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

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

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Figures

Figure 1. Age-Specific, Sex- and Cohort-Adjusted Hazard Ratios for Cardiovascular Disease and Nonvascular Mortality by Fifths of Usual Fibrinogen Level
Graphic Jump Location

Fifths of usual fibrinogen level were calculated within each study. Curves are fitted by log-linear regression lines. CI indicates confidence interval; HR, hazard ratio. The size of the data markers is proportional to the inverse of the variances of the HR estimates.

Figure 2. Age-Specific Hazard Ratios for Cardiovascular Disease and Nonvascular Mortality per 1-g/L Increase in Usual Fibrinogen Level
Graphic Jump Location

Fibrinogen level adjusted for age at screening and stratified on sex, cohort, and trial group. CI indicates confidence interval. The size of the data markers is proportional to the inverse of the variances of the hazard ratios.

Figure 3. Hazard Ratios for Cardiovascular Disease and Nonvascular Mortality per 1-g/L Increase in Usual Fibrinogen Level
Graphic Jump Location

Fibrinogen level adjusted for age at screening and stratified by sex, cohort, and trial group. CI indicates confidence interval; COPD, chronic obstructive pulmonary disease. The size of the data markers is proportional to the inverse of the variances of the hazard ratios.
*Includes International Classification of Diseases, 10th Revision (ICD-10) codes C00-C02 for cancer of the lip and tongue; ICD-10 codes C03-C06 for cancer of the gum, mouth, and palate; ICD-10 codes C09-C14 for cancer of the tonsil, oropharynx, nasopharynx, pyriform sinus, and hypopharynx; ICD-10 code C22 for cancer of the liver and intrahepatic bile; ICD-10 code C25 for cancer of the pancreas; ICD-10 codes C30-C34 for cancer of the nasal cavity and middle ear, larynx, trachea, and bronchus and lung; ICD-10 code C53 for cancer of the cervix uteri; ICD-10 codes C64-C68 for cancer of the kidney, renal pelvis, ureter, and bladder; and ICD-10 code C92 for cancer of the myeloid leukemia.
†Includes ICD-10 codes C17-C21 for cancer of the small intestine, rectosigmoid junction, rectum, and anus; ICD-10 codes C23-C24 for cancer of the gallbladder and biliary tract.
‡Includes ICD-10 code C50 for cancer of the breast; ICD-10 codes C54-C56 for cancer of the corpus uteri, uterus, and ovary; ICD-10 codes C61-C62 for cancer of the prostate and testis; and ICD-10 code C73 for cancer of the thyroid gland.
§Includes ICD-10 codes S00-T98 for injury, poisoning, and certain other consequences of external cause and ICD-10 codes V01-98 for morbidity and mortality.

Figure 4. Adjusted Hazard Ratios for Coronary Heart Disease per 1-g/L Increase in Usual Fibrinogen Level
Graphic Jump Location

Adjusted for age at screening, smoking status, systolic blood pressure, total cholesterol, and body mass index and stratified by sex, cohort, and trial group. CI indicates confidence interval. The size of the data markers is proportional to the inverse of the variances of the hazard ratios.
*Osaka cohort has been excluded from geographical location.
†Relates to time following blood collection.
‡Tertiles of total cholesterol, triglycerides, systolic blood pressure, and body mass index were defined by their respective distributions among coronary heart disease cases.
§Calculated as weight in kilograms divided by height in meters squared.

Figure 5. Adjusted Hazard Ratios for Stroke per 1-g/L Increase in Usual Fibrinogen Level
Graphic Jump Location

Adjusted for age at screening, smoking status, systolic blood pressure, total cholesterol, and body mass index and stratified by sex, cohort, and trial group. CI indicates confidence interval. The size of the data markers is proprotional to the inverse of the variances of the hazard ratios.
*Osaka cohort has been excluded from geographical location.
†Relates to time following blood collection.
‡Tertiles of total cholesterol, triglycerides, systolic blood pressure, and body mass index were defined by their respective distributions among coronary heart disease cases.
§Calculated as weight in kilograms divided by height in meters squared.

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