Seven Countries Study - Seven Countries

Description:

Long-term observational study of CAD risk factors and mortality.

Hypothesis:

To investigate the epidemiology and causes of coronary heart disease.

Study Design

Study Design:

Patients Screened: Not given
Patients Enrolled: 12,763
Mean Follow Up: Over 25 years
Mean Patient Age: Between 40 and 59 at enrollment
Female: 0

Patient Populations:

Male gender
Ages 40-59

Primary Endpoints:

All-cause mortality

Drug/Procedures Used:

Observational series

Principal Findings:

The Seven Countries Study, started in 1958, studied the risk factors of coronary heart disease in a large number of men. Its findings have been reported in a number of monographs and articles. The study is still ongoing to explore the relationship between lifestyle and health in elderly people.

Clinical diagnoses were made for coronary heart disease (CHD), 'other heart diseases' (OTH), peripheral arterial disease (PAD), stroke (STR), chronic obstructive pulmonary disease (COPD), and diabetes mellitus (DIAB). Large regional differences were found in the prevalence of the six conditions. Weak relations were found between population prevalence of each disease and population death rates for that disease. Among cohorts the relative risk of death in 15 years from any cause adjusted for other risk factors, showed little variation among countries. Pooled relative risks, adjusted by the inverse of variance (with 95% CI) were: for CHD, 1.81 (1.60-2.06); for OTH, 1.47 (1.28-1.69); for PAD, 1.64 (1.39-1.93); for STR, 1.56 (1.23-1.98); for COPD, 1.67 (1.48-1.88); and for DIAB, 1.75 (1.43-2.15). The smallest variability of prognosis among countries was found for CHD, OTH and DIAB; the largest for PAD, STR and COPD. Despite simple clinical diagnostic procedures and large differences in prevalence, the relation of established prevalent conditions to subsequent all-cause mortality is relatively uniform among countries and across these conditions, with a relative risk of dying in 15 years usually ranging between 1.5 and 2.0.

Coronary heart disease (CHD) mortality was defined as fatal myocardial infarction or sudden coronary death, and proportional hazard models were solved, for each country, with age, serum cholesterol level, systolic blood pressure and cigarette consumption as covariates. The relationships between risk factors and CHD mortality were statistically significant for all risk factors and for all countries, except for age in Croatia and Japan, cholesterol in Croatia and Japan, systolic blood pressure in Serbia and Greece, and cigarette-smoking in the Netherlands, Croatia, Serbia and Greece. When comparing all pairs of coefficients (28 comparisons for each factor) significant differences were found on four occasions for age, on six occasions for cholesterol, on no occasion for blood pressure and on four occasions for cigarette-smoking. Other tests suggested a substantial homogeneity among multivariate coefficients. Estimates for pooled coefficients were: age, in years, 0.0570 (95% confidence limits 0.0465 and 0.0673); relative risk for 5 years 1.33 (95% confidence limits 1.26 and 1.40); serum cholesterol level in mg/dl, 0.0057 (95% confidence limits 0.0045 and 0.0069); relative risk for 40 mg/dl 1.31 (95% confidence limits 1.20 and 1.31); systolic blood pressure in mmHg, 0.0160, (95% confidence limits 0.0134 and 0.0185), relative risk for 20 mmHg 1.38 (95% confidence limits 1.31 and 1.45); cigarettes per day, 0.0220 (95% confidence limits 0.0170 and 0.0272); relative risk for 10 cigarettes per day 1.25 (95% confidence limits 1.18 and 1.31). Substantial similarities were found in the multivariate coefficients of major coronary risk factors to CHD risk derived from population samples varying in CHD frequency.

An ecological analysis explored whether 'typical' clinical manifestations of coronary heart disease (CHD) such as myocardial infarction and sudden death, related to major cardiovascular risk factors in the same way as the 'atypical' manifestations, e.g. heart failure and chronic arrhythmias. There was a significant relationship of populational mean levels of serum cholesterol and of systolic blood pressure to age-adjusted death rates from typical CHD manifestations. The relationships for atypical CHD deaths were not statistically significant. In a multivariate analysis, none of the risk factors showed relevant associations with event rates, except serum cholesterol and typical CHD deaths.: The usual relationship of blood pressure and smoking habits and the differential relationship of serum cholesterol with atypical CHD (negative or absent) versus typical CHD (direct and significant) could be explained by 'two different diseases' or by a mix of poorly classified conditions among the atypical cases.

The relationship between serum total cholesterol and long-term mortality from coronary heart disease (CHD) was compared in different cultures. To increase statistical power six cohorts were formed, based on similarities in culture and cholesterol changes during the first 10 years of follow-up. Relative risks (RRs) were estimated with Cox proportional hazards (survival) analysis for 25-year CHD mortality for cholesterol quartiles and per 0.50-mmol/L (20-mg/dL) cholesterol increase. Adjustment was made for age, smoking, and systolic blood pressure. The age-standardized CHD mortality rates in the six cohorts ranged from 3% to 20%. The RRs for the highest compared with the lowest cholesterol quartile ranged from 1.5 to 2.3, except for Japan's RR of 1.1. For a cholesterol level of around 5.45 mmol/L (210 mg/dL), CHD mortality rates varied from 4% to 5% in Japan and Mediterranean Southern Europe to about 15% in Northern Europe. However, the relative increase in CHD mortality due to a given cholesterol increase was similar in all cultures except Japan. Using a linear approximation, a 0.50-mmol/L (20-mg/dL) increase in total cholesterol corresponded to an increase in CHD mortality risk of 12%, which became an increase in mortality risk of 17% when adjusted for regression dilution bias. Across cultures, cholesterol is linearly related to CHD mortality, and the relative increase in CHD mortality rates with a given cholesterol increase is the same.

There was an unexpected finding of an inverse population (ecological) relationship between mean systolic blood pressure levels and stroke death rates in the 25 years follow-up results. Mean entry population levels of systolic blood pressure among the cohorts were strongly and inversely related with their 25-year stroke death rates (R -0.55; CI -0.81 and -0.06; p = 0.0276). Within cohorts in contrast, the individual relation of blood pressure and stroke was strongly positive and significant in 14 of the 16 cohorts. Mean population levels of serum cholesterol were inversely and strongly related to stroke death rates (R -0.79; CI -0.92 and -0.46; p = 0.0003), while the partial correlation coefficient of systolic blood pressure, computed in models including serum cholesterol, became small and not significant (-0.05; CI -0.55 and +0.48; p = 0.8537). Age at death for stroke (average 68.9 +/- 7.1 years) was significantly higher than age at death from myocardial infarction and sudden death (average 65.8 +/- 7.8 years) suggesting a competition effect between the conditions.

Dietary information was collected at baseline in small random samples of each cohort. In 1987 the reported foods were bought locally and analysed chemically. COPD mortality rate ratios were calculated, for a change equivalent to 10% of the overall mean consumption of a dietary factor. There were independent inverse associations between 25-year COPD mortality and baseline consumption of fruits (rate ratio 0.49; 95% confidence interval 0.36-0.67) and fish (rate ratio, 0.97; 95% confidence interval 0.93-1.00), after adjustment for potential confounders. COPD mortality showed no statistically significant association with intake of antioxidants or vegetables. Fruit and fish consumption may partly explain population differences in COPD mortality.

A substudy investigated whether population differences in 25-year cancer mortality and mortality due to cancer of the lung, stomach, and colorectum could be explained by population differences in adherence to the European Code Against Cancer. Overall adherence to the first four recommendations of the European Code Against Cancer was inversely related to 25-year total cancer mortality but not to all-cause mortality. The association with cancer mortality was essentially due to the inverse association for adherence to the guideline on smoking only. Each decrease in the percentage of smokers of 3.4% (10% of range) was associated with a relative risk of 0.93 of dying from cancer. Adherence to the recommendation on consumption of vegetables, fruits, and fiber-rich cereals was inversely related to stomach cancer mortality, whereas adherence to the recommendation on body weight, physical activity, and intake of fat was associated with higher stomach cancer mortality.

Interpretation:

The Seven Countries Study was the first of the major epidemiological investigations of heart disease deliberately to pursue a specific nutritional hypothesis; it also set a pattern for standardising methods of examination in numerous other international and national studies.

References:

1. Circulation 1970;41(4 Suppl):I9-13. Study design and methods
2. J Cardiovasc Risk 1996;3:69-75. Risk factors for CAD: 25 year follow-up
3. Eur J Epidemiol 1997;13:379-86. Inverse relation between BP and stroke
4. Ann Med 1997;29:135-41. Chronic diseases and all-cause mortality risk
5. JAMA 1995;274(2):131-6. Serum cholesterol and CHD mortality
6. Stroke 1996;27:381-7. 25-year prediction of stroke deaths
7. Eur J Clin Nutrition 1998;52:819-25. Antioxidant intake and COPD
8. Nutrition & Cancer 1998;30:14-20. Intercohort comparisons for cancer
9. Cardiology 1998;89:59-67. Risk factors and manifestations of CAD

Clinical Topics: Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Acute Heart Failure, Smoking

Keywords: Life Style, Follow-Up Studies, Greece, Death, Sudden, Peripheral Arterial Disease, Blood Pressure, Risk Factors, Cholesterol, Fruit, Proportional Hazards Models, Vegetables, Croatia, Motor Activity, Confidence Intervals, Stomach Neoplasms, Myocardial Infarction, Stroke, Multivariate Analysis, Body Weight, Smoking, Prognosis, Pulmonary Disease, Chronic Obstructive, Heart Failure, Cereals, Lung Neoplasms, Diabetes Mellitus


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