Systematically missing confounders in individual participant data meta-analysis of observational cohort studies.

One difficulty in performing meta-analyses of observational cohort studies is that the availability of confounders may vary between cohorts, so that some cohorts provide fully adjusted analyses while others only provide partially adjusted analyses. Commonly, analyses of the association between an exposure and disease either are restricted to cohorts with full confounder information, or use all cohorts but do not fully adjust for confounding. We propose using a bivariate random-effects meta-analysis model to use information from all available cohorts while still adjusting for all the potential confounders. Our method uses both the fully adjusted and the partially adjusted estimated effects in the cohorts with full confounder information, together with an estimate of their within-cohort correlation. The method is applied to estimate the association between fibrinogen level and coronary heart disease incidence using data from 154,012 participants in 31 cohorts

Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis.

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 > or =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.

C-reactive protein, fibrin D-dimer, and risk of ischemic heart disease: the Caerphilly and Speedwell studies.

BACKGROUND: There is increasing interest in the predictive value of C-reactive protein (CRP) and fibrin D-dimer in the prediction of ischemic heart disease (IHD). We assessed their joint and independent associations with IHD in a large combined analysis of 2 population cohorts. METHODS AND RESULTS: Men aged 49 to 66 years from the general populations of Caerphilly and Speedwell were studied between 1982 and 1988 and re-examined for new IHD events at fixed intervals of approximately 105 months (Caerphilly) and 75 months (Speedwell). 3213 men had CRP and D-dimer measured at baseline and 351 (11%) had a new IHD event. Mean levels of CRP and D-dimer were significantly higher among men in whom IHD developed. The relative odds of IHD in men in the top 20% of the distribution of CRP was 2.97 (95% CI, 2.04, 4.32) and for D-dimer was 2.40 (95% CI, 1.69, 3.40); CRP and D-dimer had additive effects on risk of IHD. Multivariate analysis reduced the size of the relative odds, which remained significant for D-dimer. CONCLUSIONS: Both inflammatory and thrombogenic markers are important (and potentially additive) predictors of coronary risk.

Haemostatic/inflammatory markers predict 10-year risk of IHD at least as well as lipids: the Caerphilly collaborative studies.

AIMS: We compare the predictive values of plasma lipids (total and HDL-cholesterol, triglycerides) and three haemostatic/inflammatory risk markers for subsequent ischaemic heart disease (IHD). METHODS AND RESULTS: Two UK populations totalling 4860 men were screened for evidence of IHD between 1979 and 1983. Men were followed over 10 years and validated coronary events were recorded. Risk estimates were made using relative odds, receiver operating characteristic (ROC) curves and deciles of risk. Regression dilution effects were also examined. By 10 years, 525 men had a coronary event (fatal, non-fatal or silent myocardial infarction, MI). Two alternative multivariate models were compared - a lipid model (total, HDL-cholesterol, triglyceride) and a haemostatic/inflammatory model (fibrinogen, viscosity and white cell count). 'Correction' for regression dilution increased relative odds for most risk factors. In the distribution of predicted risk, using established risk factors in conjunction with either lipid or haemostatic/inflammatory factors, the deciles of risk analysis showed that the observed 10-year risk of IHD was 34-35% in men in the top tenth, compared to 2-3% in the lowest tenth of the distribution. CONCLUSION: At the 10 years' follow-up, major, haemostatic/inflammatory risk factors showed a graded relationship to incident IHD that was at least as strong as that given by plasma lipids. Haemostatic/inflammatory factors provide possible additional targets for intervention.

What level of physical activity protects against premature cardiovascular death? The Caerphilly study.

OBJECTIVE: To examine the optimal intensity of leisure time physical activity (LTPA) to decrease the risk of all cause, cardiovascular disease (CVD), and coronary heart disease (CHD) mortality in a population sample of middle aged British men. DESIGN: Prospective study of middle aged men with an 11 year follow up. SETTING: A whole population sample of men from Caerphilly, South Wales, UK. SUBJECTS: 1975 men aged 49-64 years without historical or clinical evidence of CHD at baseline examination. MAIN OUTCOME MEASURES: All cause, CVD, and CHD mortality. RESULTS: Total (cumulative) LTPA had a graded, significant relation with all cause, CVD, and CHD mortality but no trend with cancer deaths. When different intensities of activity were considered, light and moderate intensity LTPA had inconsistent and non-significant relations with all cause, CVD, or CHD mortality whether adjusted only for age or for other cardiovascular risk factors. In contrast a significant dose-response relation was found for heavy intensity LTPA for all cause, CVD, and CHD mortality fully adjusted for other risk factors. CONCLUSIONS: These data suggest that, in a population of men without evidence of CHD at baseline, only leisure exercise classified as heavy or vigorous was independently associated with reduced risk of premature death from CVD.

Lifestyle factors and coagulation activation markers: the Caerphilly Study.

Coagulation activation markers are being investigated as risk factors for cardiovascular disease; we examined the contribution of several lifestyle factors to variation in plasma levels of several activation markers measured in a population-based study of 1947 men. Smoking, alcohol, body mass index (BMI), leisure and work activity, social class, and use of prescribed medicines were each examined in turn. Specific assays of fibrin D-dimer and von Willebrand factor (vWF) activity showed similar relationships to lifestyle variables as we observed previously for less specific assays of D-dimer and vWF antigen. D-dimer levels increased with age, in smokers and in men taking prescribed medication, and were negatively associated with leisure time activity. vWF activity increased with age and showed a U-shaped distribution with BMI. Factors VIIc and VIIIc and thrombin-antithrombin complexes were associated with BMI, factor VIIIc and prothrombin fragments 1 + 2 (F1 + 2) were associated with age, activated partial thromboplastin time (aPTT) and F1 + 2 were associated with smoking, and aPTT showed a small negative association with alcohol consumption. We conclude that lifestyle modification has the possibility of favourably influencing several of these risk markers. In particular, cigarette smoking has a possibly reversible effect on coagulation activation (measured by F1 + 2 and D-dimer).

Central obesity: predictive value of skinfold measurements for subsequent ischaemic heart disease at 14 years follow-up in the Caerphilly Study.

OBJECTIVE: To assess the predictive value of central obesity for risk of ischaemic heart disease (IHD) in a long-term follow-up, measured by skinfold thickness in comparison to general measures of overweight and obesity such as Quetelet's index. SUBJECTS AND DESIGN: A total of 2512 men aged 45-59 y from the general population first examined in 1979-1982. Men were re-examined at approximately 5 y intervals. All fatal and non-fatal cases of IHD during a 14 y follow-up were recorded. MEASUREMENTS: Skinfold thickness was measured at four sites. Height (m) and weight (kg) were also measured and Quetelet's index (weight/height(2)) was used as the reference body mass index (BMI). RESULTS: Data were available for 2512 men among whom 411 new cases of IHD (fatal and non-fatal) occurred during 14 y of follow-up. Increasing values of BMI showed a statistically significant trend with increasing risk of new IHD that contributed independently to risk of IHD when adjusted for age, smoking habit and social class. Skinfold thickness measures were entered singly and in combination into this model with and without the additional inclusion of BMI. All individual skinfolds were significantly associated with risk of new IHD when BMI was excluded from the regression model, as was the sum of four skinfolds and the sum of subscapular and abdominal skinfolds. Only the subscapular skinfold measure contributed independently to risk of subsequent IHD when BMI was included in the model although biceps, biceps plus triceps and total sum of skinfolds were close to achieving statistical significance. The relative odds of IHD in the upper quintile of subscapular skinfold compared to the lowest was 1.9 (95% CI 1.3-2.8) when adjusted for age, smoking habit and social class. CONCLUSIONS: In general skinfold measurements contribute only marginally to improved prediction of risk of IHD as measured by BMI, but central obesity, as measured by the subscapular skinfold, is predictive of IHD independently of BMI.

Fibrin D-dimer, markers of coagulation activation and the risk of major ischaemic heart disease in the caerphilly study.

We have previously reported that plasma fibrin D-dimer (a marker of turnover of cross-linked fibrin) showed a strong and independent association with incident ischaemic heart disease (IHD) in the Caerphilly Study cohort of 1,998 men aged 49-65. To establish the specificity of this finding, we assayed plasma samples from this cohort with a more specific assay for fibrin D-dimer: this showed an association with incident IHD which was at least as strong and independent as that for the original assay (odds ratio, OR for top fifth compared to bottom fifth 3.79; 95% CI 1.77-8.10; p < 0.0001). To establish potential causes of the increased fibrin turnover, we also assayed several potential markers of coagulation activation or thrombotic tendency (prothrombin fragment F1+2, thrombin-antithrombin complexes, factor VIIc, activated partial thromboplastin time [APTT] and activated protein C resistance): none of these variables were associated with incident IHD in this cohort. We suggest that further studies are required to establish the causes of increased cross-linked fibrin turnover, which is associated with incident IHD in the general population when measured by a specific assay.

Do total and high density lipoprotein cholesterol and triglycerides act independently in the prediction of ischemic heart disease? Ten-year follow-up of Caerphilly and Speedwell Cohorts.

Several studies have suggested that men with raised plasma triglycerides (TGs) in combination with adverse levels of other lipids may be at special risk of subsequent ischemic heart disease (IHD). We examined the independent and combined effects of plasma lipids at 10 years of follow-up. We measured fasting TGs, total cholesterol (TC), and high density lipoprotein cholesterol (HDLC) in 4362 men (aged 45 to 63 years) from 2 study populations and reexamined them at intervals during a 10-year follow-up. Major IHD events (death from IHD, clinical myocardial infarction, or ECG-defined myocardial infarction) were recorded. Five hundred thirty-three major IHD events occurred. All 3 lipids were strongly and independently predictive of IHD after 10 years of follow-up. Subjects were then divided into 27 groups (ie, 3(3)) by the tertiles of TGs, TC, and HDLC. The number of events observed in each group was compared with that predicted by a logistic regression model, which included terms for the 3 lipids (without interactions) and potential confounding variables. The incidence of IHD was 22.6% in the group with the lipid risk factor combination with the highest expected risk (high TGs, high TC, and low HDLC) and 4.7% in the group with the lowest expected risk (P<0.01). A comparison of the predicted number of events in the 27 groups with the number of events observed showed that a logistic regression provided an adequate fit without the need to incorporate interactions between lipids in the model. Conclusions are as follows: (1) Serum TGs, TC, and HDLC are independently predictive of IHD at 10 years of follow-up. (2) Combinations of adverse levels of the 3 major lipid risk factors have no greater impact on IHD than that expected from their individual contributions in a logistic regression model. There was no evidence that men with low HDL/raised TGs were at significantly greater risk than that predicted from the independent effects of the 2 lipids considered individually.

C-reactive protein, fibrin D-dimer, and incident ischemic heart disease in the Speedwell study: are inflammation and fibrin turnover linked in pathogenesis?

Plasma levels of C-reactive protein (CRP, a marker of the reactant plasma protein component of the inflammatory response) and of fibrin D-dimer (a marker of cross-linked fibrin turnover) have each been associated in recent studies with the risk of future ischemic heart disease (IHD). Previous experimental studies have shown that fibrin degradation products, including D-dimer, have effects on inflammatory processes and acute-phase protein responses. In the Speedwell Prospective Study, we therefore measured CRP and D-dimer levels in stored plasma samples from 1690 men aged 49 to 67 years who were followed-up for incident IHD for an average of 75+/-4 months (mean+/-SD) and studied their associations with each other, with baseline and incident IHD, and with IHD risk factors. CRP and D-dimer levels were each associated with age, plasma fibrinogen, smoking habit, and baseline evidence of IHD. CRP was associated with D-dimer (r=0.21, P<0.00001). On univariate analyses, both CRP and D-dimer were associated with incident IHD. The incidence of IHD increased with CRP independently of the level of D-dimer (P=0.0002) and also increased with D-dimer independently of the level of CRP (P=0.048). In multivariate analyses, inclusion of D-dimer and conventional risk factors reduced the strength of the association between CRP and incident IHD; likewise, inclusion of CRP and conventional risk factors reduced the strength of the association between D-dimer and incident IHD. We conclude that although these respective markers of inflammation and fibrin turnover show modest association with each other in middle-aged men, they may have additive associations with risk of incident IHD. Further larger studies are required to test this hypothesis.

Apolipoproteins A-I, A-II and B, lipoprotein(a) and the risk of ischaemic heart disease: the Caerphilly study.

Apolipoproteins B, A-I and Lp(a) have been proposed as independent predictors of subsequent ischaemic heart disease (IHD) improving on the prediction obtained by routine lipid measurements. In this report we have investigated the relative predictive ability of apolipoproteins and plasma lipids in a prospective study of middle aged men. 2398 men aged 49-65 years from the general population of Caerphilly, South Wales, UK were screened for evidence of IHD. After an overnight fast 2225 men each provided a venous blood sample on which plasma lipids, apolipoproteins B, A-I, A-II, and lipoprotein (a) (Lp(a)) were measured. Over a follow-up period of nearly 9 years, 282 (12%) men developed major IHD. Multiple logistic regression analysis showed that after adjusting for standard cardiovascular risk factors other than lipids there was a strong trend (standardised relative odds (SRO) = 1.20; P = 0.009) for incidence of IHD to increase with apolipoprotein B. However, on further adjusting for total cholesterol this trend largely disappeared (SRO = 1.05; P = 0.57). Similarly, a trend for incidence of IHD to increase with decreasing apolipoprotein A-I (SRO = 1.18; P = 0.02) disappeared when HDL cholesterol was added to the model. Levels of apolipoprotein A-II were not related to risk of subsequent IHD. Incidence of IHD was effectively constant over nearly 90% of the range of Lp(a). Only among the 5% of men with Lp(a) greater than 70 mg dL-1 was the risk of IHD significantly (P = 0.04) greater than among men with Lp(a) less than 10 mg dL-1. Apolipoproteins B and A-I do not improve on the prediction of risk of IHD provided by total and HDL cholesterol, respectively. Apolipoprotein A-II was not related to risk of IHD. Lp(a) may be independently associated with incident IHD among the 5-10% of men with the highest levels.

C-reactive protein: relation to total mortality, cardiovascular mortality and cardiovascular risk factors in men.

BACKGROUND: There is much interest in reported associations between serum C-reactive protein and incident ischaemic heart disease. It is uncertain what this association represents. We aimed to assess the effect of confounding from a number of different sources in the Caerphilly Prospective Heart Disease Study and in particular whether the low grade inflammation indicated by C-reactive protein may be the mechanism whereby non-circulating risk factors may influence pathogenesis of ischaemic heart disease. METHODS: Plasma specimens collected during 1979-83 from 1395 men with sufficient sample remaining were assayed for serum C-reactive protein by ELISA. Subsequent mortality and incident ischaemic heart disease events were ascertained from death certificates, hospital records and electrocardiographic changes at 5-yearly follow-up examinations. RESULTS: There was a positive association between C-reactive protein and incident ischaemic heart disease (P<0.005) mainly with fatal disease (P<0.002). There was also a positive association with all-cause mortality (P<0.0001). C-reactive protein was significantly associated with a number of non-circulating risk factors including body mass index (P<0.0001), smoking (P<0.0001), low forced expiratory volume in 1 s (P<0.0001), height (P=0.025), low childhood social class (P=0.014) and age (P=0.036). C-reactive protein was also associated positively with circulating risk factors including viscosity, leukocyte count, fibrinogen (all P<0.0001) and insulin (P=0.0058). After adjustment for non-circulating risk factors the association with all-incident ischaemic heart disease and ischaemic heart disease death became non-significant, but the association with all-cause mortality remained (P=0.033). Further adjustment for fibrinogen however removed any hint of an increasing trend in odds for all three outcomes. CONCLUSION: C-reactive protein levels are raised in association with a variety of established cardiovascular risk factors. Neither C-reactive protein nor the systemic inflammation it represents appears to play a direct role in the development of ischaemic heart disease.

Comparison of weight in middle age, weight at 18 years, and weight change between, in predicting subsequent 14 year mortality and coronary events: Caerphilly Prospective Study.

OBJECTIVE: The prevalence of obesity is increasing in many European countries and in the United States. This report examines the mortality and morbidity associated with being overweight and obese in the Caerphilly Prospective Study and the relative effects of weight in middle age and self reported weight at 18 years. DESIGN: All men aged 45 to 59 years from the town of Caerphilly, South Wales and outlying villages were identified and 2512 men were examined for the first time between 1979 and 1983. Men were asked to recall their weight at 18 years of age (when the majority had been examined for National Service) so that weight then, weight at screening, and the difference could be related to their 14 year follow up from screening. A total of 2335 men could recall their weight at 18 years. By 14 years of follow up from screening 465 men had died and 382 had had coronary events. RESULTS: Mean body mass index in men who reported their weight at 18 years was 22.3 (SD 2.8) kg/m(2) and only 41 of these men (1.8%) were classified as obese (index >/= 30 kg/m(2)). The index did not predict all cause mortality when examined by quintile. For major ischaemic heart disease (non-fatal or fatal ischaemic heart disease) the relative odds was 1.73 (95% CI 1.21, 2.48) in the top fifth of the distribution (body mass index >/= 24.2 kg/m(2)) compared with the bottom fifth (body mass index <20.1 kg/m(2)). In men with an index >/= 30 kg/m(2) however, the relative odds were 2.03 (95% CI, 1.03, 4.01) for all cause mortality and 2.17 (95% CI, 1.08, 4.34) for major ischaemic heart disease, adjusted for age, smoking habit and social class. When men were recruited to the study, from 1979 to 1983; the mean body mass index had increased to 26.2 (SD 3.6), a mean increase of 3.9 kg/m(2) or 11. 2 kg; 299 men (12.1%) were classified as obese and showed significantly increased relative odds of both all cause mortality (1. 53 (95% CI 1.14, 2.06) and major ischaemic heart disease (1.55 (95% CI 1.13, 2.11)), adjusted for age, smoking habit and social class relative to the non-obese men. The effect of gain in weight from 18 years to recruitment was also examined; all cause mortality showed highest mortality in the fifth of the distribution who experienced weight loss or minimal weight gain. For major ischaemic heart disease an inconsistent, weak trend was shown, the relative odds rising to a maximum of 1.26 (0.89, 1.80) in the top fifth of weight gain compared with the bottom fifth. Weight gain showed strong associations with potential cardiovascular risk factors measured at recruitment; insulin, triglyceride, glucose, diastolic and systolic blood pressure and high density lipoprotein-cholesterol. CONCLUSIONS: Body mass at 18 years of age of 30 kg/m(2) or more conferred increased risk for all cause mortality and major ischaemic heart disease during 14 years of follow up of men aged 45 to 59 years. By the baseline examination the prevalence of obesity (body mass index >/=30) had increased from 1.8% to 12.1%; obese men also showed an excess risk of major ischaemic heart disease and overall mortality, but these risks were lower than those predicted from 18 years of age. Weight gain was strongly associated with smoking habit, the greatest weight gain being among ex-smokers and the least among light smokers. Weight gain from 18 years of age to baseline examination showed little relation with subsequent mortality and risk of major ischaemic heart disease when adjusted for age, smoking habit and social class. The lowest mortality rate occurred in the "fifth" of men who gained a mean weight of 16.1 kg. Weight gain is closely associated with some adverse cardiovascular risk factors; in particular with insulin, triglyceride, glucose and diastolic blood pressure.

Lifestyle and hemostatic risk factors for ischemic heart disease : the Caerphilly Study.

We have recently shown that fibrin D-dimer, tissue plasminogen activator (tPA) antigen, von Willebrand factor antigen, fibrinogen, plasma viscosity, and white cell count are associated with subsequent ischemic heart disease (IHD) in men aged 49 to 65 years in the Caerphilly Study from South Wales. We now report the contribution of major lifestyle factors to plasma levels of these new risk predictors for IHD. Results were available for up to 2188 men. The contribution of factors associated with lifestyle (smoking, alcohol, body mass index, leisure and work activity, social class, and use of prescribed medicines) to variation in plasma levels of 8 hemostatic variables was examined. All results were adjusted for other lifestyle variables, age, and time of day. Most hemostatic variables increased with age and smoking habit. Increasing levels of alcohol consumption were associated with increases in tPA and plasminogen activator inhibitor (PAI-1) activity and with decreases in fibrinogen and white cell count. tPA, PAI-1, fibrinogen (nephelometric), and viscosity were positively associated with body mass index. Increasing levels of leisure activity were inversely associated with D-dimer, von Willebrand factor, nephelometric fibrinogen, and viscosity. Use of prescribed medicines (a marker for chronic illness) was associated with adverse levels of D-dimer, fibrinogen, plasma viscosity, and white cell count. tPA, PAI-1, and plasma viscosity were associated with blood pressure, cholesterol, and triglycerides but not with lipoprotein(a) or homocysteine. We conclude that several lifestyle factors are associated with hemostatic risk predictors for IHD. Lifestyle modifications may reduce IHD risk partly by altering hemostatic function; large intervention studies are required to test this hypothesis.

HTS in the new millennium: the role of pharmacology and flexibility.

Over the past decade, high throughput screening (HTS) has become the focal point for discovery programs within the pharmaceutical industry. The role of this discipline has been and remains the rapid and efficient identification of lead chemical matter within chemical libraries for therapeutics development. Recent advances in molecular and computational biology, i.e., genomic sequencing and bioinformatics, have resulted in the announcement of publication of the first draft of the human genome. While much work remains before a complete and accurate genomic map will be available, there can be no doubt that the number of potential therapeutic intervention points will increase dramatically, thereby increasing the workload of early discovery groups. One current drug discovery paradigm integrates genomics, protein biosciences and HTS in establishing what the authors refer to as the "gene-to-screen" process. Adoption of the "gene-to-screen" paradigm results in a dramatic increase in the efficiency of the process of converting a novel gene coding for a putative enzymatic or receptor function into a robust and pharmacologically relevant high throughput screen. This article details aspects of the identification of lead chemical matter from HTS. Topics discussed include portfolio composition (molecular targets amenable to small molecule drug discovery), screening file content, assay formats and plating densities, and the impact of instrumentation on the ability of HTS to identify lead chemical matter.

Anger and incident heart disease in the caerphilly study.

OBJECTIVE: The idea that anger may predict ischemic heart disease (IHD) is more than 30 years old. Some, but not all, prospective studies have supported this suggestion. Attention has focused on hostility as the critical component of anger for IHD risk. This idea is explored using prospective data from the Caerphilly study. METHODS: A sample of 2890 men aged 49 to 65 years living in and around Caerphilly, South Wales, was identified. Anger was assessed using the Framingham scales comprising "anger symptoms," "anger in," "anger out," and "anger discuss." A new "suppressed anger" scale was also constructed. Cardiovascular risk factors assessed included baseline blood pressure, total and high-density lipoprotein cholesterol, fibrinogen, white cell count, psychiatric caseness as assessed by the General Health Questionnaire, social support, smoking habit, alcohol consumption, leisure exercise, body mass index, and calorie intake. Prediction of IHD, measured as the occurrence of a major event over a follow-up period of 9 years, was assessed using multiple logistic regression analysis. RESULTS: A low anger out score predicted increased risk of a major IHD event (relative odds (RO) = 1.70; 95% confidence interval = 1.26-2.29 for all RO). This association was unchanged on controlling for physiological risk factors (RO = 1.74), psychosocial risk factors (RO = 1.72), and behavioral risk factors (RO = 1.69). Suppressed anger showed associations with incident IHD similar to those of anger out but identified the population at risk more closely. CONCLUSIONS: Anger out and suppressed anger were predictive of incident IHD. Neither of these constructs are overtly similar to hostility. These findings suggest there may be mechanisms other than hostility by which anger predicts IHD risk and that a conceptually varied approach to anger is currently appropriate.

Traffic noise and cardiovascular risk: the Caerphilly and Speedwell studies, third phase--10-year follow up.

The authors tested the hypothesis that prolonged exposure to road traffic noise causes ischemic heart disease in a 10-y follow-up cohort study of middle-aged men. In the Caerphilly and Speedwell studies, 2512 and 2348 men, respectively, who were 45-59 y of age were seen in the initial cross-sectional phase and at follow-up intervals of 10 y. Adjusted odds ratios of 1.1 (95% confidence interval = 0.6, 1.9) and 0.9 (95% confidence interval = 0.6, 1.4) were found in the total cohorts. However, the relative risk was 1.3 (95% confidence interval = 0.8, 2.2) in the pooled reconstructed cohort of men who were followed for 6 y (i.e., from phase 2 to phase 3) and for whom room orientation and window-opening habits could be considered. Furthermore, the relative risk increased to 1.6 (95% confidence interval = 0.9, 3.0) in the subsample of men who had lived at least 15 y in their present homes at the time of recruitment. Living adjacent to streets with high traffic noise levels was associated with an adjusted (for covariates) increase in relative risk of 1.01-1.02/y in residence--a result that was only borderline significant (p < .10).

Polypharmacy among older men in South Wales.

OBJECTIVE: To describe the pattern of polypharmacy (PP) among older men and to relate medication use to personal, social and medical information. METHODS: Information on medication use, both prescribed and 'over the counter' (OTC), was collected from 1906 men, aged 56-75 years, observed on up to four occasions since 1979 in a community survey the Caerphilly prospective study. On each visit, a variety of questionnaires regarding personal, social and medical factors were completed, and a brief medical examination was conducted. Medication use was related to some of the questionnaire information and biological measurements collected in order to identify factors associated with PP. RESULTS: A quarter of the men (475/1906) reported using three or more prescription-only medicines (PoMs), with 9% (163) using five or more (major PP). PP was related to increasing age, lower social class, not being in employment, smoking and obesity (high body mass index). Men with a medical history, especially of high blood pressure, angina, heart attack, or hospital admission in the last 5 years, comprised a large proportion of those on major PP. Higher levels of PoM use by this group had been apparent over the previous 14 years. Men on PP reported lower levels of self-rated health and higher rates of non-PoM use. Cardiovascular and, to a lesser extent, central nervous and respiratory system drugs were the main medicines used by men on major PP. CONCLUSIONS: PP is common among men aged 56-75 years in Caerphilly, South Wales. It is related to many personal, social and medical factors, and associated with lower self-rated health status and greater use of non-PoMs. Cardiovascular medicines are the main contributor to major PP. Those on PP require regular review and, where possible, PP should be reduced as it has many potential adverse effects.

Fasting plasma glucose and subsequent macrovascular disease after 10 years follow-up: a collaborative study on two populations.

The American Diabetes Association recently proposed a new, lower, cut-point of 7.0 mmol/l for diagnosis of diabetes mellitus. We examined data from the Caerphilly and Speedwell cohorts to determine possible cut-points of fasting plasma glucose for increased risk of subsequent ischaemic heart disease (IHD). Men (n = 4860) from the general population of a town in South Wales and a practice-based population in Bristol aged 45-63 years were first examined in 1979-83, and re-examined at intervals, and these data relate to follow-up at about 10 years (120 months, Caerphilly) (112 months, Speedwell). Clinically recognized diabetics (n = 94) experienced a higher mortality rate and an excess number of major IHD events. Among non-diabetics, mean blood glucose was 5.0 mmol/l and a significant excess of major IHD events occurred above this point even when the data were fully adjusted for all other IHD risk factors. Risk of major IHD was greatest for non-diabetic men with plasma glucose levels between 7.0 and 7.7 mmol/l. Under 7.0 mmol/l, the excess event rate was modest, however. Glucose levels were not associated with excess all-cause mortality among these non-diabetic men. These data, based on the excess risk of macrovascular disease experienced by a British cohort of non-diabetic men, accord with the proposals to base the diagnosis of diabetes on a cut point of 7.0 rather than 7.8 mmol/l.

Factor VIII, von Willebrand factor and the risk of major ischaemic heart disease in the Caerphilly Heart Study.

The relationships of three measurements of the factor VIII/von Willebrand factor (VWF) complex (factor VIII activity, FVIIIc (one-stage assay); VWF antigen, VWF Ag (ELISA); and VWF activity, VWF act, measured by a recently-developed ELISA) to major ischaemic heart disease (IHD) events were studied in 1997 men aged 49-65 years, in the second phase of the Caerphilly Heart Study. These variables were related using logistic regression analysis to myocardial infarction or IHD death, which occurred in 129 men during an average follow-up period of 61 months. All three measurements were highly correlated (r = 0.63-0.77), and each was significantly associated with incident major IHD on univariate analyses (relative odds in highest fifth compared to lowest fifth, 1.68-1.90; P = 0.028-0.006) and on multivariate analyses adjusting for major IHD risk factors and for baseline IHD. Neither FVIIIc nor VWF act was significantly related to incident IHD following adjustment for VWF Ag. We therefore suggest that the associations between these three measurements of the factor VIII/VWF complex and incident IHD might have at least three explanations: VWF Ag is a marker of arterial endothelial disturbance; VWF act promotes platelet adhesion/aggregation and hence the platelet component of arterial thrombosis; and FVIIIc promotes fibrin formation and hence the fibrin component of arterial thrombosis.