Hyperfibrinogenemia is an independent risk factor for cardiovascular events in stroke survivors. Intervention trials with fibrinogen lowering measures may be warranted.

The hypothesis that fibrinogen is closely related to cardiovascular risk has been strengthened through the results of various lines of research, which this review will aim to unravel. Several prospective epidemiological studies convincingly show elevated fibrinogen to represent a major, independent cardiovascular risk factor. Cross-sectional studies strongly associate fibrinogen and conventional cardiovascular risk factors. Clinical cohort studies demonstrate that increased fibrinogen is also a risk factor for the sequelae of cardiovascular disease. Our knowledge about the determinants of the variable plasma level of fibrinogen in health and disease is incomplete. Understanding of the mechanisms that might be involved in the atherothrombogenic action of fibrinogen is also fragmentary. Fibrinogen strongly affects blood coagulation, blood rheology and platelet aggregation. In addition, it has direct effects on the vascular wall and is a prominent acute phase reactant. All of these phenomena might constitute pathophysiological mechanisms involved in the association between fibrinogen and cardiovascular events. Their relative importance is unclear at present. Even though many crucial questions await conclusive answers, little doubt exists that fibrinogen represents a major, independent risk factor.

A causal link between plasma fibrinogen levels and the risk of cardiovascular disease is now reasonably well established. Therefore the therapeutic lowering of fibrinogen has become a relevant area of research. Several options to achieve this aim have been reported in the literature. Changes in lifestyle can affect the fibrinogen level, of which smoking cessation is by far the most effective; weight or stress reduction or an increase in regular physical activity may have less pronounced effects; dietary changes appear to have even less effect, though a regular, moderate alcohol consumption may result in a small reduction. Many oral drugs have been shown to lower fibrinogen; however, the data should be viewed critically. In particular, the clinical situation in which a drug is administered must be considered and risk:benefit analyses should be performed before a drug is recommended for this indication. Among the oral fibrinogen-lowering drugs, fibrates rank first (e.g. bezafibrate has been reported to reduce increased fibrinogen by as much as 40%, and ticlopidine can induce a reduction of about 15% if fibrinogen was elevated at baseline). Whether concentration within the normal range can be altered by oral medication is less clear. Finally (and obviously), intravenous fibrinolytic agents or heparin-induced extracorporeal low-density lipoprotein precipitation will lower fibrinogen dramatically; yet these procedures are rarely indicated for this purpose alone. All options to lower fibrinogen also have prominent effects on other cardiovascular functions; thus, an intervention trial may not be the most appropriate method of testing the validity of the hypothesis of fibrinogen as a cardiovascular risk factor.

Pentoxifylline was first introduced in Germany twenty years ago. Today it is the best researched oral drug for intermittent claudication. A total of seventeen placebo-controlled trials could be retrieved from the world literature. The majority of these studies show that pentoxifylline will prolong the walking distance in a statistically significant way. Even though these trials are conducted with considerable scientific rigor, important flaws can be identified. Whether the symptomatic improvement is clinically relevant is difficult to say and may depend on the patient's individual situation. These collective data show that pentoxifylline prolongs the walking distance in patients with intermittent claudication.

Summary. Several studies have reported a strong association between various markers of the acute-phase response and death from cardiovascular diseases and all-cause mortality. Inflammation at a low level of intensity may be a common phenomenon associated with the majority of causes of death owing to chronic diseases. We sought to investigate the association of plasma viscosity with all-cause mortality in a cohort of apparently healthy men. The study population consisted of 964 men aged 45±64 years at entry, randomly selected from the general population and taking part in the first MONICA±Augsburg survey 1984±85. The main outcome measure was all-cause mortality. During 8 years of follow-up, there were 81 deaths (37 cardiovascular deaths, 23 deaths from cancer and 21 deaths from other causes). There was a strong positive and statistically significant ageadjusted relationship between plasma viscosity and all-cause mortality. The relative risk of death for a one standard deviation increase in plasma viscosity (0´070 mPa/s) was 1´45 [95% confidence interval (CI) 1´19±1´76]. After further adjusting for smoking, total cholesterol, body mass index, blood pressure and education, a relative risk of 1´41 (95% CI 1´14±1´74) resulted. Other risk variables had only negligible confounding effects. The relative risk of the median of the top quintile of the plasma viscosity distribution compared with the median of the bottom quintile, computed from the adjusted model, was 2´68 (95% CI 1´63±4´42). These findings suggest that plasma viscosity may have considerable potential to predict death from all causes in middle-aged men.