CVD Risk Prediction Improved by Homocysteine
By Charles Bankhead, Staff Writer,
Published: August 22, 2011
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
Action Points
Explain that an analysis of two large databases found that adding homocysteine determination to the Framingham Risk Score significantly improved prediction of cardiovascular disease events.
Note that adding homocysteine reclassified risk for approximately 20% of patients in the intermediate cardiovascular disease risk category.
Risk stratification for cardiovascular disease (CVD) improved significantly with the addition of homocysteine level to the Framingham Risk Score, investigators reported.
A homocysteine level >15 µmol/L predicted as much as a 172% increased risk of CVD across two disparate cohorts. In particular, the addition of homocysteine to traditional risk factors led to reclassification of about 20% of patients in the intermediate-risk category, as reported in the Journal of the American College of Cardiology.
"Our results lend support to previously published data exploring the association between homocysteine and cardiovascular disease and coronary heart disease (CHD) events," Luis Afonso, MD, of Wayne State University in Detroit, and coauthors wrote in conclusion.
"Of note, unlike any previous study, our analyses were adjusted for C-reactive protein (CRP), an independent predictor of future CVD events."
Traditional risk factors account for a majority of CVD risk, but a substantial minority of events remains incompletely explained. In an effort to hone risk prediction, investigators have examined numerous nontraditional factors, especially biomarkers, such as CRP, coronary artery calcium, and homocysteine level.
Studies of homocysteine as a CVD risk factor have yielded inconsistent results. Moreover, previous studies have focused largely on Caucasian populations and patients with pre-existing CVD.
"To date, no study has systematically explored the predictive value of homocysteine beyond existing risk predicted by the Framingham Risk Score (particularly in individuals without overt CVD) or assessed whether homocysteine level contributes to reclassification of individuals in the intermediate-risk Framingham Risk Score category," the authors wrote.
To address limitations of previous studies, Afonso and colleagues examined the risk-prediction value of homocysteine in two data sets: the Multi-Ethnic Study of Atherosclerosis (MESA), a community-based, ethnically diverse cohort of healthy adults; and the Third National Health and Nutrition Examination Survey (NHANES III), a representative sample of the general population.
The authors investigated potential associations of homocysteine with composite CVD and hard CHD events in MESA and with CVD and CHD mortality in NHANES III.
Composite CVD comprised myocardial infarction, resuscitated cardiac arrest, definite angina, probable angina, stroke, stroke death, CHD death, other atherosclerotic death, and other CVD death. A hard CHD event was defined as MI, resuscitated cardiac arrest, or CHD death.
Risk estimates for MESA were based on six years of follow-up. Framingham Risk Score (based on 10-year risk) was adjusted to obtain six-year estimated risk. Patients were assigned to four risk categories: very low, <3%; low, 3% to <6%; intermediate, 6% to 12%; and high, >12%.
The NHANES data set had 15 years of follow-up and was adjusted to obtain 10-year risk estimates: very low, <5%; low, 5% to <10%; intermediate, 10% to <20%; and high, >20%.
The final analyses comprised 6,450 study participants from MESA and 6,797 NHANES III participants.
After adjustment for traditional risk factors and CRP, a homocysteine level >15 µmol/L was associated with a hazard ratio of:
1.79 for composite CVD (P=0.006)
2.22 for CHD events (P=0.01)
2.72 for CVD mortality (P<0.001)
2.61 for CHD mortality (P<0.001)
When added to the Framingham Risk Score, homocysteine led to reclassification of 12.9% and 18.3% of the MESA and NHANES III cohorts overall and to reclassification of 21.2% and 19.2% of the intermediate-risk patients in the MESA and NHANES III cohorts, respectively.
Investigators also analyzed the data sets by means of the net reclassification improvement (NRI) index, using Framingham Risk Score with and without homocysteine. The addition of homocysteine resulted in significant reclassification in the MESA (NRI 0.35, P<0.001) and NHANES III cohorts (NRI 0.57, P<0.001).
The analyses showed increases in the area under the receiver operating characteristic curve of 0.025, indicating a 2.5% increase in probability of an event, indicating a 2.5% improvement, authors of an editorial noted.
"This small increase is typical of models that already contain at least a handful of strong predictors," Arduino A. Mangoni, MD, of the University of Aberdeen in Scotland, and Richard J. Woodman, PhD, of Flinders University in Adelaide, Australia, wrote.
"It is often hard to be convinced that such small changes will translate into meaningful differences in patient management, even if from a public health perspective, changes of this magnitude might be meaningful."
Nonetheless, the study "provides a sound rationale for adding homocysteine in CVD risk assessment," Mangoni and Woodman added. However, they offered several reasons for cautious interpretation of the results:
Framingham Risk Score is not universally accepted for risk assessment
The Framingham model's applicability outside the U.S. has yet to be proven
Use of the Framingham model in the NHANES cohort might have been inappropriate because several participants had a history of MI or cerebrovascular disease
The NRI by itself does not indicate whether reclassification occurred
Afonso and colleagues also acknowledged the study was limited by having a single baseline homocysteine measurement, which could vary based on a number of factors including food intake, position when blood drawn, time of day, as well as cobalamin and folate levels.