be clinically useful for reclassifying intermediate-risk patients' risk for major CHD events (912). Key to these criteria is the concept that the value a new risk factor adds to a risk scoring system (such as the Framingham system) cannot be judged solely by its ability to predict major CHD events independent of other risk factors. Most studies use a hazard ratio (or other risk ratio) to measure how well a new risk factor predicts major CHD events, controlling for the Framingham risk factors. From a clinical viewpoint, calculating a risk ratio is a necessary but far from sufficient step because it does not enable judgment of the effect of using the new test in persons classified as intermediate-risk by the Framingham risk score. Table 1. Criteria for Evaluating the Clinical Value of a New Risk Factor Studies may also measure how well a new prognostic risk factor improves discrimination when incorporated into the Framingham risk score. However, a marker that has a small effect on discrimination may have a large effect on the reclassification of persons from 1 risk group to another (1318). To estimate the effect of a new risk factor on reclassification, investigators must compare the proportion of persons classified as high-risk by each model, then assess whether the agreement between the predicted and actual event rates in subgroups of persons who have different levels of risk (that is, calibration) has improved. Measuring discrimination is insufficient to judge the clinical effect of the new test without also measuring calibration and reclassification (19). A better approach is to calculate the Framingham risk score, classify all participants, and then see how well the new risk factor reclassifies those who were assigned to the intermediate-risk group. This sequential approach provides a direct measure of the number or proportion of intermediate-risk persons who could be reclassified by the new test. This type of analysis provides the best information about the clinical effect of using the new test to further stratify intermediate-risk patients. Using these considerations and the criteria in Table 1 as a guide, we conducted a series of systematic reviews to help the U.S. Preventive Services Task Force (USPSTF) determine which of 9 risk factors should be used to further stratify intermediate-risk persons. Members of the USPSTF determined the risk factors to evaluate: anklebrachial index (ABI), leukocyte count, fasting blood glucose level, periodontal disease, carotid intimamedia thickness (IMT), coronary artery calcium (CAC) score as measured by electron-beam computed tomography, serum homocysteine level, lipoprotein(a) level, and C-reactive protein (CRP) level. The details of several of these reviews are published elsewhere (2023). We provide a summary overview of the main findings of this series of systematic reviews. Methods We searched MEDLINE for English-language articles (1966 through September 2008) by using the Medical Subject Heading terms cohort studies and cardiovascular diseases in combination with terms for each of the tests under study. We also searched the reference lists of published reports. We included only studies that recruited participants with no known cardiovascular disease, reported major CHD events, and adjusted for 6 or 7 Framingham risk factors (5 or 6, if participants with diabetes were excluded) in this summary. When we found several reports based on the same cohort, we used the most recent analysis unless an older one used stronger analytic methods. The systematic reviews were originally conducted for literature searches through 2006. Several of those reviews were published or submitted for publication as separate papers. For the current review, we updated the literature searches through September 2008 for ABI, leukocyte count, fasting blood glucose level, carotid IMT, and lipoprotein(a) level. We updated the literature search for electron-beam computed tomography through July 2008. Critical Appraisal and Quality of Evidence To assess the quality of each study, we used the USPSTF criteria for cohort studies (10) and applied a modified Grading of Recommendations, Assessment, Development, and Evaluation framework to assess the overall quality of evidence for each risk factor (24). Specifically, we considered the limitations, consistency, precision, applicability to the target population (intermediate-risk adults with no known cardiovascular disease), doseresponse relationship, and likelihood of publication bias for the entire set of studies about the risk factor. These ratings for the overall quality of evidence reflect our confidence in the estimate of the risk factor's usefulness for reclassifying intermediate-risk persons as high-risk. The ratings also reflect appropriate control for confounders and applicability to intermediate-risk persons, among other considerations. Appropriate Control for Confounding With the Framingham Risk Factors Most novel risk factors are correlated with Framingham risk factors, so investigators who do not adjust or adjust inappropriately for 1 or more Framingham factors may overestimate the novel factor's predictive ability (25, 26). Inappropriate adjustment occurs when a variable (for example, a self-reported history of taking medication for cholesterol) is used as a proxy for a better predictor (such as measured total cholesterol or high-density lipoprotein cholesterol levels). We can have confidence in a study's results only when all Framingham risk factors have been correctly measured and adjusted for. Applicability to Intermediate-Risk Persons Cohorts that included intermediate-risk persons provide more pertinent information about risk factors. Estimates of the predictive ability of a particular marker vary depending on the pattern and prevalence of other risk factors in the population (19). A few studies used the Framingham risk score to classify participants, which provided direct information about the proportion who were at intermediate risk and the effect of using the new test. In most studies, however, we used average annual event rates and the prevalence of the Framingham risk factors to infer that the study population included intermediate-risk persons. Other Considerations We also considered the other criteria listed in Table 1. For some of these criteria (such as test reliability, convenience, cost, or safety), we used information not otherwise included in the literature search. Role of the Funding Source This study was funded by the Agency for Healthcare Research and Quality under a contract to support the work of the USPSTF. Agency staff and USPSTF members participated in development of the initial scope of this work and reviewed interim analyses and the final report. A draft version was distributed to content experts for review. Agency approval was required before this manuscript could be submitted for publication, but the authors are solely responsible for the content and the decision to submit it for publication. Results The Appendix Table shows how often a particular risk factor was evaluated among the 75 cohorts that have studied at least 1 novel risk factor. Serum tests that can be done on stored samples, such as for CRP, homocysteine, or lipoprotein(a), have been evaluated in the largest, highest-quality, and most diverse population-based studies. The strongest evaluations came from studies in which the cohorts had been followed for 10 years or more and all Framingham risk factors were measured before treatment for hyperlipidemia or hypertension was initiated. Conversely, data about electron-beam computed tomography, carotid IMT, and periodontal disease are relatively sparse. Because radiologic tests (electron-beam computed tomography and carotid IMT) and physical examination (ABI and periodontal examinations) cannot be done retrospectively, few studies of the large, widely studied cohorts used in cardiovascular epidemiology research evaluated these risk factors. Most evaluations of these tests were weaker, in that persons were followed for less time or had incomplete evaluations that did not measure all relevant Framingham risk factors at the time of inception. Many of the cohorts listed in the Appendix Table had no publications that met the inclusion criteria for our reviews. Many