Fibrinogen as a risk factor for coronary heart disease and mortality in middle-aged men and women

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1 European Heart Journal (998) 9, 55 6 as a risk factor for coronary heart disease and mortality in middle-aged men and women The Scottish Heart Health Study M. Woodward*, G. D. O. Lowe, A. Rumley and H. Tunstall-Pedoe* *Cardiovascular Epidemiology Unit, University of Dundee, Dundee, Scotland; Department of Applied Statistics, University of Reading, Reading; University Department of Medicine, Glasgow Royal Infirmary, Glasgow, Scotland, U.K. Aims was measured in 5095 men and 4860 men aged in a random population sample from 5 districts of Scotland recruited during : the Scottish Heart Health Study. was then related to the chance of fatal and non-fatal coronary events and death from any cause during a subsequent follow-up period of around 8 years. Methods and results was measured by the Clauss assay. The effect of fibrinogen on coronary heart disease and death was assessed through age-adjusted means and Cox proportional hazards regression models, accounting for age, cotinine (a measure of tobacco smoke inhalation) and other major coronary risk factors. was found to be an important risk factor for coronary heart disease in men and women, with and without pre-existing coronary heart disease. There appears to be a threshold effect, with those in the highest fifth of the distribution having a much increased risk. Estimated ageadjusted hazard ratios by sex and pre-existing coronary heart disease group for the highest to lowest fifth of fibrinogen range between 9 and is also important as a risk factor for coronary death and all-causes mortality, with a similar threshold effect. Comparing the two extreme fifths, the hazard ratios for coronary death are 0 and 4, and for all-cause mortality are 59 and 0, for men and women respectively. Adjustment for cotinine reduces the hazard ratios, but further adjustment for the other risk factors has little effect for coronary heart disease events. After full adjustment there is a remaining significant (P<0 05) hazard ratio for coronary death and death from any cause and for a coronary heart disease event for those free of coronary heart disease at baseline, amongst men, comparing the highest to the lowest fifth. Conclusion is a strong predictor of coronary heart disease, fatal or non-fatal, new or recurrent, and of death from an unspecified cause, for both men and women. Its effect is only partially attributable to other coronary risk factors, the most important of which is smoking. (Eur Heart J 998; 9: 55 6) Key Words:, coronary heart disease, all-causes mortality. Introduction There is increasing interest in the role of fibrinogen in the pathogenesis of cardiovascular disease, including coronary heart disease [ 4]. Seven prospective studies [5 ] have each observed an increase in incident coronary heart disease risk with increasing plasma fibrinogen level: meta-analyses suggest an odds ratio of in the upper third compared to the lowest third of fibrinogen distributions [,4]. Several issues remain to be addressed. First, the different fibrinogen risk profiles for fatal and Revision submitted 5 May 997, and accepted 6 May 997. Correspondence: Professor H. Tunstall-Pedoe, Cardiovascular Epidemiology Unit, Ninewells Hospital, Dundee DD 9SY, Scotland, U.K X/98/ $8.00/0 hj97057 non-fatal coronary heart disease events and for allcauses mortality: a study with a large number of these events is required to answer this. Second, the different risk profiles in men and women: only one previous report has included women, many of whom were elderly [9]. Third, the different risk profiles in persons with and without baseline evidence of coronary heart disease: only one previous report has addressed this question, and only in men [0]. Fourth, the predictive value of fibrinogen, within important medical subgroups, when measured by an assay which is widely used in routine laboratories: only one previous study [] has used the routine Clauss assay [], which shows good interlaboratory agreement [4] and for which an International Standard is now available [5]. Finally, the possible interactions between fibrinogen and the three major risk 998 The European Society of Cardiology

2 56 M. Woodward et al. factors for coronary heart disease: serum total cholesterol, blood pressure and tobacco inhalation. Interactions between fibrinogen and cholesterol [], blood pressure [7] and smoking habit [6] have been suggested in some previous studies. Again, large numbers are required to provide evidence of interaction. We have addressed these questions in the Scottish Heart Health Study (SHHS): a large random sample of middle-aged men and women in Scotland [7]. Plasma fibrinogen was measured by the Clauss assay: we have previously reported its distributions and relationships to baseline variables in the majority (but not the totality) of the SHHS population [7 0]. We have also previously presented brief overviews of the ageadjusted effects in the SHHS of 7 lifestyle and risk factors (including fibrinogen) for coronary heart disease and death. [] Subject and methods Recruitment and baseline procedures have been described previously [7,8,]. Briefly, men and women aged were recruited, between , from general practitioner lists in 5 districts of Scotland by random sampling. Each subject received a set of questions by post, which included a food-frequency questionnaire [], the Bortner type A personality scoring system [4], the Rose chest pain questionnaire [5] and questions about physical activity. They later attended a local clinic where trained project nurses administered various procedures including height, weight and blood pressure measurements, blood collection and a -lead electrocardiogram (ECG). Total and HDL-cholesterol, triglycerides and cotinine (an objective measure of tobacco smoke inhalation [6] ) were measured in serum. Plasma fibrinogen was measured in stored ( 40 C) citrated plasma samples by the Clauss assay [] in a Coag-A-Mate X semi-automated coagulometer, using the manufacturer s reagents and standards (Organon Teknika, Cambridge, U.K.). Internal quality control was performed by regular analyses of stored plasma aliquots, and was satisfactory during the assay period. External quality control, through the UK-NEQAS scheme, was also satisfactory. Assays were performed in , prior to the introduction of the first fibrinogen international standard in 99 [5]. At baseline, subjects were classified positive for myocardial infarction if they reported a previous doctor diagnosis or if they exhibited Q/QS patterns on their ECG [7]. Subjects who were not positive for myocardial infarction but reported a previous doctor diagnosis of angina or gave the appropriate sequence of answers to the Rose chest pain questionnaire [5] were classified positive for angina. Subjects who were either positive for myocardial infarction, positive for angina or otherwise exhibited symptoms of ischaemia on their ECG [7] or gave answers to the Rose chest pain questionnaire that are indicative of possible myocardial infarction [5] were classified positive for baseline coronary heart disease. Information on hospital discharges and operations up to the end of 99 was obtained from the Information and Statistics Division of the Common Services Agency in Edinburgh, and case records were requested for verification from the hospitals concerned. Copies of death certificates were collected over the same period. This gave data over an average of 7 7 years of follow-up. A coronary heart disease event at follow-up can either be non-fatal or fatal. Non-fatal events arise from either diagnosis of myocardial infarction at hospital, using WHO MONICA criteria [8], or coronary artery surgery (coronary artery bypass graft or percutaneous coronary angioplasty). We define all coronary heart disease to include coronary death, non-fatal infarction and coronary artery surgery with the exception that a recurrence of a non-fatal infarction in a survivor does not qualify. That is, the event had to be a progression in severity. Variation in fibrinogen by baseline coronary heart disease and follow-up outcome was assessed by calculating age-adjusted means. Age was used in its raw, ungrouped, form in this and other analyses. Due to the positive skew in fibrinogen, the raw values were log transformed before analysis. Cox proportional hazards regression models were used to determine the hazard ratios for incident coronary heart disease and mortality by fifths of fibrinogen, adjusted for other coronary risk factors. Continuous risk factors were, like fibrinogen, modelled in groups according to their fifths. The risk factors chosen as potential confounders are those found important as predictors for coronary heart disease in other studies and which were measured in the current study. Model checking was carried out; alternative regression models were also used, but not reported here since they gave similar results. Results Stored citrated plasma fibrinogen samples were available for assay at baseline in 9955 (85%) of the 69 SHHS participants. During the follow-up period, 5 (6%) of the 5095 men with known fibrinogen died; deaths were attributed to coronary heart disease. Of the 97 men free of coronary heart disease at baseline, 95 (5%) experienced a coronary event, compared to 96 (8%) of the 069 men with coronary heart disease at baseline. Of the 4860 women with known fibrinogen, 6 (%) died, 5 being coronary deaths. Coronary events were experienced by 69 (%) of the 75 women without coronary heart disease at baseline, and by 79 (8%) of the 997 women with coronary heart disease at baseline. Annual incidence rates (per thousand) for coronary events, coronary deaths and deaths from any cause were 0 6, 4 and 8 5, respectively, for men and 4, 0 9 and 4 4, respectively, for women. Table shows how average fibrinogen varies by baseline coronary heart disease group and followup outcomes. clearly rises with increasing Eur Heart J, Vol. 9, January 998

3 The Scottish Heart Health Study 57 Table Age-adjusted means (95% confidence intervals) of fibrinogen (g. l ) by baseline coronary heart disease (CHD) status, follow-up outcome and sex. Sample size is given in square brackets Follow-up outcome Baseline CHD status No CHD Angina MI Total Men [97] [04] [86] [5095] No event 0 ( 8, ) 5 ( 7, 4) 7 ( 7, 47) ( 0, 4) [454] Non-fatal CHD 4 ( 4, 45)** 9 ( 09, 5) 47 ( 8, 67) 5 ( 7, 4)** [56] Non-CHD death 6 ( 6, 47)** 49 ( 0, 8) 66 ( 9, 09) 40 (, 50)*** [9] CHD death 7 ( 0, 55)* 59 ( 7, 95) 7 ( 50, 98)** 50 ( 9, 6)*** [] Women [75] [45] [85] [4860] No event 7 ( 5, 9) 4 ( 4, 48) 44 ( 7, 6) 9 ( 7, ) [4586] Non-fatal CHD 60 ( 4, 79)*** (, 56) ( 77, 96)** 55 ( 4, 68)*** [] Non-CHD death 49 ( 5, 64)** 8 ( 46, )* 08 (, 4 6) 5 ( 40, 64)*** [7] CHD death 59 (, 04) 9 ( 9, 95) 95 ( 47, 5) 58 ( 6, 8)** [5] Includes not knowns and non-specific coronary heart disease Notes: Angina excludes those with myocardial infarction (MI) also; non-fatal coronary heart disease excludes those who later died. Significance tests compare with the no event group after age adjustment and log transformation within column: *=0 0<P<0 05, **=0 0<P<0 00, ***=P<0 00; else P>0. Means and confidence intervals are back-transformed after calculation on the logarithmic scale. severity of coronary heart disease at baseline. Whatever the baseline coronary heart disease status, those with relatively high fibrinogen appear to have a greater chance of experiencing coronary heart disease or death during follow-up. For men, average fibrinogen generally increases from the group with no event during follow-up to those having a non-fatal coronary heart disease event to those dying from non-coronary heart disease causes to those dying from coronary heart disease. The only exception is a slight drop between the first and second of these groups for men with baseline angina, which is explainable by random variation. For women the pattern is less clear, possibly due to the smaller number of events. Those women with no follow-up event generally have a lower fibrinogen than others, but there is no consistent difference between the groups representing the three different kinds of event. Notice that the significance of test results across the table cannot be compared to rank the magnitude of effects, because of variation in sample size. Further, note that during prolonged follow-up a number of the no-event subjects will move into other outcome groups and hence comparisons must be interpreted with caution [9]. Percentiles of fibrinogen for this study are given in Table. The tertiles, median and quintiles for women are all slightly higher than those for men. The skewness in the distribution is clear. Table considers the hazard for a coronary heart disease event by fifths of fibrinogen separately for men and women, and for coronary heart disease and no coronary heart disease at baseline. The effect of fibrinogen is shown after three different types of adjustment: age-adjusted, adjusted for cotinine and age, and adjusted for major coronary risk factors plus age. The risk factors are cotinine, systolic and diastolic blood pressure, total and HDL-cholesterol, triglycerides, body mass index (weight/height ), Bortner score, self-reported Table Percentiles of fibrinogen (g. l )bysex Percentile Men Women Minimum Maximum alcohol and vitamin C consumption and self-reported activity in work and in leisure (both reported as inactive/ average/active). HDL-cholesterol, Bortner score, alcohol and vitamin C consumption and the two types of activity all act inversely; the other variables are positively associated with coronary heart disease. Each fibrinogen fifth is compared to the lowest fifth (hazard=). The pattern of increasing risk by increasing fibrinogen is clear in all parts of Table. For men there is a slightly increased hazard going from the lowest fifth to any of the middle three fifths of fibrinogen, which are all fairly similar in terms of risk. The hazard increases considerably from the lowest to highest fifth. For women the pattern across the fifths is less clear, which is again probably due to the smaller number of events, as reflected in the wide confidence intervals. However, a step up to the highest fifth is apparent for women who were free of coronary heart disease at baseline. Adjustment for cotinine, with or without the other coronary risk factors, reduces hazard ratios. Nevertheless, adjustment for all the risk factors leaves a Eur Heart J, Vol. 9, January 998

4 58 M. Woodward et al. Table Hazard ratios for follow-up coronary heart disease event (fatal or non-fatal) by fibrinogen fifths, baseline coronary heart disease status and sex. 95% confidence limits are given in round brackets. Sample size is given in square brackets fifth No baseline CHD Baseline CHD Age-adjusted -adjusted Multiple adjusted Age-adjusted -adjusted Multiple-adjusted Men [97] [74] [807] [069] [88] [0] (0 75, 04) 6 (0 7, 5) 0 (0 77, 0) 6 (0 7, 9) 5 (0 6, 0) 07 (0 6, 90) 58 (0 98, 54) 74 ( 0, 0) 4 (0 85, ) 4 (0 85, 4) 4 (0 80, 48) 6 (0 7, 5) 4 9 (0 85, 7) 4 (0 69, ) 08 (0 6, 84) 4 (0 7, 09) 05 (0 59, 89) 0 9 (0 5, 6) 5 5 ( 4, 56) 7 (0 97, 0) 7 ( 04, 86) 95 ( 0, 6) 7 ( 00, 9) 6 (0 98, 7) Women [75] [79] [68] [997] [88] [96] 4 (0 86, 6 79) 66 (0 56, 4 86) 68 (0 58, 4 9) 4 (0 50, 0) 5 (0 4, 8) (0 47, 6) 89 ( 05, 7 97) 85 (0 65, 5 8) 04 (0 7, 5 7) 0 98 (0 9, 4) 0 87 (0, 0) 0 86 (0, 5) 4 80 (0 6, 5 7) 08 (0 5, ) 5 (0 8, 47) 0 (0 94, 4 70) 76 (0 7, 4 ) 77 (0 75, 4 6) ( 85, 7) 78 ( 0, 7 50) 54 (0 94, 6 8) 9 (0 86, 4 0) (0 55, 8) 0 (0 5, 8) Adjustment for cotinine in addition to age. Multiple adjustment for age, cotinine, systolic and diastolic blood pressure, total and HDL-cholesterol, triglycerides, body mass index, Bortner score, alcohol and vitamin C consumption, activity in work and activity in leisure. Table 4 Hazard ratios for death during follow-up by fibrinogen fifths and sex. 95% confidence limits are given in round brackets. Sample size is given in square brackets fifth Coronary death Death from any cause Age-adjusted -adjusted Multiple adjusted Age-adjusted -adjusted Multiple-adjusted Men [5095] [44] [494] [5095] [44] [494] 8 (0 70, 7) 9 (0 78, 4 7) 9 (0 68, 8) 40 (0 9, ) 5 (0 9, 48) 6 (0 89, 09) 6 (0 69, 66) 60 ( 0, 6 09) 6 (0 68, 7) 4 (0 88, 0) 70 ( 06, 7) 6 (0 8, 9) 4 49 (0 78, 88) 07 (0 87, 4 95) (0 6, 44) 56 ( 04, ) 48 (0 9, 9) (0 87, 0) 5 0 ( 66, 5 45) 7 ( 6, 8 48) (, 4 8) 59 ( 78, 76) 5 ( 60, 9) 06 ( 9, 05) Women [4860] [405] [4749] [4860] [405] [4749] 0 88 (0 8, 4 8) 0 8 (0, 5 77) 0 5 (0 08, ) 0 87 (0 48, 59) 0 7 (0 7, 45) 0 7 (0 8, ) 9 (0, 5 84) (0, 6 80) (0 5, 4 95) 09 (0 6, 9) 0 97 (0 5, 80) 0 90 (0 5, 59) 4 5 (0 58, 7 97) 04 (0 4, 9 76) 56 (0 8, 6 4) 0 (0 69, 07) 0 94 (0 5, 74) 0 87 (0 49, 5) 5 4 (0 98, 87) 8 (0 5, 0 95) 90 (0 48, 7 50) 0 ( 4, 6) 64 (0 94, 86) 54 (0 9, 58) Adjustment for cotinine in addition to age. Multiple adjustment for age, cotinine, systolic and diastolic blood pressure, total and HDL-cholesterol, triglycerides, body mass index, Bortner score, alcohol and vitamin C consumption, activity in work and activity in leisure. formally significant (P<0 05) hazard ratio for the fifth vs first fifth for men without coronary heart disease at baseline. Once adjustment has been made for cotinine, the remaining variables have little extra effect. Adjustment for total cholesterol and for systolic blood pressure, both in addition to age, has little effect (results not shown). Table 4 repeats the analyses of Table, but for the outcomes death from any cause and its subset coronary death. Again, the hazard increases with increasing fibrinogen fifth in a non-linear fashion with the highest fifth having much the highest hazard. The hazard ratios are higher for coronary death than for any cause, and are higher than for coronary events (Table ) in men, but lower in women. Adjustment for cotinine, alone or together with the other risk factors, usually reduces the hazard ratios slightly, but the hazard ratios for the fifth vs first fifth for men are still significant (P<0 05). Again, adjustment for total cholesterol, and for systolic pressure, has little effect in the presence of age (results not shown). There are no statistically significant (P<0 05) two-way interactions (as measured by the Cox model) between fibrinogen and the three established major coronary risk factors: (systolic) blood pressure, serum total cholesterol and smoking (measured by serum cotinine). This statement is true whether coronary heart disease events or deaths are analysed, for both men and Eur Heart J, Vol. 9, January 998

5 The Scottish Heart Health Study 59 Systolic BP Cholesterol Figure Hazard ratios for all coronary heart disease (see text for definition) amongst men. The hazard ratios shown are all relative to the lowest third of serum total cholesterol, systolic blood pressure, plasma fibrinogen and serum cotinine (hazard=). Each of the four variables illustrated is adjusted for the other three and for age, but no interaction effect is included. women, and whether the four variables are considered in fifths or thirds. The joint effect of the three classical risk factors and fibrinogen, adjusted for age, was assessed for men by considering the four variables, divided into thirds, as predictors of coronary death, all-causes death and all coronary heart disease. Of these, only all coronary heart disease is illustrated here, by Fig. (n=45). This shows the estimated effects of the four variables on coronary heart disease, cross-adjusted for each other and for age. These model-based estimates were found to be consistent with observed outcomes. For instance, the base group (combination of the four lowest thirds) had zero events from 76 subjects and the group defined by the combination of the four highest thirds had events (%) from 94 subjects. This compares with an estimated risk ratio of 6 6. The hazard ratio that compares the highest to lowest third of fibrinogen, adjusted for age and the classical risks, was statistically significant (P<0 05) Eur Heart J, Vol. 9, January 998

6 60 M. Woodward et al. whatever the definition of event. is the least important of the four variables shown in Fig. for predicting coronary heart disease, but more important than systolic blood pressure and cholesterol for predicting death from any cause, and the most important of the four for predicting coronary death, according to the ranks of the cross-adjusted, extreme hazard ratios. Discussion This report is the largest follow-up study to date of plasma fibrinogen in relation to coronary heart disease and death. During around subject years of follow-up, a total of 487 deaths and a further 68 coronary heart disease events without death were observed. The results confirm and extend the findings of seven previously reported studies [ ]. They establish that fibrinogen, as measured using a widely-performed routine assay, is a strong predictor of coronary heart disease events (fatal and non-fatal), with or without baseline coronary heart disease, and of mortality, in a large sample of middle-aged men and women. There is considerable evidence of a threshold effect, with subjects in the highest fifth of the fibrinogen distribution having a distinctly elevated risk. shows no interactions with the other major coronary risk factors, and its association with incident coronary heart disease or mortality is not entirely attributable to cholesterol or blood pressure or an extensive set of coronary risk factors. Smoking (measured by cotinine) appears to have the most important confounding effect for the fibrinogen-coronary heart disease relationship, presumably because fibrinogen is one mechanism by which smoking promotes coronary heart disease. Several of the previous prospective studies [6,8,9,,] have presented fibrinogen results by thirds. We have preferred to use fifths here because they provide more information, and because our data set is large enough to provide reliable estimates in most cases. Thirds are used in Fig. simply for clarity of presentation. For comparison with other studies, age-adjusted hazard ratios by thirds were also calculated. The age-adjusted hazard ratio (with 95% confidence interval) that compares the highest to lowest third for progressive coronary heart disease is 78 ( 5, 5) for men, which compares with the meta analysis odds ratio of from earlier studies [,4], although comparison is not straightforward because study designs do vary. appeared similarly predictive of nonfatal coronary heart disease events, fatal coronary heart disease events and total mortality. The hazard ratio for coronary heart disease events appeared similar in the % of persons aged who had baseline evidence of coronary heart disease, and in those who did not; this is in keeping with one previous study of men with and without such evidence [0]. A previous study [0] that considered the risk of myocardial infarction or coronary death for patients with angina found fibrinogen risks somewhat higher than our results for the hazard of a coronary heart disease event in the baseline coronary heart disease group. This is probably because it studied selected subjects undergoing coronary angiography, often for unstable angina. Only one previous study included similar numbers of men and women, many of whom were elderly [9]. The present study included men and women: the predictive value of fibrinogen for coronary heart disease events and mortality appeared similar in men and women, considering the lower incidence of events and hence the wider confidence intervals for women. While some previous studies have suggested that there may be positive interactions between fibrinogen and serum cholesterol [], blood-pressure [7] or smoking habit [6] and cardiovascular risk [7,], or prevalent arterial disease [6], the present, larger study did not show evidence of interactions between fibrinogen, any of these three classical major risk factors, and coronary heart disease risk. However, results for interaction depend on how interaction was measured; here the Cox model assumes a multiplicative effect on hazard ratios. While fibrinogen was weakly related to baseline cholesterol and blood pressure, especially in women [8], the predictive value of fibrinogen for coronary heart disease and mortality was minimally affected by these two risk factors. The present study [8]. like all previous large studies [ ], has observed a dose-dependent, partlyreversible association between cigarette-smoking and plasma fibrinogen level. This association may reflect elevation in plasma fibrinogen due to smoking-induced disturbance of vascular endothelium or pulmonary epithelium, which induces release of cytokines such as interleukin-6 which increase hepatic synthesis of fibrinogen [ 4]. There are several plausible biological mechanisms through which increasing fibrinogen levels may promote coronary heart disease, including atherogenesis, thrombogenesis, and ischaemia due to increased plasma and blood viscosity [ 4]. Three previous studies have suggested that much of the relationship between smoking and coronary heart disease risk may be mediated by increased plasma fibrinogen [,,]. In the WHO study of clofibrate in coronary heart disease prevention, clofibrate appeared to abolish the hyperfibrinogenaemia in smokers [], as well as reducing the incidence of coronary heart disease [4]. Following smoking cessation, reduction in coronary heart disease risk follows a similar time-course to decrease in plasma fibrinogen [5]. When smoking adjustment was performed, the predictive value of fibrinogen for coronary heart disease risk was reduced, as would be expected for a major population determinant of both fibrinogen level and of coronary heart disease. Nevertheless, fibrinogen still added to coronary heart disease prediction by smoking, cholesterol and blood pressure (Fig. ) and remained a significant predictor of both fatal coronary heart disease and of mortality after smoking adjustment. Hence, fibrinogen had a predictive value for both coronary heart disease and mortality, independent of age and Eur Heart J, Vol. 9, January 998

7 The Scottish Heart Health Study 6 smoking. Indeed, out of 7 lifestyle and risk factor variables in SHHS, fibrinogen was one of the strongest predictors of mortality. In contrast, serum cholesterol was not a predictor of mortality []. The predictive effect of fibrinogen for death does not appear to be merely a marker of some imminently fatal process, such as underlying cancer or tissue necrosis, because fibrinogen had a virtually identical effect on deaths occurring more than 4 years after baseline in this study (results not presented). Unfortunately, there are too few non-coronary deaths for any specific cause to warrant a detailed analysis of the effect of fibrinogen on other causes of death, such as cancer. These types of analyses should be feasible when the SHHS has been followed for a longer duration. Whether or not increasing fibrinogen levels play a causal role in coronary heart disease remains to be established by ongoing randomized trials of chronic plasma fibrinogen reduction, for example by fibrates [,]. High fibrinogen levels are likely to occur long before cardiovascular disease because of the associations of fibrinogen gene polymorphisms, which are related to high fibrinogen levels, with both extensive arterial disease [6,7] and venous thrombosis [8]. Acute reduction in fibrinogen, by defibrinogenation with ancrod, may reduce the incidence and extent of venous thrombosis [9], as well as reducing the neurological deficit in acute stroke [40], possibly through antithrombotic and rheological effects [ 4]. The results of the present study add to the evidence that plasma fibrinogen is a predictor of coronary heart disease events and mortality, especially at extreme levels. They also support the case for evaluation of fibrinogen in stratification of cardiovascular risk, and the case for randomized trials of fibrinogen reduction in coronary heart disease prevention, whether primary or secondary. The SHHS was primarily funded by the Chief Scientist Office of the Scottish Office Department of Health. The views expressed here are those of the authors and not necessarily of this office. We thank Roger Tavendale for laboratory work, Richard A Brook and Marilyn Collins for database management and Alex Owen for typing this manuscript. References [] Meade TW. Haemostatic function, arterial disease and the prevention of arterial thrombosis. Baillière s Clin Haematol 994; 7: [] Ernst E, Resch KL. as a cardiovascular risk factor: a meta-analysis and review of the literature. Ann Intern Med 99; 8: [] Lowe GDO, Fowkes FGR, Koenig W, Mannucci PM, eds. and cardiovascular disease. Eur Heart J 995; 6 (Suppl A). [4] Resch KL, Ernst E. 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