Fibrinogen, a cardiovascular risk factor

The notion that fibrinogen is related to cardiovascular diseases was first voiced in the 1950s [1-4], when its level was found to be increased in patients with ischemic heart disease. During the last decade, substantial evidence has accumulated suggesting that fibrinogen represents a major risk factor for cardiovascular disease [5]. Most importantly, several prospective trials revealed that fibrinogen has a strong predictive power, and numerous pathways have been identified through which fibrinogen can promote atherothrombosis [6]. Much of this relatively new knowledge is not yet generally accepted. Our aims, therefore, are to perform a meta-analysis of the existing prospective epidemiologic trials, to discuss clinical findings related to fibrinogen, and to consider the causality of the association of fibrinogen and cardiovascular disease. A computerized literature search (1980 to 1992) identified all epidemiologic studies on the topic. Nonepidemiologic investigations were retrieved by similar searches. All papers were then scanned for further relevant references. We included all prospective epidemiologic studies in our review. Because other types of investigation are too numerous to be all admitted, we selected them based on clinical relevance and study design. Prospective Epidemiologic Data Seven epidemiologic studies have so far provided prospective data on fibrinogen and cardiovascular disease. Table 1 summarizes their methods and Table 2 shows their main results. In the Northwick Park Heart Study, white men aged 40 to 64 years were tested for a range of clotting factors, including fibrinogen. The sample was drawn from factory workers, from civil servants, and from postal workers; the participation rate was approximately 80%. Pre-existing disease was not an exclusion criterion. Follow-up of 4 years (a review by an independent panel of physicians [7]), showed that 49 persons had died, 27 from cardiovascular disease. Fatal coronary events and fibrinogen were significantly associated, which was independent of other risk factors and stronger than the analogous association for total cholesterol. Other causes of death were not related to fibrinogen levels. Fifteen of the 24 patients who died of ischemic heart disease were in the high tertile of fibrinogen (>3.2 g/L). At 10 years' follow-up [8], 109 men had had a first coronary event. Multiple regression analyses showed an association between fibrinogen and fatal or nonfatal myocardial infarction, which was again independent of other risk factors. Approximately half of all the coronary events occurred in the high tertile of fibrinogen. The association was strongest for events occurring early ( 5 years) after recruitment. Table 1. Methods of the Prospective Epidemiologic Studies of Fibrinogen Table 2. Results of the Prospective Epidemiologic Studies of Fibrinogen In the Speedwell Study, the baseline fibrinogen level, measured in parallel by two different methods, was positively associated with prevalent ischemic heart disease and its risk factors [9]. The study was later expanded into the Caerphilly Speedwell Collaborative Heart Disease Studies [10]. Its baseline data revealed a strong association of smoking with fibrinogen. In fact, all studies have confirmed this inter-relationship. The prospective evaluation of this investigation with an average follow-up of 5.1 and 3.2 years, respectively, included a total of 251 major coronary events [11]. A multivariate analysis showed that fibrinogen was an independent risk factor. Its predictive power was comparable to, if not stronger than, that of a set of accepted risk factors, total cholesterol, blood pressure, and body mass index. In the Gothenburg Study [12], fibrinogen, blood pressure, total cholesterol, and smoking habits were quantified in a random sample of men born in 1913. Eighty-one percent of the target population, then aged 54 years, were recruited. After a mean follow-up period of 13.5 years, there had been 92 myocardial infarctions, 37 strokes, and 60 deaths due to noncardiovascular causes. These events had been verified by a combination of interviews, review of medical records, death certificates, autopsies, as well as registers for myocardial infarction and stroke. The autopsy rate was more than 80%. Univariate analyses identified smoking, cholesterol, and fibrinogen as risk factors for ischemic heart disease, whereas blood pressure and fibrinogen were risk factors for stroke. In a multivariate analysis (adjusting for blood pressure, cholesterol, and smoking), the association between fibrinogen and cardiovascular disease was weaker but still statistically significant for stroke. The study was recently extended to a 21-year follow-up, during which time 119 myocardial infarctions, 81 strokes, and 333 deaths due to other causes had occurred [13]. Fibrinogen was again positively associated with the incidence of ischemic heart disease in a univariate analysis, whereas in the multivariate evaluation, stroke and total mortality rate were statistically associated with fibrinogen. The strength of this study is the completeness of its data collection. The sampling method used makes it likely that a representative sample of Swedish men was recruited. The study is, however, prone to type 2 error because of the small sample size. No exclusions were made for treated pre-existing disease; therefore the possibility of a confounding effect of therapy on baseline measurements is conceivable. For the Leigh study, men aged 40 to 69 years, initially free of ischemic heart disease, diabetes, or hypertension, were recruited from one general practice in the United Kingdom [14]. Of all men eligible (n = 505), 76% were examined, whereas the rest were excluded. After a mean follow-up of 7.3 years (range, 0.1 to 16.1 years), 40 cases of myocardial infarction had occurred. Fibrinogen was positively correlated with its incidence. In hypertensive patients, for instance, the incidence was six times higher when fibrinogen levels exceeded 3.5 g/L compared to the subpopulation with values below this threshold. Multivariate analyses showed that the predictive power of all variables, in descending order, were fibrinogen, age, systolic blood pressure, total cholesterol, obesity, number of cigarettes smoked per day, and very-low-density lipoprotein levels. The odds ratio of the high compared with the low fibrinogen tertile was quite large: 21.1 (CI, 4.5 to 64.4). Unfortunately the study is burdened with serious drawbacks: It deals with a highly selected population, includes only 76% of the target population, and has a very nonuniform follow-up period; thus its results are difficult to generalize. The study has therefore been excluded from the meta-analysis. The tenth biennial examination of the Framingham Study evaluated the interrelation of fibrinogen with smoking. Participants with a history of cardiovascular disease were excluded from this analysis. The average age at baseline was 55 years (range, 47 to 79 years). The results confirmed a dose-dependent increase in fibrinogen with smoking [15]. During a 14-year follow-up period (starting in 1968), the risk for cardiovascular disease in men and women increased quasi-linearly as a function of initial fibrinogen levels. The age-adjusted incidence in male smokers with high fibrinogen levels was doubled compared with a low-fibrinogen subgroup. As in the Northwick Park Heart Study [7, 8], the effect was more pronounced in younger men. Using the same data, fibrinogen was shown to be a risk factor for ischemic heart disease, independent of smoking or other accepted risk factors [16]. In women, the magnitude of the fibrinogen-mediated risk declined with age and had no apparent effect beyond the age of 70 years. Fibrinogen was also a risk factor for stroke in men, but not in women. The relative effect of fibrinogen was comparable to that of high blood pressure, obesity, smoking, or diabetes. A further analysis of the Framingham material [17] revealed that in men the fibrinogen risk ratio was greatest for stroke, intermediate for myocardial infarction, and smallest for peripheral arterial occlusive disease. For women, the risk ratio was greatest for ischemic heart disease. The PROCAM study [18] examined men aged 40 to 65 years who had no history of myocardial infarction or stroke. Its design is similar to that of the Framingham Study. The PROCAM study was started in 1979, and only in 1981 was fibrinogen added to the test battery. Fifteen cardiovascular events were observed in a subsample of 1674 men during 2 years of follow-up. They were verified by questionnaire, re-examination, and by questioning families, family doctors, and hospital representatives. Ten of these events fell into the high fibrinogen tertile. When this trial was extended to 2817 men, also followed for 2 years, 55 coronary events had occurred. Twenty-nine were located in the upper and 10 were in the lowest fibrinogen tertile [19]. These reports are still preliminary in character; so far only subgroup analyses have been published. Because approximately 20 000 persons were included in the original sample, one would expect important data to be published in the near future. The above studies either did not consider low-density lipoprotein (LDL) in their statistical models or quantified this variable by inadequate methods. Because LDL is one of the strongest predictors of ischemic heart disease, the predictive power of fibrinogen might have been overestimated by previous investigators. The GRIPS Study [20], a prospective cohort study on a random, population-based sample of men aged 40 to 60 years and initially free of cardiovascular disease, attempted to overcome this drawback. One hundred seven myocardial infarctions had occurred after 5 years of follow-up. Fibrinogen was a strong predictor in an univariate model. Using a multivariate regression model, which accounted for LDL, the relationship weakened, although it remained statisticall