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.

Platelet aggregation in whole blood is a paradoxical predictor of ischaemic stroke: Caerphilly Prospective Study revisited.

The Caerphilly Prospective Study demonstrates a paradoxical association of increased ischaemic stroke risk with decreased whole blood adenosine diphosphate (ADP) induced platelet sensitivity. A reanalysis of this association examines whether other haematological indices and prevalent disease at baseline may explain this finding. There were 1506 men free of clinical cardiovascular disease at baseline, with 85 men manifesting a first ischaemic stroke event over 8.3 years of follow-up in this population-based prospective cohort study. Using two different approaches, the paradoxical findings are confirmed and associations are slightly stronger after accounting for red cell, platelet, and white cell indices. A U-shaped relation of stroke with platelet count is noted. These findings are consistent with the existence of sub-clinical endothelial disease and compensatory mechanisms down-regulating ADP-induced aggregation sensitivity. They support an allostasis model of causality for understanding the paradox. A public health approach to prevention could have measurable impact if intervention strategies can be developed to alter early stages of disease appropriate to such mechanisms of causation.

Milk consumption, stroke, and heart attack risk: evidence from the Caerphilly cohort of older men.

OBJECTIVE: To examine associations between milk consumption and incident heart disease and stroke. DESIGN: A representative population sample of men was asked to weigh and record their food intake for seven days. The total consumption of milk was obtained from these records. Details of all deaths and vascular events were collected during the following 20 years. Incident ischaemic strokes and heart disease events were diagnosed by standard criteria. SETTING: The Caerphilly cohort, a representative population sample of men in South Wales, aged 45-59 when first seen in 1979-83. PARTICIPANTS: A representative 3:10 subsample of the men in the cohort. MAIN RESULTS: 665 men (87% of those approached) returned satisfactory seven day diet diaries. After adjustment, the relative odds of an event in the men whose milk consumption was the median or higher, relative to those with lower intakes of milk, were 0.52 (0.27 to 0.99) for an ischaemic stroke and 0.88 (0.56 to 1.40) for an ischaemic heart disease event. Deaths from all causes were similar in the two milk consumption groups (relative odds 1.08; 0.74 to 1.58). CONCLUSIONS: These results give no convincing evidence of an increased risk of vascular disease from milk drinking. Rather, the subjects who drank more than the median amount of milk had a reduced risk of an ischaemic stroke, and possibly a reduced risk of an ischaemic heart disease event. These conclusions are in agreement with the results of a previously reported overview of 10 large, long term cohort studies based on food frequency intake records.

Long term effect of breast feeding: cognitive function in the Caerphilly cohort.

STUDY OBJECTIVE: There is evidence suggesting that artificial feeding is associated with a reduction in cognitive function in infants and children, in contrast with breast feeding, but the available evidence suffers from confounding by social and educational factors. An opportunity arose in the Caerphilly cohort study to examine relations between cognitive function in older men and their feeding as infants, when breast feeding was usual. DESIGN: A prospective cohort study. SETTING: Caerphilly, South Wales, UK, was a deprived coal mining community when the men had been born in 1920-35. Most had been breast fed as infants. PARTICIPANTS: 779 men aged 60-74 years when tested. The men had earlier been asked to obtain from their mothers their birth weight, and how they had been fed as infants. RESULTS: Complete data were obtained for 779 men. In those whose birth weight had been at or above the median, the adjusted mean cognitive function was only slightly and non-significantly lower in those who had been artificially fed. In the men whose birth weight had been below the median, having been artificially fed was associated with significantly lower results in both a test of reasoning (the AH4) and word power (the national adult reading test (NART)). Two standard deviations below the median birth weight, artificial feeding was associated with a reduction of six points (70% of a SD) on word power (the NART). CONCLUSIONS: In men whose birth weight had been low, having been artificially fed is associated with poorer cognitive function in late adult life.

Sorting of the human folate receptor in MDCK cells.

The human folate receptor (hFR) is a glycosylphosphatidy-linositol (GPI) linked plasma membrane protein that mediates delivery of folates into cells. We studied the sorting of the hFR using transfection of the hFR cDNA into MDCK cells. MDCK cells are polarized epithelial cells that preferentially sort GPI-linked proteins to their apical membrane. Unlike other GPI-tailed proteins, we found that in MDCK cells, hFR is functional on both the apical and basolateral surfaces. We verified that the same hFR cDNA that transfected into CHO cells produces the hFR protein that is GPI-linked. We also measured the hFR expression on the plasma membrane of type III paroxysmal nocturnal hemoglobinuria (PNH) human erythrocytes. PNH is a disease that is characterized by the inability of cells to express membrane proteins requiring a GPI anchor. Despite this defect, and different from other GPI-tailed proteins, we found similar levels of hFR in normal and type III PNH human erythrocytes. The results suggest the hypothesis that there may be multiple mechanisms for targeting hFR to the plasma membrane.

Milk drinking, ischaemic heart disease and ischaemic stroke I. Evidence from the Caerphilly cohort.

OBJECTIVE: To test the hypothesis that milk drinking increases the risk of ischaemic heart disease (IHD) and ischaemic stroke in a prospective study. DESIGN: In the Caerphilly Cohort Study dietary data, including milk consumption, were collected by a semiquantitative food frequency questionnaire in 1979-1983. The cohort has been followed for 20-24 y and incident IHD and stroke events identified. SUBJECTS: A representative population sample in South Wales, of 2512 men, aged 45-59 y at recruitment. MAIN OUTCOME MEASURES: In total, 493 men had an IHD event and 185 an ischaemic stroke during follow-up. RESULTS: After adjustment, the hazard ratio in men with a milk consumption of one pint (0.57 l) or more per day, relative to men who stated that they consumed no milk, is 0.71 (0.40-1.26) for IHD and 0.66 (0.24-1.81) for ischaemic stroke. At baseline, 606 men had had clinical or ECG evidence of vascular disease, and in these the vascular risk was even lower (0.37; 0.15-0.90). The hazard ratio for IHD and ischaemic stroke combined is 0.64 (0.39-1.06) in all men and 0.37 (0.15-0.90) in those who had had a prior vascular event. CONCLUSION: The data provide no convincing evidence that milk consumption is associated with an increase in vascular disease risk. Evidence from an overview of all published cohort studies on this topic should be informative. SPONSORSHIP: : The Medical Research Council, the University of Wales College of Medicine and Bristol University. Current support is from the Food Standards Agency.

Milk drinking, ischaemic heart disease and ischaemic stroke II. Evidence from cohort studies.

OBJECTIVE: Milk consumption is considered a risk factor for vascular disease on the basis of relevant biological mechanisms and data from ecological studies. The aim was to identify published prospective studies of milk drinking and vascular disease, and conduct an overview. DESIGN: The literature was searched for cohort studies, in which an estimate of the consumption of milk, or the intake of calcium from dairy sources, has been related to incident vascular disease. MAIN OUTCOME MEASURES: Ischaemic heart disease and ischaemic stroke. RESULTS: In total, 10 studies were identified. Their results show a high degree of consistency in the reported risk for heart disease and stroke, all but one study suggesting a relative risk of less than one in subjects with the highest intakes of milk. A pooled estimate of relative odds in these subjects, relative to the risk in subjects with the lowest consumption, is 0.87 (95% CI 0.74-1.03) for ischaemic heart disease and 0.83 (0.77-0.90) for ischaemic stroke. The odds ratio for any vascular event is 0.84 (0.78-0.90). CONCLUSIONS: Cohort studies provide no convincing evidence that milk is harmful. While there still could be residual confounding from unidentified factors, the studies, taken together, suggest that milk drinking may be associated with a small but worthwhile reduction in heart disease and stroke risk. SPONSORSHIP: The University of Wales College of Medicine and Bristol University. Current support is from the Food Standards Agency.

Bleeding time, stroke and myocardial infarction: the Caerphilly prospective study.

The stressed bleeding time is a simple 'global' test of haemostasis, dependent upon platelet function, rheology, thrombosis and intimal function. It could be of considerable value in clinical practice if it were shown to be predictive of vascular disease events. A stressed bleeding time test was done on 1319 men aged 55-69 years in the Caerphilly Cohort Study of Heart Disease, Stroke and Cognitive Decline. The men were followed-up and during the following 7-10 years 155 men had a myocardial infarction (MI) and 72 an ischaemic stroke. The mean bleeding time was 323 (SD 113)s. This was shorter in men who smoked by an average of 45 s, and lengthened in men who took aspirin daily by 40s. After making statistical adjustments for numerous possible confounding factors, the relative odds (ROs) of an MI within the third of men with the longest bleeding times, compared to the third with the shortest times, was 0.90 (0.40-2.03). For ischaemic stroke, the ROs in the third of men with the longest times were 1.42 (0.39-5.21). The stressed bleeding time does not predict either MI or ischaemic stroke. It has no place in health screening.

Lack of benefit of dietary advice to men with angina: results of a controlled trial.

OBJECTIVE: To see whether mortality among men with angina can be reduced by dietary advice. DESIGN: A randomized controlled factorial trial. SETTING: Male patients of general practitioners in south Wales. SUBJECTS: A total of 3114 men under 70 y of age with angina. INTERVENTIONS: Subjects were randomly allocated to four groups: (1) advised to eat two portions of oily fish each week, or to take three fish oil capsules daily; (2) advised to eat more fruit, vegetables and oats; (3) given both the above types of advice; and (4) given no specific dietary advice. Mortality was ascertained after 3-9 y. RESULTS: Compliance was better with the fish advice than with the fruit advice. All-cause mortality was not reduced by either form of advice, and no other effects were attributable to fruit advice. Risk of cardiac death was higher among subjects advised to take oily fish than among those not so advised; the adjusted hazard ratio was 1.26 (95% confidence interval 1.00, 1.58; P=0.047), and even greater for sudden cardiac death (1.54; 95% CI 1.06, 2.23; P=0.025). The excess risk was largely located among the subgroup given fish oil capsules. There was no evidence that it was due to interactions with medication. CONCLUSIONS: Advice to eat more fruit was poorly complied with and had no detectable effect on mortality. Men advised to eat oily fish, and particularly those supplied with fish oil capsules, had a higher risk of cardiac death. This result is unexplained; it may arise from risk compensation or some other effect on patients' or doctors' behaviour.

The long-term effect of dietary advice in men with coronary disease: follow-up of the Diet and Reinfarction trial (DART).

OBJECTIVE: To assess the long-term effect of dietary advice on diet and mortality after a randomised trial of men with a recent history of myocardial infarction. DESIGN: Questionnaire survey and mortality follow-up after a trial of dietary advice. SETTING: Twenty-one hospitals in south Wales and south-west England. SUBJECTS: Former participants in the Diet and Reinfarction Trial. MAIN OUTCOME MEASURES: Current fish intake and cereal fibre intake. All-cause mortality, stroke mortality and coronary mortality. RESULTS: By February 2000, after 21147 person years of follow-up, 1083 (53%) of the men had died. Completed questionnaires were obtained from 879 (85%) of the 1030 men alive at the beginning of 1999. Relative increases in fish and fibre intake were still present at 10 y but were much smaller. The early reduction in all-cause mortality observed in those given fish advice (unadjusted hazard 0.70 (95% CI 0.54, 0.92)) was followed by an increased risk over the next 3 y (unadjusted hazard 1.31 (95% CI 1.01, 1.70). Fat and fibre advice had no clear effect on coronary or all-cause mortality. The risk of stroke death was increased in the fat advice group-the overall unadjusted hazard was 2.03 (95% CI 1.14, 3.63). CONCLUSIONS: In this follow-up of a trial of intensive dietary advice following myocardial infarction we did not observe any substantial long-term survival benefit. Further trials of fish and fibre advice are feasible and necessary to clarify the role of these foods in coronary disease.

The EUROSTROKE cohorts: a short description and data analytical approach.

This paper describes the design and methodology of the participating cohorts in the EUROSTROKE project. Information is given about the cohort sampling, its size, the follow up procedures and event classification. Information is also given about the measurement of the cardiovascular and cerebrovascular risk factors in each of the cohorts separately. The cohorts described are the Caerphilly study in Cardiff, United Kingdom; the Kuopio Ischaemic Heart disease study in Kuopio, Finland; the Portugal study in Coimbra, Portugal; the EPIC cohort in Athens, Greece; the Ilsa study from Firenze, Italy; the Rotterdam Study in Rotterdam, the Netherlands, and the Novosibirsk cohort in Novosibirsk, Russia.

Left ventricular hypertrophy and risk of fatal and non-fatal stroke. EUROSTROKE: a collaborative study among research centres in Europe.

BACKGROUND: This study investigated the association between electrocardiographically assessed left ventricular hypertrophy (LVH) and fatal, non-fatal, haemorrhagic and ischaemic stroke in four European cohorts participating in EUROSTROKE. METHODS: EUROSTROKE is a collaborative project among ongoing European cohort studies to investigate differences in incidence of, and risk factors for, stroke between countries. EUROSTROKE is designed as a nested case-control study. For each stroke case, two controls were sampled. Strokes were classified according to MONICA criteria or reviewed by a panel of four neurologists. LVH was assessed according to the Minnesota code or the automated diagnostic MEANS classification system. For this analysis, data on LVH and stroke were available from cohorts in Cardiff (84 cases/200 controls), Kuopio (60/116), Rotterdam (114/334), and Novosibirsk (62/168). Results are adjusted for age and sex. RESULTS: LVH was associated with a twofold increased risk of stroke (odds ratio 2.1 (95% CI 1.3 to 3.5). The risk was particularly pronounced for fatal stroke (4.0 (95% CI 2.1 to 7.9)), whereas the risk was non-significantly increased for non-fatal stroke (1.5 (95% CI 0.8 to 2.7)). The increased risk was more pronounced in smokers: for total stroke 3.5 (95% CI 1.5 to 8.1) versus 1.6 (95% CI 0.8 to 3.1) in non-smokers. Adjustment for systolic blood pressure and body mass index attenuated the associations. LVH was not preferentially associated with a particular type of stroke, although the association with cerebral infarction was stronger. CONCLUSION: This analysis of the EUROSTROKE project indicates that LVH assessed by electrocardiogram is a predictor of stroke. The association seems to be stronger for fatal stroke than for non-fatal stroke and is more pronounced in smokers.

Level of fibrinogen and risk of fatal and non-fatal stroke. EUROSTROKE: a collaborative study among research centres in Europe.

BACKGROUND: It is well established that raised levels of fibrinogen increase the risk of coronary heart disease. For stroke, however, data are much more limited and restricted to overall stroke. This study investigated the association between fibrinogen and fatal, non-fatal, haemorrhagic and ischaemic stroke in three European cohorts participating in EUROSTROKE. METHODS: EUROSTROKE is a collaborative project among ongoing European cohort studies on incidence and risk factors of stroke. EUROSTROKE is designed as a nested case-control study. For each stroke case, two controls were sampled. Strokes were classified according to MONICA criteria or reviewed by a panel of four neurologists. Recently, data on stroke and fibrinogen became available from cohorts in Cardiff (79 cases/194 controls), Kuopio (74/124), and Rotterdam (62/203). Results were adjusted for age, sex, smoking, and systolic blood pressure. RESULTS: The risk of stroke gradually increased with increasing fibrinogen levels: the odds ratios per quartile increase were 1.08 (95% CI 0.63 to 1.84), 1.91 (1.12 to 3.26) and 2.78 (1.64 to 4.72), respectively. This association was similar for ischaemic (n=138) and haemorrhagic stroke (n=25). Associations between fibrinogen and stroke were similar across strata of smoking, diabetes mellitus, previous myocardial infarction, and HDL cholesterol. The odds ratio, however, tended to increase with increasing systolic blood pressure: from 1.21 among those with a systolic pressure <120 mm Hg to 1.99 among subjects with a systolic pressure of 160 mm Hg or above. CONCLUSION: This analysis of the EUROSTROKE project indicates that fibrinogen is a powerful predictor of stroke. Results did not disclose a differential in this relation of fibrinogen and fatal or non-fatal stroke, or with type of stroke (ischaemic or haemorrhagic).

Total and HDL cholesterol and risk of stroke. EUROSTROKE: a collaborative study among research centres in Europe.

BACKGROUND: Controversy remains on the relation between serum lipids levels and stroke risk. This paper investigated the association of total and HDL cholesterol level to fatal and non-fatal, and haemorrhagic and ischaemic stroke in four European cohorts participating in EUROSTROKE. METHODS: EUROSTROKE is a collaborative project among ongoing European cohort studies on incidence and risk factors of stroke. EUROSTROKE is designed as a nested case-control study. For each stroke case, two controls were sampled. Strokes were classified according to MONICA criteria or reviewed by a panel of four neurologists. At present, data on stroke and risk factors were available from cohorts in Cardiff (84 cases), Kuopio (74 cases), Rotterdam (157 cases), and Novosibirsk (79 cases). RESULTS: Pooled analyses showed no significant association between total cholesterol and risk of stroke (odds ratio for increase of 1 mmol/l in cholesterol of 0.98 (95% CI 0.88 to 1.09)). Analyses for haemorrhagic stroke and cerebral infarction revealed odds ratios of 0.80 (95% CI 0.61 to 1.05) and 1.06 (95% CI 0.94 to 1.19), respectively. The association of HDL cholesterol to stroke was different in men compared with women. In men, there was a general trend towards a lower risk of stroke with an increase in HDL (odds ratio per 1 mmol/l increase in HDL cholesterol 0.68 (95% CI 0.40 to 1.16)). In women, however, an increase in HDL was associated with a significant increased risk of non-fatal stroke and of cerebral infarction (odds ratios of 2.46 (95% 0.1.20 to 5.04) and 2.52 (95% CI 1.15 to 5.50), respectively. The difference between men and women in the association of HDL with stroke seemed to differ mainly in smokers and never smokers, but not among ex smokers. CONCLUSION: This analysis of the EUROSTROKE project could not disclose an association of total cholesterol with fatal, non-fatal, haemorrhagic or ischaemic stroke. HDL cholesterol however, seemed to be related to stroke differently in men than in women.

Gamma-glutamyltransferase and risk of stroke: the EUROSTROKE project.

BACKGROUND: Alcohol consumption has been implicated in the aetiology of stroke. As data on alcohol consumption obtained by questionnaire are susceptible to misclassification, this study evaluated the association between gamma-glutamyltransferase (gamma-GT), as a marker for alcohol consumption, and fatal, non-fatal, haemorrhagic and ischaemic stroke in three European cohort studies, participating in EUROSTROKE. METHODS: EUROSTROKE is a collaborative project among ongoing European cohort studies on incidence and risk factors of stroke. EUROSTROKE is designed as a nested case-control study. For each stroke case, two controls were sampled. Strokes were classified according to MONICA criteria or reviewed by a panel of four neurologists. At present, data on stroke and gamma-GT were available from cohorts in Cardiff (57 cases), Kuopio (66 cases), and Rotterdam (108 cases). RESULTS: An increase in gamma-GT of one standard deviation (28.7 IU/ml) was associated with an age and sex adjusted 26% (95% CI 5 to 53) increase in risk of stroke. Adjustment for confounding variables such as drug use, history of myocardial infarction, total cholesterol, and diabetes mellitus did not materially attenuate the association. The risk of haemorrhagic stroke increased linearly with increase in gamma-GT. The association for cerebral infarction was not graded: the risk increased beyond the first quartile, and remained increased. The association of gamma-GT with stroke was significantly stronger among subjects without diabetes mellitus compared with subjects with diabetes mellitus (no association observed). CONCLUSION: This EUROSTROKE analysis showed that an increased gamma-GT, as a marker of alcohol consumption, is associated with increased risk of stroke, in particular haemorrhagic stroke.

Prediction of stroke in the general population in Europe (EUROSTROKE): Is there a role for fibrinogen and electrocardiography?

BACKGROUND: To decide whether a person with certain characteristics should be given any kind of intervention to prevent a cardiovascular event, it would be helpful to classify subjects in low, medium and high risk categories. The study evaluated which well known cerebrovascular and cardiovascular correlates, in particular fibrinogen level and ECG characteristics, are able to predict the occurrence of stroke in men of the general population using data from three European cohorts participating in EUROSTROKE. METHODS: EUROSTROKE is a collaborative project among ongoing European population based cohort studies and designed as a prospective nested case-control study. For each stroke case two controls were sampled. Strokes were classified according to MONICA criteria or reviewed by a panel of four neurologists. Complete data were available of 698 men (219 stroke events) from cohorts in Cardiff (84 cases/200 controls), Kuopio (74/148) and Rotterdam (61/131). Multivariable logistic regression modeling was used to evaluate which information from history, physical examination (for example, blood pressure), blood lipids, and fibrinogen and ECG measurements independently contributed to the prediction of stroke. The area under receiver operating characteristic curve (ROC area) was used to estimate the predictive ability of models. RESULTS: Independent predictors from medical history and physical examination were age, stroke history, medically treated hypertension, smoking, diabetes mellitus and diastolic blood pressure. The ROC area of this model was 0.69. After validating and transforming this model to an easy applicable rule, 40% of all future stroke cases could be predicted. Adding pulse rate, body mass index, blood lipids, fibrinogen level and ECG parameters did not improve the classification of subjects in low, medium and high risk. Results were similar when fibrinogen was dichotomised at the upper tertile or quintile. CONCLUSION: In the general male population the future occurrence of stroke may be predicted using easy obtainable information from medical history and physical examination. Measurement of pulse rate, body mass index, blood lipids, fibrinogen level and ECG characteristics do not contribute to the risk stratification of stroke and have no value in the screening for stroke in the general male population.

Ischaemic heart disease and Cag A strains of Helicobacter pylori in the Caerphilly heart disease study.

OBJECTIVE: To look for the presence of the more virulent strains of Helicobacter pylori (H pylori) in men who developed ischaemic heart disease over a 10 year period and in controls. DESIGN: The Caerphilly prospective heart disease study recruited 2512 men aged 45-59 years during 1979-83. Western blot analysis or enzyme linked immunosorbent assay (ELISA) was performed on serum taken from those who subsequently died of ischaemic heart disease, or developed non-fatal myocardial infarction, to determine H pylori and Cag A status. Similar information was available on age matched controls. RESULTS: During the first decade of the study, 312 men died of ischaemic heart disease or developed non-fatal myocardial infarction. Serum was available from 172 of these (55%). There was no evidence of an association between Cag A seropositivity and incident ischaemic heart disease or ischaemic heart disease mortality, either before or after adjustment for potential confounders (adjusted odds ratios 1.18 (95% confidence interval (CI) 0.76 to 1.85) and 1.13 (95% CI 0.61 to 2.07), respectively). Further, the odds ratios for ischaemic heart disease incidence and ischaemic heart disease mortality by H pylori seropositivity did not appear to depend on the presence or absence of Cag A strains (p = 0.76 and 0.77, respectively). CONCLUSIONS: In this cohort of middle aged men, followed over a 10 year period, there is little evidence of an association between Cag A seropositivity and either incident ischaemic heart disease or ischaemic heart disease mortality.

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.