Biomarkers Improve Cardiovascular Risk Stratification

By Charles Bankhead ,
UPPSALA, Sweden,15 may 2008-- In older men, a panel of biomarkers associated with heart and kidney disease significantly improved risk stratification for cardiovascular death, investigators here said.
Incorporating four biomarkers into a hazards model that included traditional risk factors improved overall risk prediction (P<0.001) whether the men had cardiovascular disease at baseline or not, Johan Arnlov, M.D., Ph.D., of the University of Uppsala, and colleagues reported in the May 15 issue of the New England Journal of Medicine.
Predictive ability remained significant when the model was evaluated by different statistical methods.
"If these results are validated, the incorporation of these [biomarkers] in clinical practice for the prediction of death from cardiovascular causes could be accomplished quickly, since the measurement of these biomarkers is already well established for diagnostic use," the authors concluded.
Conventional cardiovascular risk factors, such as hypertension and hypercholesterolemia, do not directly reflect clinical conditions associated with an increased risk of cardiovascular death. These conditions include myocardial cell damage, left ventricular dysfunction, renal failure, and inflammation.
Several biomarkers have been shown to increase the risk of cardiovascular events independently of established risk factors, the authors noted. However, the markers have not demonstrated the ability to improve risk stratification of individual patients by area under the receiver-operating-characteristic curve (AUC).
So the researchers sought to determine whether combining four biomarkers with conventional risk factors would improve risk assessment.
The biomarkers chosen were troponin I, N-terminal pro-brain natriuretic peptide, cystatin C, and C-reactive protein.
The study involved 1,135 participants in the Uppsala Longitudinal Study of Adult Men, a community-based cohort of men born from 1920 through 1924. Data for the study came from the third examination cycle of the cohort, when participants' age was approximately 71. Blood samples were obtained at baseline (1991 through 1995) and stored for an average of 11 years.
During a median follow-up of 10 years, 315 participants died; 136 of the deaths were cardiovascular in nature. Investigators found that including the biomarkers in the hazards model improved risk stratification from an AUC of 0.664 with risk factors alone to 0.766 (P<0.001) for the entire cohort.
A separate analysis of 661 men who were free of cardiovascular disease at baseline demonstrated an improvement in AUC from 0.688 to 0.748 (P=0.03).
The authors cautioned that the findings "should not be construed as implying a direct benefit of a reduction in the biomarkers." In contrast to data supporting modification of conventional cardiovascular risk factors, "there is currently little evidence that reducing the levels of the biomarkers will reduce the risk," they said.
The findings indicate that "measurable progress with the use of biomarkers could be possible," James A. de Lemos, M.D., of the University of Texas in Dallas, and Donald M. Lloyd-Jones, M.D., of Northwestern University in Chicago, said in an accompanying editorial.
The study improved on previous attempts to use biomarkers for risk stratification by use of better markers, Drs. de Lemos and Lloyd-Jones said. Each of the four biomarkers used in the study more accurately reflects renal and heart impairment and tissue damage compared with markers examined in previous studies.
The precision of the biomarker panel requires additional work, the editorialists continued. For example, the model inappropriately reclassified 69 patients who did not have cardiovascular disease at baseline.
"These findings need to be validated in younger cohorts of men and women that include only patients who are free of cardiovascular disease and should be updated iteratively as newer and better biomarkers emerge from discovery research programs," Drs. de Lemos and Lloyd-Jones concluded.
The study was supported by grants from the Swedish Research Council, Swedish Heart-Lung Foundation, theErik, Karin, och Gosta Selander Foundation, the Loo och Hans Osterman Foundation, the Ernfors Foundation, the Thuring Foundation, Stiftelsen Sigurd och Elsa Goljes Minne, and Uppsala University. Reagents and assay instruments were supplied by Beckman Coulter and Roche Diagnostics.
Dr. Arnlov reported no conflicts of interest. Dr. de Lemos disclosed grant support and consulting fees from Biosite/Inverness and consulting fees from Roche Diagnostics.
Primary source: New England Journal of MedicineSource reference:Zethelius B, et al "Use of multiple biomarkers to improve the prediction of death from cardiovascular causes" N Engl J Med 2008; 358: 2107-2116. Additional source: New England Journal of MedicineSource reference: de Lemos JA, Lloyd-Jones DM "Multiple biomarker panels for cardiovascular risk assessment" N Engl J Med 2008; 358: 2172-2174.