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Fibrinogen as a Cardiovascular Risk Factor: A Meta-Analysis and Review of the Literature

Edzard Ernst, MD, PhD; and Karl Ludwig Resch, MD
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From the University of Vienna, Austria.

Copyright 2004 by the American College of Physicians

Ann Intern Med. 1993;118(12):956-963. doi:10.7326/0003-4819-118-12-199306150-00008
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Purpose: To evaluate the possibility that fibrinogen represents a cardiovascular risk factor.

Data Identification: A computerized literature search (1980 to 1992) identified all published epidemiologic studies on fibrinogen and cardiovascular disease. Clinical and basic research data were found by separate searches. References of all papers thus obtained were studied and relevant papers included.

Study Selection: Six prospective epidemiologic studies were included in a meta-analysis (one study was excluded because the study population was nonrepresentative). Clinical papers were reviewed separately for other evidence of causation.

Data Extraction: The correlation of fibrinogen levels on the subsequent incidence of myocardial infarction, stroke, and peripheral arterial occlusive disease was assessed and the causality of the association was analyzed. Calculations were made to examine fibrinogen level (in tertiles) versus cardiovascular risk. Odds ratios of high versus low tertile were computed.

Results of Data Analysis: All prospective studies showed that fibrinogen was associated with subsequent myocardial infarction or stroke. A total of 92 147 person-years was covered by these investigations. Odds ratios varied between 1.8 (95% CI, 1.2 to 2.5) in the Framingham and 4.1 (CI, 2.3 to 6.9) in the GRIPS study, with a summary odds ratio of 2.3 (CI, 1.9 to 2.8). Associations existed between fibrinogen and other cardiovascular risk factors, but after multivariate analysis, only the association between fibrinogen and cardiovascular events remained. The majority of the preconditions for causality were fulfilled, indicating that fibrinogen is pathophysiologically related to cardiovascular events.

Conclusions: Fibrinogen can be considered a major cardiovascular risk factor. Future studies of cardiovascular morbidity and death should include this variable.


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Figure 1.
Cardiovascular events by tertiles of fibrinogen levels in six prospective studies.

Each study is represented by one symbol. Tertiles are connected by lines. Tertiles are defined as follows. Gothenburg: mean value of re-events: myocardial infarction, 3.56 g/mL; stroke, 3.70 g/mL (no standard deviations, no cut-off points provided); Framingham: cut-off points, 2.65 g/mL, 3.12 g/mL; Prospective Cardiovascular Munster Study (PROCAM): cut-off points, 2.22 g/mL; 3.12 g/mL; Northwick Park Heart Study (NPHS): cut-off points, 2.70 g/mL; 3.19 g/mL; the Caerphilly and Speedwell Collaborative Heart Disease Studies (CSCHDS): mean value, 4.09 0.92 g/mL (no cut-off points provided); the Gottingen Risk, Incidence, and Prevalence Study (GRIPS): cut-off points, 3.22 g/mL; 3.91 g/mL.

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Figure 2.
Odds ratios for cardiovascular events in persons with fibrinogen levels in the upper tertile compared to the lower tertile.

Odds ratios and 95% confidence intervals in prospective epidemiologic studies. IHD = ischemic heart disease. CSCHDS = The Caerphilly and Speedwell Collaborative Heart Disease Studies; GRIPS = The Gottingen Risk, Incidence, and Prevalence Study; NPHS = Northwick Park Heart Study; PROCAM = Prospective Cardiovascular Munster Study.

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