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October 12, 2005

Plasma Fibrinogen Level and the Risk of Major Cardiovascular Diseases and Nonvascular MortalityAn Individual Participant Meta-analysis

Author Affiliations

*Authors/Writing Committee of the Fibrinogen Studies Collaboration: John Danesh, DPhil, Department of Public Health and Primary Care, University of Cambridge, Cambridge, England; Sarah Lewington, DPhil, Clinical Trial Service Unit, University of Oxford, Oxford, England; Simon G. Thompson, DSc, Medical Research Council Biostatistics Unit, Institute of Public Health, Cambridge, England; Gordon D. O. Lowe, FRCP, Division of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland; Rory Collins, FMedSci, Clinical Trial Service Unit, University of Oxford, Oxford, England.

Authors/Members of the Fibrinogen Studies Collaboration:AMIS: J. B. Kostis, A. C. Wilson. Atherosclerosis Risk in Communities Study: A. R. Folsom, K. Wu. BIP Registry: M. Benderly, U. Goldbourt. Bruneck Study: J. Willeit, S. Kiechl. Caerphilly Study: J. W. G. Yarnell, P. M. Sweetnam, P. C. Elwood (this prospective cohort study was undertaken by the former UK Medical Research Council Epidemiology Unit [South Wales] and was funded by the Medical Research Council/Institute of Public Health; its data archive is maintained by the Department of Social Medicine, University of Bristol). Cardiovascular Health Study: M. Cushman, B. M. Psaty, R. P. Tracy (see http://chs-nhlbi.org for acknowledgments). Copenhagen City Heart Study: A. Tybjærg-Hansen. ECAT Angina Pectoris Study: F. Haverkate, M. P. M. de Maat, S. G. Thompson. Edinburgh Artery Study & Edinburgh Claudication Study: F. G. R. Fowkes, A. J. Lee, F. B. Smith. FINRISK 1992 Hemostasis Study: V. Salomaa, K. Harald, V. Rasi, E. Vahtera, P. Jousilahti, J. Pekkanen. Framingham Study: R. D’Agostino, W. B. Kannel, P. W. F. Wilson, G. Tofler. FRECVE: C. L. Arocha-Piñango, A. Rodriguez-Larralde, E. Nagy, M. Mijares, R. Espinosa, E. Rodriquez-Roa, E. Ryder, M. P. Diez-Ewald, G. Campos, V. Fernandez, E. Torres, E. Coll. GISSI Prevenzione: R. Marchioli, F. Valagussa. Göteborg 1913 & Göteborg 1933: A. Rosengren, L. Wilhelmsen, G. Lappas, H. Eriksson. GRIPS Study: P. Cremer, D. Nagel. Honolulu Heart Program: J. D. Curb, B. Rodriguez, K. Yano. Kuopio IHD Study: J. T. Salonen, K. Nyyssönen, T.-P. Tuomainen. Malmö: B. Hedblad, P. Lind. MONICA/KORA-Augsburg: H. Loewel, W. Koenig. Northwick Park Heart Study I: T. W. Meade, J. A. Cooper, B. De Stavola, C. Knottenbelt. Northwick Park Heart Study II: G. J. Miller, J. A. Cooper, K. A. Bauer, R. D. Rosenberg. Osaka Study: S. Sato, A. Kitamura, Y. Naito, H Iso. Platelet Activation and Inflammation Study: V. Salomaa, K. Harald, V. Rasi, E. Vahtera, P. Jousilahti, T. Palosuo. PRIME Study: P. Ducimetiere, P. Amouyel, D. Arveiler, A. E. Evans, J. Ferrieres, I. Juhan-Vague, A. Bingham. PROCAM Study: H. Schulte, G. Assmann. Quebec Cardiovascular Study: B. Cantin, B. Lamarche, J.-P. Després, G. R. Dagenais. Scottish Heart Health Study: H. Tunstall-Pedoe, G. D. O. Lowe, M. Woodward. Speedwell: Y. Ben-Shlomo, G. Davey Smith. Strong Heart Study: V. Palmieri, J. L. Yeh. Thrombosis Prevention Trial: T. W. Meade, A. Rudnicka, C. Knottenbelt, J. A. Cooper. US Physicians Health Study: P. Ridker. VITA: F. Rodeghiero, A. Tosetto. West of Scotland Coronary Prevention Study: J. Shepherd, G. D. O. Lowe, I. Ford, M. Robertson. Whitehall II: E. Brunner, M. Shipley. Zutphen Elderly Study: E. J. M. Feskens, D. Kromhout.

Authors/Independent Statistical Analyses/Secretariat: Data management and statistical analyses were supervised and conducted by the following team of academic epidemiologists, statisticians, programmers, and data managers: R. Collins, J. Danesh (coordinator and corresponding author), A. Dickinson, B. Ireland, K. Juzwishin, S. Kaptoge, S. Lewington, G. D. O. Lowe, A. Memon, N. Sarwar, S. G. Thompson, M. Walker, J. Wheeler, I. White, A. Wood.

Other Members of the Fibrinogen Studies Collaboration: P. Brennan, L. Chambless, H. W. Hense, D. Levy.

JAMA. 2005;294(14):1799-1809. doi:10.1001/jama.294.14.1799

Context Plasma fibrinogen levels may be associated with the risk of coronary heart disease (CHD) and stroke.

Objective To assess the relationships of fibrinogen levels with risk of major vascular and with risk of nonvascular outcomes based on individual participant data.

Data Sources Relevant studies were identified by computer-assisted searches, hand searches of reference lists, and personal communication with relevant investigators.

Study Selection All identified prospective studies were included with information available on baseline fibrinogen levels and details of subsequent major vascular morbidity and/or cause-specific mortality during at least 1 year of follow-up. Studies were excluded if they recruited participants on the basis of having had a previous history of cardiovascular disease; participants with known preexisting CHD or stroke were excluded.

Data Extraction Individual records were provided on each of 154 211 participants in 31 prospective studies. During 1.38 million person-years of follow-up, there were 6944 first nonfatal myocardial infarctions or stroke events and 13 210 deaths. Cause-specific mortality was generally available. Analyses involved proportional hazards modeling with adjustment for confounding by known cardiovascular risk factors and for regression dilution bias.

Data Synthesis Within each age group considered (40-59, 60-69, and ≥70 years), there was an approximately log-linear association with usual fibrinogen level for the risk of any CHD, any stroke, other vascular (eg, non-CHD, nonstroke) mortality, and nonvascular mortality. There was no evidence of a threshold within the range of usual fibrinogen level studied at any age. The age- and sex- adjusted hazard ratio per 1-g/L increase in usual fibrinogen level for CHD was 2.42 (95% confidence interval [CI], 2.24-2.60); stroke, 2.06 (95% CI, 1.83-2.33); other vascular mortality, 2.76 (95% CI, 2.28-3.35); and nonvascular mortality, 2.03 (95% CI, 1.90-2.18). The hazard ratios for CHD and stroke were reduced to about 1.8 after further adjustment for measured values of several established vascular risk factors. In a subset of 7011 participants with available C-reactive protein values, the findings for CHD were essentially unchanged following additional adjustment for C-reactive protein. The associations of fibrinogen level with CHD or stroke did not differ substantially according to sex, smoking, blood pressure, blood lipid levels, or several features of study design.

Conclusions In this large individual participant meta-analysis, moderately strong associations were found between usual plasma fibrinogen level and the risks of CHD, stroke, other vascular mortality, and nonvascular mortality in a wide range of circumstances in healthy middle-aged adults. Assessment of any causal relevance of elevated fibrinogen levels to disease requires additional research.