Cardiovascular Risk Prediction: Two More Studies, Little Progress

Two studies published in JAMA provide new data — and, perhaps, some additional clarity — about using additional markers to help improve risk prediction for coronary heart disease (CHD) and cardiovascular disease (CVD).

In one study, Joseph Yeboah and colleagues used data from 1330 intermediate-risk participants in the Multi-Ethnic Study of Atherosclerosis (MESA)  to analyze the prognostic value of 6 risk markers: coronary artery calcium (CAC), carotid intima-media thickness (CIMT), ankle-brachial index (ABI), brachial flow-mediated dilation (FMD), high-sensitivity C-reactive protein (CRP), and family history of CHD.

After a median follow-up of 7.6 years, four risk markers (CAC, ABI, CRP, and family history) were found to be independent risk factors for CHD. CAC provided “the highest improvement in discrimination” over traditional risk scores. “The present study,” wrote the authors, “provides additional support for the use of CAC as a tool for refining cardiovascular risk prediction in individuals classified as intermediate risk.” However, “broad recommendations” about CAC should not be made until the associated problems of radiation exposure and incidental findings are addressed, they cautioned.

In the other study, Hester Den Ruijter and colleagues focused on CIMT, performing a meta-analysis in which they analyzed individual patient data from 14 studies and 45,828 patients. They found that adding CIMT provided only a small improvement in net reclassification which, they concluded, was “unlikely to be of clinical importance.”

In an accompanying editorial, J. Michael Gaziano and Peter Wilson write that “although there has been a great deal of work on the improvement in prediction modeling, less work has been done in 2 areas: the cost and risk in the screened population and risk prediction over time.” Using the example of an intermediate-risk patient who is a possible candidate for lipid-lowering therapy, they note that although CAC improves classification “at a single point in time,” most physicians evaluate patients over time and will often repeat tests to track trends over time. In this context, radiation exposure and costs may limit the utility of CAC.

Here are the press releases from JAMA:

Measure of Coronary Artery Calcium Associated With Improved Prediction of Cardiovascular Disease Risk

CHICAGO – In a comparison of novel cardiovascular risk markers, coronary artery calcium, ankle-brachial index, high-sensitivity C-reactive protein, and family history were independent predictors of coronary heart disease/cardiovascular disease in intermediate-risk individuals beyond traditional risk factors, with coronary artery calcium providing superior discrimination and risk reclassification compared with other risk markers, according to a study in the August 22/29 issue of JAMA.

“Current trends in primary prevention of cardiovascular disease (CVD) emphasize the need to treat individuals based on their global cardiovascular risk. Accordingly, practice guidelines recommend approaches to classify individuals as high, intermediate, or low risk using the Framingham Risk Score (FRS) or other similar CVD risk prediction models. However, there is increasing recognition of the imprecision of these classifications such that the intermediate-risk group actually represents a composite of higher-risk individuals for whom more aggressive (i.e., drug) therapy might be indicated. The intermediate-risk group also contains lower-risk individuals in whom CVD might be managed with lifestyle measures alone. This recognition has motivated researchers to identify markers that could offer greater discrimination of higher- and lower-risk patients within the intermediate-risk group,” according to background information in the article.

“Risk markers including coronary artery calcium (CAC), carotid intima-media thickness (CIMT), ankle-brachial index (ABI), brachial flow-mediated dilation (FMD), high-sensitivity C-reactive protein (CRP), and family history of coronary heart disease (CHD) have been reported to improve on the Framingham Risk Score for prediction of CHD, but there are no direct comparisons of these markers for risk prediction in a single cohort,” the authors write.

Joseph Yeboah, M.D., M.S., of the Wake Forest University School of Medicine, Winston-Salem, N.C., and colleagues assessed the improvements in CHD/CVD prediction accuracy and reclassification to high- and low-risk categories using CIMT, CAC, FMD, ABI, high-sensitivity CRP, and family history of CHD in asymptomatic adults classified as intermediate risk who participated in the Multi-Ethnic Study of Atherosclerosis (MESA). Of 6,814 MESA participants from 6 U.S. field centers, 1,330 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. Analysis was conducted to compare incremental contributions of each marker when added to the FRS, plus race/ethnicity. Incident CHD was defined as heart attack, angina followed by revascularization, resuscitated cardiac arrest, or CHD death. Incident CVD additionally included stroke or CVD death.

After a median (midpoint) follow-up of 7.6 years, 94 participants (7.1 percent) experienced a CHD event and 123 (9.2 percent) experienced a CVD event. After analyses, the researchers found that each of the novel risk markers was associated with incident CHD; however, after adjusting for confounders, the associations with CIMT and FMD were no longer significant. Among all of the risk markers, CAC had the strongest association. Similarly, for incident CVD, each of the markers was associated with events except high-sensitivity CRP. However, after adjusting for confounders, the associations between CIMT and FMD were no longer significant. CAC also had the strongest association in the multivariable models for CVD.

“The current study shows that among 6 of the most promising novel risk markers, CAC provides the highest improvement in discrimination over the FRS and Reynolds score (RS) in individuals classified as intermediate risk. The present study provides additional support for the use of CAC as a tool for refining cardiovascular risk prediction in individuals classified as intermediate risk by the FRS or the RS,” the authors write. “Additional research is warranted to explore further both the costs and benefits of CAC screening in intermediate-risk individuals.”

(JAMA. 2012;308[8]:788-795.)

Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc. 

Editorial: Cardiovascular Risk Assessment in the 21st Century

In an accompanying editorial, J. Michael Gaziano, M.D., M.P.H., of the Boston VA Healthcare System, Brigham and Women’s Hospital, Harvard Medical School, Boston, (and Contributing Editor, JAMA), and Peter W. F. Wilson, M.D., of the Atlanta VA Medical Center and Emory Clinical Cardiovascular Research Institute, comment on the two studies in this issue of JAMA on assessing cardiovascular risk.

“These reports illustrate the means by which the enhancement of a given model such as FRS with additional data is evaluated. Area under the receiver operating characteristic curve has been used for many diagnostic tests. A clinically useful approach describes the proportion of individuals who are reclassified, known as the net reclassification index. However, not all reclassifications are created equally. Refining risk estimation at the low or high end of the risk spectrum is not helpful because it will not likely alter management. On the other hand, reclassification can assist in decision making for patients who are near clinical decision boundaries. For this reason, both studies provided information on the reclassification that occurred among those at 5 percent to 20 percent risk. In this intermediate range, risk estimates inform clinical decisions about certain interventions.”

(JAMA. 2012;308[8]:816-817)

Addition of Carotid Artery Wall Thickness to Risk Model Associated With Small Improvement in Prediction of Heart Attack, Stroke

CHICAGO – In an analysis of data from previously published studies that included more than 45,000 patients, the value of adding to the Framingham Risk Score a measure of the common carotid artery intima-media thickness (CIMT; a measurement of the thickness of the carotid artery wall) in 10-year risk prediction of first-time heart attack or stroke was small and unlikely to be of clinical importance, according to an article in the August 22/29 issue of JAMA.

“Cardiovascular disease is among the leading causes of morbidity and mortality worldwide. Preventive treatment of high-risk asymptomatic individuals depends on accurate prediction of a person’s risk to develop a cardiovascular event. Currently, cardiovascular risk prediction in asymptomatic individuals is based on the level of cardiovascular risk factors incorporated in scoring equations. Several scores are available, with the Framingham Risk Score (FRS) among the most widely used. These risk equations perform reasonably well, yet there remains considerable overlap in estimated risk between those who are affected by a cardiovascular event and those who are not,” according to background information in the article.

Measurement of CIMT has been proposed to be added to cardiovascular risk factors to improve individual risk assessment. “So far, individual studies reported on the added value of CIMT measurements in cardiovascular risk prediction, but the evidence is not consistent across studies,” the authors write.

Hester M. Den Ruijter, Ph.D., of the University Medical Center Utrecht, the Netherlands, and colleagues conducted a meta-analysis to determine whether common CIMT has added value in 10-year risk prediction of first-time heart attacks or strokes, above that of the Framingham Risk Score. The authors searched the medical literature and identified relevant studies for inclusion in the analysis. Studies were included if participants were drawn from the general population, common CIMT was measured at baseline, and individuals were followed up for first-time heart attack or stroke.

This analysis included 14 studies contributing data for 45,828 individuals. During a median (midpoint) follow-up of 11 years, 4,007 first-time heart attacks or strokes occurred. The researchers refitted the risk factors of the Framingham Risk Score and then extended the model with common CIMT measurements to estimate the absolute 10-year risks to develop a first-time heart attack or stroke in both models. More than 90 percent of the individuals remained in the same risk category. The numbers of individuals shifting downward or upward without and with events were similar. The net reclassification improvement with the addition of common CIMT was small (0.8 percent were correctly reclassified). In those at intermediate risk, the net reclassification improvement was 3.6 percent in all individuals, with no differences between men and women.

“Our results suggest that common CIMT measurements should not routinely be performed in the general population, as the overall added value may be too limited to result in health benefits,” the authors write. “However, as the interest in risk prediction is currently shifting from a 10-year risk to lifetime risk, the added value of a CIMT measurement and its cost-effectiveness using a horizon of 20 to 30 years may be worthwhile to explore.”

(JAMA. 2012;308[8]:796-803)

Editor’s Note: This project is supported by a grant from the Netherlands Organisation for Health Research and Development. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

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