1 Department of Primary Care and Population Sciences, Royal Free and University College Medical School, London NW3 2PF, UK
2 Department of Community Health Sciences, St George's Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK
Correspondence: Mrs Mary Walker, Department of Primary Care and Population Sciences, Royal Free and University College Medical School, London NW3 2PF, UK. E-mail: mary.walker{at}pcps.ucl.ac.uk
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How did the study come about? |
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Professor Gerry Shaper and colleagues submitted a 5-year proposal to the Medical Research Council: to examine the factors responsible for the considerable regional variation in coronary heart disease, hypertension, and stroke in Great Britain, and to determine the causes of these conditions in order to provide a rational basis for recommendations towards their prevention.
This proposal embraced the water hardness hypothesis but extended the potential of the data collected to produce a more substantial and wider ranging enquiry into the causes of CHD both at the individual and the regional level: The British Regional Heart Study (BRHS).
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Funding |
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Since the inception of the study, the BRHS research team has been based at the Royal Free Hospital School of Medicine, and subsequently at the merged Royal Free and University College Medical School, London.
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What does it cover and how has this changed? |
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While the primary focus remains the aetiology and prevention of CVD, there is now an additional interest in the social and geographical patterns of CV-related disabilities, clinical prevention and care in an older male cohort.
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Who is in the sample? |
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The sampling frame was based in General Practice at a time when age-sex registers were uncommon (1977), but General Practice lists covered >95% of the population. With the help of the District Medical Officer (Community Health Physician) in each town, a single group General Practice was identified based on the following criteria:
The men
Almost 10 000 middle-aged men aged 4059, (400 from each town) were drawn at random from four, 5-year stratified age bands of each practice age-sex register. These had to be made for the purpose in 18 of the 24 practices selected.
Invitations were sent, signed by their GPs, encouraging the men to attend the cardiovascular health check at a local venue, usually the Practice premises.
A few men (<10) in each town, who were physically or mentally unable to attend, were excluded from the invitation list by the GP.
With a 78% response rate, a total of 7735 men aged 4059 years (approximately 300 from each town) were recruited and examined.1 Table 1 shows the social class distribution of participants.
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How often have they been followed-up? |
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Office of National Statistics (ONS): General Register Office (GRO) Southport and Edinburgh
Family Practitioner Committees, now Patient Registration Departments in Health Authorities
A Practice Co-ordinator in each of the 24 original General Practices
The new GPs with whom a subject re-registered after moving home
The men themselves (five postal questionnaires, one re-examination). Further details in Table 2.
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Local sources of morbidity and mobility data
At 2-yearly intervals the participating General Practices are sent a standard form (Appendix), requesting confirmation of each subject's continuing registration, current address, and any new cardiovascular events and new diagnoses of cancer or diabetes that have occurred within the last 2 years. Any removal and re-registration of a subject is traced to the new GP. The study now includes over 1400 GPs nationwide, in addition to the 24 original practices.
All new major CHD events reported by the practices are followed-up with an enquiry form to the GP or hospital consultant to obtain confirmatory evidence that case criteria have been met.
Case criteria for GP reports
Myocardial infarction
Definite: A history of typical features including chest pain, supported by ECG evidence and/or abnormal enzyme levels. (WHO criteria, two out of three of above).
Possible: A clinical diagnosis only, based on typical features including chest pain. Include MI picked up by routine ECG without typical history.
Angina
Typical effort or stress-related chest pain.
Stroke
An acute disturbance of cerebral function of vascular origin, lasting 24 hours. Include subarachnoid haemorrhage, cerebral haemorrhage, or thrombosis.
Transient ischaemic attack
Disturbance of cerebral function of vascular origin, lasting <24 hours and leaving no residual deficit.
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What has been measured? |
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*Additional measurements made at re-examination only.
Anthropometry
Height (m), Weight (kg), BMI (kg/m2)
*Bio-impedance, waist and hip circumference, triceps and sub-scapular skin-folds.
Physiological
Blood pressure, mean of two readings: using the LSH&TM sphygmomanometer.
*Dinamap 1846
Lung function (Vitalograph: FVC, FEV1,)
ECG computer interpreted (3-lead orthogonal)
*(12 lead Siemens Sicard 460)
Blood sample
Biochemistry, haematology, trace metals, blood group.
Frozen sera stored for future measurements, e.g. fatty acids, homocysteine, C-reactive protein, from nested case-control studies.
*Rheology, carboxyhaemoglobin, HbA1c and cells for DNA profiling.
Urine sample
24hr + spot urine and tap water samples from 1500 sub-group at baseline only.
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Baseline questionnaire (Q1) |
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Postal questionnaires |
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Attrition of sample |
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25 new GPs failed to reply to our enquiry
Response to postal questionnaires ranged from 98%, after 5 years, to 80% for the most recent enquiry. On each occasion a small number of men who had not previously replied completed a questionnaire for the first time and 12 people who had never completed a postal questionnaire attended the re-examination.
To date, only 15 (0.2%) survivors have never completed a questionnaire since baseline and 68% (3234) have responded to all communications. This, combined with a 98% follow-up through GP reporting on surviving participants, provides a powerful perspective on how middle-aged British men have fared during the past 25 years. Continuing follow-up of these men, now aged 6587 years, has become a valuable resource for research into the health status of the elderly.
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Key findings |
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High prevalence of CHD
At the baseline examination, a quarter of all men had some evidence of established CHD (history of anginal chest pain, possible myocardial infarction and/or electrocardiographic abnormalities suggestive of myocardial ischaemia or infarction) and only 20% of this group were known to their GP.3
Key role of major CHD risk factors
The early results showed that high serum total cholesterol, high blood pressure, and cigarette smoking were strong, independent risk factors, widely distributed in the population. At entry, 41% of the sample were current cigarette smokers, mean systolic blood pressure was 145 mmHg and mean serum total cholesterol 6.3mmol/l. Based on the blood pressure distribution, the top 60% of the study population had at least a twofold risk of CHD as a result of their blood pressure level alone, compared with men in the lowest fifth of the distribution; similar results applied for blood cholesterol.4
Recently, the combined importance of cigarette smoking, blood cholesterol, and blood pressure to population levels of CHD have been reassessed taking into account within-person variation in blood cholesterol and blood pressure. Results showed that 80% of all CHD events occurring during middle-age would have been prevented had everyone experienced the average risks of non-smoking men in the bottom fifths of the blood cholesterol and blood pressure distributions.5
Alcohol
The accepted interpretation of the J-shaped curve relating alcohol intake to mortality or CHD is that the lowest point on the curve (light/moderate drinking) represents optimum exposure to alcohol and that the increased risk in non-drinkers reflects the consequence of sub-optimum exposure. However, non-drinkers, both ex-drinkers and lifelong teetotallers, consistently show an increased prevalence of conditions likely to increase morbidity and mortality compared with occasional or light drinkers. In addition, regular light drinkers tend to have characteristics extremely advantageous to health. Changes take place in alcohol intake in individuals over time, with a strong downward drift from heavy or moderate drinking towards non-drinking, affected to a considerable extent by the accumulation of ill health and medication. Reduction in alcohol intake or giving up drinking is associated with higher rates of new diagnoses than remaining stable in alcohol intake and also with higher rates of both cardiovascular and non-cardiovascular mortality. The use of non-drinkers as a baseline, and failure or inability to adequately take into account the characteristics of subjects in the different alcohol intake categories, exaggerates the risk of CHD events and all-cause mortality in non-drinkers and the benefits of light/moderate alcohol intake.6
Weight
In 1980, the prevalence of obesity (BMI 30 kg/m2) in the study sample was 8.2%. By 2000 this figure had more than doubled to 17.4%, with a town range from 8.1% in Guildford to 29.0% in Falkirk. The risk of cardiovascular mortality, heart attack, and diabetes, as well as levels of a wide range of risk factors, all increased progressively from a BMI <20 kg/m2. The findings indicate that the ideal or desirable BMI, that is the level associated with the lowest CVD morbidity and all-cause mortality, is around 22 kg/m2 in middle-aged men.7
In relation to weight change (observed over a 5-year period), the lowest risk of heart attack was seen in those with stable weight or those with moderate weight gain (410%). Considerable weight gain (>10%) was associated with increased risk of a heart attack, but no benefit was seen with weight loss, even in overweight/obese men. This suggests that prevention of overweight and obesity is likely to be a more important long-term target than weight reduction.8
Sustained weight loss or fluctuation is associated with higher mortality rates. However, this appeared to be accounted for by disadvantageous lifestyle factors (smoking) and pre-existing disease, suggesting that weight loss and weight fluctuation themselves do not cause an increased risk of death.9
Physical activity
Moderate physical activity (equivalent to a 30-minute brisk walk) was found to significantly reduce the risk of heart attack in men with and without pre-existing disease.10 Furthermore, maintaining or taking up light or moderate physical activity, even in later life, reduces all-cause mortality and CVD risk in older men.11 Vigorous (sporting) exercise although beneficial, is not essential in order to obtain these effects. An increase in risk associated with vigorous activity was only observed in hypertensive subjects.12
Combined effects of behavioural risk factors on survival
A survival analysis has shown that a 50-year old man who is a lean, active, never-smoker has an 80% chance of surviving 15 years free from CVD disabilities compared with the 40% chance of an obese, inactive smoker.13
Identifying subjects at high risk of CHD
Using combinations of risk factors and markers of established CHD, scoring systems were developed, which identified up to 59% of major CHD events in the top 20% of the 'risk score' distribution. A simplified score for use in General Practice (based on smoking duration, systolic blood pressure, a history of pre-existing CHD, a history of chest pain on exertion, an early parental death from CHD, and a diagnosis of diabetes) predicted 53% of major CHD events in the top 20% of the score distribution. No other combination of risk exposures could improve on these predictions.14 More recently, we have demonstrated that the Framingham risk equations (which are currently used throughout the UK in primary prevention) substantially overestimate true coronary risk among men in the BRHS.15
Subsequent work, evaluating the potential effectiveness of different 'high-risk' and 'population' approaches to the primary prevention of CVD, taking into account the underestimation of the latter caused by measurement imprecision16 ('regression dilution bias') indicates that high-risk approaches to primary prevention are likely to have only a marginal impact on population levels of CVD, unless applied to a large proportion of the population. In contrast, small downwards shifts in the population distributions of two key risk factors (blood cholesterol and blood pressure) could substantially reduce future levels.17
Novel risk factors
Baseline stored serum specimens have been used to examine new aetiological hypotheses for risk of CHD and stroke using nested case-control studies and meta-analytical approaches. In this way the contributions of homocysteine,18 Helicobacter pylori,19 and other infectious agents, markers of chronic inflammation20 and haemostatic factors have been studied.21
Geographical/social variations
An ecological analysis had previously been carried out on data from 1969 to 1973 on 253 British towns, investigating in particular the association between water softness and CVD mortality. After adjustment for confounding factors, the unexplained excess CVD mortality was small (1015%), and no strategic change in water quality delivery appeared to be warranted.22
The well-established regional variations in CVD mortality were studied within the BRHS and the national twofold difference in incidence was seen between the towns. Using multilevel modelling, the geographical variation in CHD risk has been explored by including both ecological and personal risk factors. Geographical variations in cigarette smoking and blood pressure contributed substantially to this variation in risk, both for CHD23 and stroke.24 It was estimated that smoking, blood pressure, physical activity, social class, and height together explained 77% of this variation. Mean cholesterol levels were high by international standards in all towns (conferring a similar high risk throughout) and therefore did not contribute to the observed regional variation.
Inequalities in access to care
The incidence of re-vascularization procedures (CABG, PTCA) during the 1990s was lower in older men, council house residents, households without a car, and men living outside the South of England, particularly after markers of clinical need were taken into account.25 The use of medication in secondary prevention also favoured younger men, though there was little social class gradient seen.26
Initiatives emerging from the BRHS
In 1986, the BRHS extended its observations of blood pressure to younger men and women (aged 2529)27 and to primary school children in nine of the BRHS towns.28 A subsequent study has investigated the emergence of CVD risk factors in children in five exceptionally high and five exceptionally low CVD mortality areas.29
In 1996, ultrasound studies of the carotid and femoral arteries were carried out in a high and a low-risk town (Dewsbury and Maidstone) on the 400 existing men and 400 newly recruited, age-matched women.30 More recently (19992001) a team from Bristol has recruited a cohort of women (the British Women's Heart and Health Study (BWHHS), from the remaining 22 towns, to match in age the current cohort of men.31
Communications
These and many more results can be found in the BRHS Bibliography of indexed abstracts 19802001 (hard copy available on request) and on the BRHS website. This is updated in June and December each year with each new edition of the study's Newsletter, reporting current work in progress, recent publications and conference presentations.
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Strengths of the BRHS |
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Follow-up through General Practice has maintained 98% coverage of the cohort. Attrition due to death and emigration is representative of the source population.
Long-term co-operation from the cohort has been impressive.
Measurements have been validated, data entry verified and record keeping maintained to an exceptionally high standard.
Detailed postal questionnaires provide an update on risk factor changes and self-reported information on diagnoses and treatments.
With an increasingly wide range of exposures and growing numbers of outcome events, the value of the cohort is increasing with time.
Continuity of funding and a stable research team has enabled maximum efficiency and output.
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Weaknesses |
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Funding was initially declined for non-fatal CVD events and for the study of women. Both these issues have been redressed. Dietary data were not collected at baseline.
The baseline collection of stored sera was commenced late; samples were only available for the last 18 of 24 study towns.
A 20-year interval occurred before each subject was re-measured.
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Access to further information |
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All study questionnaires, data collection documents and newsletters are available in pdf format and there is an inter-active hypertext Bibliography of over 250 publications, including 19 theses, with keywords, titles, and abstracts leading to a full on line pdf text, where it has been made available by the journal.
Enquiries and requests for further information should be made to lucy.lennon{at}pcps.ucl.ac.uk. Tel. 020 7830 2335
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Appendix |
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Acknowledgments |
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References |
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2 Thomas MC, Walker M, Lennon LT, Thomson AG, Lampe FC, Shaper AG. Non-attendance at re-examination 20 years after screening in the British Regional Heart Study. J Public Health Medicine 2002;24:28591.
3 Shaper AG, Cook DG, Walker M, Macfarlane PW. Prevalence of ischaemic heart disease in middle aged British men. Br Heart J 1984;51:595605.[Abstract]
4 Shaper AG, Pocock SJ, Walker M, Phillips AN, Whitehead TP, Macfarlane PW. Risk factors for ischaemic heart disease: the prospective phase of the British Regional Heart Study. J Epidemiol Community Health 1985;39:197209.[Abstract]
5 Emberson JR, Whincup PH, Morris RW, Walker M. Re-assessing the contribution of serum total cholesterol, blood pressure and cigarette smoking to the aetiology of coronary heart disease: impact of regression dilution bias. Eur Heart J 2003;24:171926.
6 Shaper AG, Wannamethee SG. The J-shaped curve and changes in drinking habit. In: Alcohol and Cardiovascular Diseases. Novartis Foundation Symposium 216. 1998, pp. 17388.
7 Shaper AG, Wannamethee SG, Walker M. Bodyweight: implications for the prevention of coronary heart disease, stroke and diabetes mellitus in a cohort study of middle-aged men. BMJ 1997;314:131117.
8 Walker M, Wannamethee G, Whincup PH, Shaper AG. Weight change and risk of heart attack in middle-aged British men. Int J Epidemiol 1995;24:694703.[Abstract]
9 Wannamethee SG, Shaper AG, Walker M. Weight Change, Weight Fluctuation, and Mortality. Arch Int Med 2002;162:257580.[CrossRef][ISI]
10 Shaper AG, Wannamethee G, Weatherall R. Physical activity and ischaemic heart disease in middle-aged British men. Br Heart J 1991;66:38494.[Abstract]
11 Wannamethee SG, Shaper AG, Walker M. Changes in physical activity, mortality and incidence of CHD in older men. Lancet 1998;351:160308.[CrossRef][ISI][Medline]
12 Shaper AG, Wannamethee G, Walker M. Physical activity, hypertension and risk of heart attack in men without evidence of ischaemic heart disease. J Hum Hypertens 1994;8:310.[ISI][Medline]
13 Wannamethee SG, Shaper AG Walker M, Ebrahim S. Lifestyle and 15-year survival free of heart attack, stroke and diabetes in middle aged British men. Arch Intern Med 1998;158:243340.
14 Shaper AG, Pocock SJ, Phillips AN, Walker M. Identifying men at high risk of heart attacks: strategy for use in general practice. BMJ 1986;293:47479.[ISI][Medline]
15 Brindle P, Emberson JR, Lampe FC et al. Coronary risk-assessment: Framingham-based methods over-estimate risk in British middle-aged men. BMJ 2003;327:126772.
16 Emberson JR, Whincup PH, Morris RW, Walker M, Lowe GDO, Rumley A. Extent of regression dilution for established and novel coronary risk factors: results from the British Regional Heart Study. Eur J CVD Prev Rehab 2004;11:12534.
17 Emberson JR, Whincup PH, Morris RW, Walker M, Ebrahim S. Evaluating the impact of population and high risk strategies for the primary prevention of cardiovascular disease. Eur Heart J 2004;25:48491.
18 Homocysteine Studies Collaboration. Homocysteine and risk of ischaemic heart disease and stroke: 6000 events in 30 observational studies. JAMA 2002;288:201522.
19 Whincup P, Danesh J, Walker M et al. Prospective study of potentially virulent strains of Helicobacter pylori and coronary heart disease in middle-aged men. Circulation 2000;101:164752.
20 Danesh J, Whincup P, Walker M et al. Low grade inflammation and coronary heart disease: prospective study and updated meta-analysis. BMJ 2000;321:199204.
21 Danesh J, Whincup P, Walker M et al. Fibrin D-dimer and coronary heart disease: prospective study and meta-analysis. Circulation 2001;103:232327.
22 Pocock SJ, Shaper AG, Cook DG et al. British Regional Heart Study: geographic variations in cardiovascular mortality, and the role of water quality. BMJ 1980;280:124349.[ISI][Medline]
23 Morris RW, Whincup PH, Lampe FC, Walker M, Wannamethee SG, Shaper AG. Geographic variation in incidence of coronary heart disease in Britain: the contribution of established risk factors. Heart 2001;86:27783.
24 Morris RW, Whincup PH, Emberson JR, Lampe FC, Walker M, Shaper AG. North-south gradients in Britain for stroke and CHD: are they explained by the same factors? Stroke 2003;34:260409.
25 Morris RW, Whincup PH, Papacosta O, Walker M, Thomson A. Inequalities in coronary re-vascularisation during the 1990sprospective study in older British men. Heart 2004 (In press).
26 Whincup PH, Emberson J, Lennon L, Walker M, Papacosta O. Low prevalence of lipid lowering drug use in older men with established coronary heart disease. Heart 2002;88:2529.
27 Bruce NG, Cook DG, Shaper AG, Thomson AG. Geographical variations in blood pressure in British men and women. J Clin Epidemiol 1990;3:38598.[CrossRef]
28 Whincup PH, Cook DG, Papacosta O, Walker M. Childhood blood pressure, body build, and birthweight: geographical associations with cardiovascular mortality. J Epidemiol Community Health 1992;46:396402.[Abstract]
29 Whincup PH, Cook DG, Adshead F et al. Cardiovascular risk factors in British children from towns with widely differing adult cardiovascular mortality. BMJ 1996;313:7984.
30 Ebrahim S, Papacosta O, Whincup P et al. Carotid plaque, intima media thickness, cardiovascular risk factors, and prevalent cardiovascular disease in men and women: the British Regional Heart Study. Stroke 1999;30:84150.
31 Lawlor DA, Bedford C, Taylor M, Ebrahim S. Geographical variation in cardiovascular disease, risk factors, and their control in older women: British Women's Heart and Health Study. J Epidemiol Community Health 2003;57:13440.