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Association of Fibrinogen, C-reactive Protein, Albumin, or Leukocyte Count With Coronary Heart Disease: Meta-analyses of Prospective Studies

John Danesh, MBChB, MSc; Rory Collins, MBBS, MSc; Paul Appleby, MSc; Richard Peto, FRS
JAMA. 1998;279(18):1477-1482. doi:10.1001/jama.279.18.1477.
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Context.— A large number of epidemiologic studies have reported on associations between various "inflammatory" factors and coronary heart disease (CHD).

Objective.— To assess the associations of blood levels of fibrinogen, C-reactive protein (CRP), and albumin and leukocyte count with the subsequent risk of CHD.

Data Sources.— Meta-analyses of any long-term prospective studies of CHD published before 1998 on any of these 4 factors. Studies were identified by MEDLINE searches, scanning of relevant reference lists, hand searching of cardiology, epidemiology, and other relevant journals, and discussions with authors of relevant reports.

Study Selection.— All relevant studies identified were included.

Data Extraction.— The following information was abstracted from published reports (supplemented, in several cases, by the authors): size and type of cohort, mean age, mean duration of follow-up, assay methods, degree of adjustment for confounders, and relationship of CHD risk to the baseline assay results.

Data Synthesis.— For fibrinogen, with 4018 CHD cases in 18 studies, comparison of individuals in the top third with those in the bottom third of the baseline measurements yielded a combined risk ratio of 1.8 (95% confidence interval [CI], 1.6-2.0) associated with a difference in long-term usual mean fibrinogen levels of 2.9 µmol/L (0.1 g/dL) between the top and bottom thirds (10.3 vs 7.4 µmol/L [0.35 vs 0.25 g/dL]). For CRP, with 1053 CHD cases in 7 studies, the combined risk ratio of 1.7 (95% CI, 1.4-2.1) was associated with a difference of 1.4 mg/L (2.4 vs 1.0 mg/L). For albumin, with 3770 CHD cases in 8 studies, the combined risk ratio of 1.5 (95% CI, 1.3-1.7) was associated with a difference of 4 g/L (38 vs 42 g/L, ie, an inverse association). For leukocyte count, with 5337 CHD cases in the 7 largest studies, the combined risk ratio of 1.4 (95% CI, 1.3-1.5) was associated with a difference of 2.8×109/L (8.4 vs 5.6×109/L). Each of these overall results was highly significant (P<.0001).

Conclusions.— The published results from these prospective studies are remarkably consistent for each factor, indicating moderate but highly statistically significant associations with CHD. Hence, even though mechanisms that might account for these associations are not clear, further study of the relevance of these factors to the causation of CHD is warranted.

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Figure 1.—Prospective studies of fibrinogen and coronary heart disease. Risk ratios compare top and bottom thirds of baseline measurements. For all figures, black squares indicate the risk ratio in each study, with the square size proportional to the number of cases and the horizontal lines representing the 99% confidence intervals (CI). The combined risk ratio and its 95% CI are indicated by unshaded diamonds for subtotals and by shaded diamonds for grand totals. NR indicates not reported; +, adjustment for age and sex only; ++, for these plus smoking; +++, for these plus some other standard vascular risk factors; ++++, for these plus markers of social class; and +++++, for these plus information on chronic disease at baseline.
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Figure 2.—Prospective studies of C-reactive protein and coronary heart disease. Risk ratios compare top and bottom thirds of baseline measurements. The legend to Figure 1 explains the symbols.
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Figure 3.—Prospective studies of albumin and coronary heart disease. Risk ratios compare bottom and top thirds of baseline measurements. The legend to Figure 1 explains the symbols.
Graphic Jump Location
Figure 4.—Prospective studies of leukocyte count and coronary heart disease. Risk ratios compare top and bottom thirds of baseline measurements. The legend to Figure 1 explains the symbols.

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