Clinical Laboratory Strategies: February 28, 2008
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Predicting Short-term Mortality from Nontraditional Factors
Inflammation, Thrombosis Biomarkers May Foretell Risk

By Phil Kibak

Traditional cardiovascular disease risk factors, such as serum cholesterol levels, hypertension, and diabetes are reliable predictors of late-term cardiovascular events but they are relatively poor at foretelling near-term events. This issue of Strategies examines a recent study suggesting that increases in serum biomarkers of inflammation and thrombosis are associated with elevated risk for short-term cardiovascular mortality and all-cause mortality in patients with peripheral artery disease (PAD), a condition that raises the risk of heart attack or stroke.

New research from a multicenter team of scientists suggests that measuring serum levels of three biomarkers—D-dimer, CRP, and serum amyloid A— may predict the short-term outcome of patients with PAD, which, if confirmed by future studies, could help guide patient management (Ann Intern Med  2008; 148: 85–93).

Room for Nontraditional Risk Factors

“We followed these patients annually, and we found that those who had high levels of CRP, D-dimer, and serum amyloid A were at higher risk of death from all causes during the first year after measurement of these markers, as well as during the interval between the first and second year after marker measurement,” said Mary McDermott, MD, Associate Professor of Medicine and Preventive Medicine at Northwestern University Feinberg School of Medicine in Chicago, and one of the researchers who conducted the study. “But those high levels were not associated with an increased risk of all-cause mortality between the second and third year after measurement. For cardiovascular mortality, the findings were similar for CRP and serum amyloid A, but high levels of D-dimer did predict an increased risk of death for all three follow-up intervals studied.”

McDermott and her colleagues measured levels of these biomarkers in 377 PAD patients annually for 3 years. By the end of the study, 76 patients had died, 31 from cardiovascular disease. Higher levels of D-dimer, CRP, and serum amyloid A were associated with higher all-cause mortality among patients who died within 1 year of biomarker measurement (hazard ratio [HR] 1.20, 1.13, and 1.12, respectively) and among patients who died 1–2 years after biomarker measurement (HR 1.14, 1.15, and 1.13, respectively). Analyses for all-cause mortality were adjusted for age, sex, race, diabetes mellitus, smoking, ankle-brachial index, number of other cardiovascular diseases, and cancer. Analyses for cardiovascular mortality were adjusted for the same factors except cancer.

“Several other studies that looked at baseline measurements of these markers but did not follow up with annual measures also have shown that the relationship between high levels of them and the risk of cardiovascular events is stronger in the short term,” explained McDermott. “Our study is preliminary and the small numbers limited our statistical power to fully examine these relationships. Therefore, we think it’s too early to say that clinicians should start measuring these markers annually and use the results to guide short-term therapy. But the findings are intriguing because they’re different from what we know about traditional risk factors and long-term versus short-term outcome.”

Cholesterol, hypertension, and diabetes are predictive of cardiovascular events and mortality over a much longer time, and these can be targeted for long-term prevention, explained McDermott. “But a high serum total cholesterol is not a very good indicator of the risk of a cardiovascular event in the next year. In fact, as people become more frail late in life, we can find a confounding effect, that their cholesterol levels tend to get lower.”

Ready for Clinical Use?

“This is a very elegant study and it adds to the totality of evidence that inflammation does play a role in the development of cardiovascular disease and acute cardiac events, but it doesn’t change the way physicians are going to practice,” said Roger S. Blumenthal, MD,  Professor of Medicine and Director of the Ciccarone Preventive Cardiology Center at The Johns Hopkins Medical Institutions in Baltimore, Md. “Physicians and patients need to take better control of those things that can be controlled, such as use of aspirin-like drugs to reduce the risk of clot formation, hypertension and cholesterol management, improved dietary habits, smoking cessation, and exercise.”

He added that the findings of the study could likely be extended beyond people with PAD to the general population. “There’s other data showing that CRP can help to predict which people would be expected to experience heart attack or stroke over the next 5–10 years. This extends the data to include different biomarkers, such as D-dimer, which is already known to be a good predictor of deep vein thrombosis or pulmonary embolism.”

Joseph McConnell, PhD, Laboratory Director in Cardiovascular Laboratory Medicine at the Mayo Clinic and Foundation in Rochester, Minn. agrees that more studies are needed to extend these findings and that the results of this study should not affect current clinical practice. He stated that “it does, however, point out that different markers may be used to assess different aspects of cardiovascular disease, some predicting near-term risk for events or death, while others like traditional lipid analyses reflect the extent of atherogenesis and more long-term risk.”

McConnell, who is a past chair of the AACC’s Lipoproteins and Vascular Diseases Division, cited a study he and his colleagues conducted in which they correlated biomarkers to angiographic coronary artery disease and events in 504 patients who underwent clinically indicated angiography and were followed for 4 years (Eur Heart J  2005;  26(2): 137–144). “We found that markers associated with events were completely different from those associated with angiographic coronary disease. Traditional markers like lipids and apolipoproteins were associated with atherosclerotic burden but not with cardiac events, while markers of inflammation like CRP, fibrinogen, and Lipoprotein-associated phospholipase A2 were associated with outcomes, such as death, MI, stroke, and revascularization. The findings in this Annals of Internal Medicine report and in the Mayo study lend support to the hypothesis that near-term events may be best predicted by these inflammatory or thrombosis markers and not traditional lipid measures. As pointed out by the authors, this clearly needs further study to elucidate possible mechanisms and to determine if clinical intervention is clinically effective.” 

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