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2.  Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials 
BMJ : British Medical Journal  2003;326(7404):1427.
Objective To determine the average reduction in blood pressure, prevalence of adverse effects, and reduction in risk of stroke and ischaemic heart disease events produced by the five main categories of blood pressure lowering drugs according to dose, singly and in combination.
Design Meta-analysis of 354 randomised double blind placebo controlled trials of thiazides, β blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and calcium channel blockers in fixed dose.
Subjects 40 000 treated patients and 16 000 patients given placebo.
Main outcome measures Placebo adjusted reductions in systolic and diastolic blood pressure and prevalence of adverse effects, according to dose expressed as a multiple of the standard (recommended) doses of the drugs.
Results All five categories of drug produced similar reductions in blood pressure. The average reduction was 9.1 mm Hg systolic and 5.5 mm Hg diastolic at standard dose and 7.1 mm Hg systolic and 4.4 mm Hg diastolic (20% lower) at half standard dose. The drugs reduced blood pressure from all pretreatment levels, more so from higher levels; for a 10 mm Hg higher blood pressure the reduction was 1.0 mm Hg systolic and 1.1 mm Hg diastolic greater. The blood pressure lowering effects of different categories of drugs were additive. Symptoms attributable to thiazides, β blockers, and calcium channel blockers were strongly dose related; symptoms caused by ACE inhibitors (mainly cough) were not dose related. Angiotensin II receptor antagonists caused no excess of symptoms. The prevalence of symptoms with two drugs in combination was less than additive. Adverse metabolic effects (such as changes in cholesterol or potassium) were negligible at half standard dose.
Conclusions Combination low dose drug treatment increases efficacy and reduces adverse effects. From the average blood pressure in people who have strokes (150/90 mm Hg) three drugs at half standard dose are estimated to lower blood pressure by 20 mm Hg systolic and 11 mm Hg diastolic and thereby reduce the risk of stroke by 63% and ischaemic heart disease events by 46% at age 60-69.
PMCID: PMC162261  PMID: 12829555
3.  Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis 
BMJ : British Medical Journal  2003;326(7404):1423.
Objectives To determine by how much statins reduce serum concentrations of low density lipoprotein (LDL) cholesterol and incidence of ischaemic heart disease (IHD) events and stroke, according to drug, dose, and duration of treatment.
Design Three meta-analyses: 164 short term randomised placebo controlled trials of six statins and LDL cholesterol reduction; 58 randomised trials of cholesterol lowering by any means and IHD events; and nine cohort studies and the same 58 trials on stoke.
Main outcome measures Reductions in LDL cholesterol according to statin and dose; reduction in IHD events and stroke for a specified reduction in LDL cholesterol.
Results Reductions in LDL cholesterol (in the 164 trials) were 2.8 mmol/l (60%) with rosuvastatin 80 mg/day, 2.6 mmol/l (55%) with atorvastatin 80 mg/day, 1.8 mmol/l (40%) with atorvastatin 10 mg/day, lovastatin 40 mg/day, simvastatin 40 mg/day, or rosuvastatin 5 mg/day, all from pretreatment concentrations of 4.8 mmol/l. Pravastatin and fluvastatin achieved smaller reductions. In the 58 trials, for an LDL cholesterol reduction of 1.0 mmol/l the risk of IHD events was reduced by 11% in the first year of treatment, 24% in the second year, 33% in years three to five, and by 36% thereafter (P < 0.001 for trend). IHD events were reduced by 20%, 31%, and 51% in trials grouped by LDL cholesterol reduction (means 0.5 mmol/l, 1.0 mmol/l, and 1.6 mmol/l) after results from first two years of treatment were excluded (P < 0.001 for trend). After several years a reduction of 1.8 mmol/l would reduce IHD events by an estimated 61%. Results from the same 58 trials, corroborated by results from the nine cohort studies, show that lowering LDL cholesterol decreases all stroke by 10% for a 1 mmol/l reduction and 17% for a 1.8 mmol/l reduction. Estimates allow for the fact that trials tended to recruit people with vascular disease, among whom the effect of LDL cholesterol reduction on stroke is greater because of their higher risk of thromboembolic stroke (rather than haemorrhagic stroke) compared with people in the general population.
Conclusions Statins can lower LDL cholesterol concentration by an average of 1.8 mmol/l which reduces the risk of IHD events by about 60% and stroke by 17%.
PMCID: PMC162260  PMID: 12829554
4.  Risk factor thresholds: their existence under scrutiny 
BMJ : British Medical Journal  2002;324(7353):1570-1576.
PMCID: PMC1123506  PMID: 12089098
5.  Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies 
Objectives To determine the quantitative efficacy of different classes of blood pressure lowering drugs in preventing coronary heart disease (CHD) and stroke, and who should receive treatment.
Design Meta-analysis.
Data source Medline (1966-2007).
Study selection Randomised trials of blood pressure lowering drugs recording CHD events and strokes. 108 trials studied differences in blood pressure between study drug and placebo (or control group not receiving the study drug) (“blood pressure difference trials”), and 46 trials compared drugs (“drug comparison trials”). Seven trials with three randomised groups fell into both categories. The results were interpreted in the context of those expected from the largest published meta-analysis of cohort studies, totalling 958 000 people.
Participants 464 000 people defined into three mutually exclusive categories: participants with no history of vascular disease, a history of CHD, or a history of stroke.
Results In the blood pressure difference trials β blockers had a special effect over and above that due to blood pressure reduction in preventing recurrent CHD events in people with a history of CHD: risk reduction 29% (95% confidence interval 22% to 34%) compared with 15% (11% to 19%) in trials of other drugs. The extra effect was limited to a few years after myocardial infarction, with a risk reduction of 31% compared with 13% in people with CHD with no recent infarct (P=0.04). In the other blood pressure difference trials (excluding CHD events in trials of β blockers in people with CHD), there was a 22% reduction in CHD events (17% to 27%) and a 41% (33% to 48%) reduction in stroke for a blood pressure reduction of 10 mm Hg systolic or 5 mm Hg diastolic, similar to the reductions of 25% (CHD) and 36% (stroke) expected for the same difference in blood pressure from the cohort study meta-analysis, indicating that the benefit is explained by blood pressure reduction itself. The five main classes of blood pressure lowering drugs (thiazides, β blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers) were similarly effective (within a few percentage points) in preventing CHD events and strokes, with the exception that calcium channel blockers had a greater preventive effect on stroke (relative risk 0.92, 95% confidence interval 0.85 to 0.98). The percentage reductions in CHD events and stroke were similar in people with and without cardiovascular disease and regardless of blood pressure before treatment (down to 110 mm Hg systolic and 70 mm Hg diastolic). Combining our results with those from two other studies (the meta-analyses of blood pressure cohort studies and of trials determining the blood pressure lowering effects of drugs according to dose) showed that in people aged 60-69 with a diastolic blood pressure before treatment of 90 mm Hg, three drugs at half standard dose in combination reduced the risk of CHD by an estimated 46% and of stroke by 62%; one drug at standard dose had about half this effect. The present meta-analysis also showed that drugs other than calcium channel blockers (with the exception of non-cardioselective β blockers) reduced the incidence of heart failure by 24% (19% to 28%) and calcium channel blockers by 19% (6% to 31%).
Conclusions With the exception of the extra protective effect of β blockers given shortly after a myocardial infarction and the minor additional effect of calcium channel blockers in preventing stroke, all the classes of blood pressure lowering drugs have a similar effect in reducing CHD events and stroke for a given reduction in blood pressure so excluding material pleiotropic effects. The proportional reduction in cardiovascular disease events was the same or similar regardless of pretreatment blood pressure and the presence or absence of existing cardiovascular disease. Guidelines on the use of blood pressure lowering drugs can be simplified so that drugs are offered to people with all levels of blood pressure. Our results indicate the importance of lowering blood pressure in everyone over a certain age, rather than measuring it in everyone and treating it in some.
PMCID: PMC2684577  PMID: 19454737
6.  Environmental tobacco smoke exposure and ischaemic heart disease: an evaluation of the evidence. 
BMJ : British Medical Journal  1997;315(7114):973-980.
OBJECTIVES: To estimate the risk of ischaemic heart disease caused by exposure to environmental tobacco smoke and to explain why the associated excess risk is almost half that of smoking 20 cigarettes per day when the exposure is only about 1% that of smoking. DESIGN: Meta-analysis of all 19 acceptable published studies of risk of ischaemic heart disease in lifelong non-smokers who live with a smoker and in those who live with a non-smoker, five large prospective studies of smoking and ischaemic heart disease, and studies of platelet aggregation and studies of diet according to exposure to tobacco smoke. RESULTS: The relative risk of ischaemic heart disease associated with exposure to environmental tobacco smoke was 1.30 (95% confidence interval 1.22 to 1.38) at age 65. At the same age the estimated relative risk associated with smoking one cigarette per day was similar (1.39 (1.18 to 1.64)), while for 20 per day it was 1.78 (1.31 to 2.44). Two separate analyses indicated that non-smokers who live with smokers eat a diet that places them at a 6% higher risk of ischaemic heart disease, so the direct effect of environmental tobacco smoke is to increase risk by 23% (14% to 33%), since 1.30/1.06 = 1.23. Platelet aggregation provides a plausible and quantitatively consistent mechanism for the low dose effect. The increase in platelet aggregation produced experimentally by exposure to environmental tobacco smoke would be expected to have acute effects increasing the risk of ischaemic heart disease by 34%. CONCLUSION: Breathing other people's smoke is an important and avoidable cause of ischaemic heart disease, increasing a person's risk by a quarter.
PMCID: PMC2127675  PMID: 9365294
7.  Disagreements are not substantial. 
BMJ : British Medical Journal  1994;308(6935):1027-1029.
PMCID: PMC2539874  PMID: 8167518
8.  Systematic underestimation of association between serum cholesterol concentration and ischaemic heart disease in observational studies: data from the BUPA study. 
BMJ : British Medical Journal  1994;308(6925):363-366.
OBJECTIVE--To estimate the size of the association between serum concentration of low density lipoprotein cholesterol and mortality from ischaemic heart disease. DESIGN--Prospective study of total serum cholesterol concentration and mortality from ischaemic heart disease in 21,515 men (538 deaths) and study of total cholesterol concentration measured on two occasions an average of three years apart in 5696 men in whom low density lipoprotein cholesterol concentration was also measured on the second occasion. SUBJECTS--Men who attended the medical centre of the British United Provident Association (BUPA) in London between 1975 and 1982. MAIN OUTCOME MEASURE--The difference in mortality from ischaemic heart disease for a 0.6 mmol/l difference in concentration of low density lipoprotein cholesterol after adjustment for, firstly, regression dilution bias, which arises from the random fluctuation of serum cholesterol concentration in people over time, and, secondly, the surrogate dilution effect, which arises because differences in total cholesterol concentration between people reflect smaller differences in low density lipoprotein cholesterol concentration. RESULTS--The observed difference in mortality from ischaemic heart disease associated with a difference of 0.6 mmol/l in total serum cholesterol concentration was 17% but increased to 24% after correction for the regression dilution bias and to 27% (95% confidence interval 21% to 33%) after adjustment for both sources of underestimation, which provides an estimate of the difference in mortality for a true difference of 0.6 mmol/l in low density lipoprotein cholesterol concentration. The association was greater at younger ages. The estimated decrease in mortality from all causes was 6% before and 10% (1% to 17%) after adjustment for the two sources of underestimation. There was no excess mortality from any cause associated with low cholesterol concentration. CONCLUSIONS--The association between serum cholesterol concentration and ischaemic heart disease is materially stronger than directly inferred from prospective studies. This has important implications for the health benefit of achieving low cholesterol concentrations.
PMCID: PMC2539480  PMID: 8124143
9.  By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease? 
BMJ : British Medical Journal  1994;308(6925):367-372.
OBJECTIVE--To estimate by how much and how quickly a given reduction in serum cholesterol concentration will reduce the risk of ischaemic heart disease. DESIGN--Data on the incidence of ischaemic heart disease and serum cholesterol concentration were analysed from 10 prospective (cohort) studies, three international studies in different communities, and 28 randomised controlled trials (with mortality data analysed according to allocated treatment to ensure the avoidance of bias). MAIN OUTCOME MEASURE--Decrease in incidence of ischaemic heart disease or mortality for a 0.6 mmol/l (about 10%) decrease in serum cholesterol concentration. RESULTS--For men results from the cohort studies showed that a decrease of serum cholesterol concentration of 0.6 mmol/l (about 10%) was associated with a decrease in incidence of ischaemic heart disease of 54% at age 40 years, 39% at age 50, 27% at 60, 20% at 70, and 19% at 80. The combined estimate from the three international studies (for ages 55-64 years) was 38% (95% confidence interval 33% to 42%), somewhat greater than the cohort study estimate of 27%. The reductions in incidence of ischaemic heart disease in the randomised trials (for ages 55-64 years) were 7% (0 to 14%) in the first two years, 22% (15% to 28%) from 2.1-5 years, and 25% (15% to 35%) after five years, the last estimate being close to the estimate of 27% for the long term reduction from the cohort studies. The data for women are limited but indicate a similar effect. CONCLUSIONS--The results from the cohort studies, international comparisons, and clinical trials are remarkably consistent. The cohort studies, based on half a million men and 18,000 ischaemic heart disease events, estimate that a long term reduction in serum cholesterol concentration of 0.6 mmol/l (10%), which can be achieved by moderate dietary change, lowers the risk of ischaemic heart disease by 50% at age 40, falling to 20% at age 70. The randomised trials, based on 45,000 men and 4000 ischaemic heart disease events show that the full effect of the reduction in risk is achieved by five years.
PMCID: PMC2539460  PMID: 8043072
10.  A strategy to reduce cardiovascular disease by more than 80% 
BMJ : British Medical Journal  2003;326(7404):1419.
Objectives To determine the combination of drugs and vitamins, and their doses, for use in a single daily pill to achieve a large effect in preventing cardiovascular disease with minimal adverse effects. The strategy was to simultaneously reduce four cardiovascular risk factors (low density lipoprotein cholesterol, blood pressure, serum homocysteine, and platelet function) regardless of pretreatment levels.
Design We quantified the efficacy and adverse effects of the proposed formulation from published meta-analyses of randomised trials and cohort studies and a meta-analysis of 15 trials of low dose (50-125 mg/day) aspirin.
Outcome measures Proportional reduction in ischaemic heart disease (IHD) events and strokes; life years gained; and prevalence of adverse effects.
Results The formulation which met our objectives was: a statin (for example, atorvastatin (daily dose 10 mg) or simvastatin (40 mg)); three blood pressure lowering drugs (for example, a thiazide, a β blocker, and an angiotensin converting enzyme inhibitor), each at half standard dose; folic acid (0.8 mg); and aspirin (75 mg). We estimate that the combination (which we call the Polypill) reduces IHD events by 88% (95% confidence interval 84% to 91%) and stroke by 80% (71% to 87%). One third of people taking this pill from age 55 would benefit, gaining on average about 11 years of life free from an IHD event or stroke. Summing the adverse effects of the components observed in randomised trials shows that the Polypill would cause symptoms in 8-15% of people (depending on the precise formulation).
Conclusion The Polypill strategy could largely prevent heart attacks and stroke if taken by everyone aged 55 and older and everyone with existing cardiovascular disease. It would be acceptably safe and with widespread use would have a greater impact on the prevention of disease in the Western world than any other single intervention.
PMCID: PMC162259  PMID: 12829553
11.  Why is mortality higher in poorer areas and in more northern areas of England and Wales? 
STUDY OBJECTIVE: To identify and quantify the factors responsible for the differences in mortality between affluent and deprived areas, the north and the south, and urban and rural areas in England and Wales. DESIGN: A multiple Poisson regression analysis of cause specific mortality in the 403 local authority districts, each classified by deprivation (using the Jarman Index), latitude (from 50 degrees to 55 degrees north) and urbanisation, adjusting for age, sex, and proportion of ethnic minorities. SETTING: England and Wales 1992. MAIN RESULTS: All cause mortality was 15% higher in the districts comprising the most compared with the least deprived tenth of the population, 23% higher in the most northern (55 degrees) than in the most southern (50 degrees) districts, and 4% higher in metropolitan (within large cities) than rural districts. Nationally these differences were associated with 40,000, 65,000, and 15,000 excess deaths respectively. More than two thirds of the overall excess mortality with deprivation, latitude, and urbanisation was from three diseases--ischaemic heart disease, lung cancer, and chronic bronchitis and emphysema. The excess mortality from these and other diseases closely matched that predicted from differences according to deprivation and latitude in smoking, heavy alcohol consumption, Helicobacter pylori infection, and temperature, and thus could be attributed to these causes. About 85% of the overall excess mortality with deprivation was attributable to heavier smoking and 6% to heavier alcohol consumption, but diet varied little. Deaths more directly related to deprivation (such as those caused by H pylori infection, drug misuse, psychoses) accounted for an estimated 12% of the excess deaths, but variation in provision and uptake of healthcare services only 1%. The direct effects of deprivation are more strongly related to morbidity than mortality. Of the difference in mortality with latitude, about 45% was attributable to differences in smoking, and 25% to climate (mainly the association of cardiovascular and respiratory disease with cold). The differences with urbanisation were mainly because of smoking. CONCLUSIONS: Differences in the prevalence of smoking account for much of the variation in mortality between areas. Alcohol accounts for some, diet little. The more direct material effect of deprivation contributes to the variation in mortality but is particularly important with respect to differences in morbidity.
PMCID: PMC1756726  PMID: 9764254
12.  Chlamydia pneumoniae infection and mortality from ischaemic heart disease: large prospective study 
BMJ : British Medical Journal  2000;321(7255):204-207.
To determine whether there is an independent association between infection with Chlamydia pneumoniae and ischaemic heart disease.
Prospective study using a nested case-control design.
Medical centre in London run by BUPA, a private medical organisation.
21 520 professional men aged 35-64 who attended for a medical examination in London between 1975 and 1982.
Main outcome measure
Death from ischaemic heart disease.
The distributions of concentrations of IgG and IgA antibodies to C pneumoniae were similar in the 647 men who subsequently died of ischaemic heart disease and in 1294 age matched controls who did not. There was no material association with heart disease irrespective of the cut-off point chosen to define seropositivity. At a cut-off point that defines 15% of controls as positive, for example, the odds ratios were 1.26 (95% confidence interval 0.95 to 1.68) for IgG and 1.09 (0.82 to 1.43) for IgA.
No material association was found between infection with C pneumoniae and ischaemic heart disease. The size and prospective design of the study and the socioeconomic homogeneity of the cohort minimise both random and systematic error.
PMCID: PMC27436  PMID: 10903649
13.  Helicobacter pylori infection and mortality from ischaemic heart disease: negative result from a large, prospective study. 
BMJ : British Medical Journal  1997;315(7117):1199-1201.
OBJECTIVE: To determine whether there is an independent association between Helicobacter pylori infection of the stomach and ischaemic heart disease. DESIGN: Prospective study with measurement of IgG antibody titres specific to H pylori on stored serum samples from 648 men who died from ischaemic heart disease and 1296 age matched controls who did not (nested case-control design). SUBJECTS: 21,520 professional men aged 35-64 who attended the British United Provident Association (BUPA) medical centre in London between 1975 and 1982 for routine medical examination. MAIN OUTCOME MEASURE: Death from ischaemic heart disease. RESULTS: The odds of death from ischaemic heart disease in men with H pylori infection relative to that in men without infection was 1.06 (95% confidence interval 0.86 to 1.31). In a separate group of 206 people attending the centre, plasma fibrinogen was virtually the same in those who were positive for H pylori (2.62 g/l) and those who were negative (2.64 g/l). CONCLUSIONS: A study that by its size and design minimised both random error and socioeconomic bias found no relation between H pylori infection and ischaemic heart disease. The validity of the study was shown by its confirmation of the recognised association between H pylori infection and stomach cancer (odds ratio 4.0 (1.9 to 8.2); P < 0.001). Eradication of H pylori infection may greatly reduce the incidence of stomach cancer, one of the most common causes of death from cancer worldwide, but it cannot be expected to have any effect in preventing ischaemic heart disease.
PMCID: PMC2127748  PMID: 9393222
14.  The accumulated evidence on lung cancer and environmental tobacco smoke. 
BMJ : British Medical Journal  1997;315(7114):980-988.
OBJECTIVE: To estimate the risk of lung cancer in lifelong non-smokers exposed to environmental tobacco smoke. DESIGN: Analysis of 37 published epidemiological studies of the risk of lung cancer (4626 cases) in non-smokers who did and did not live with a smoker. The risk estimate was compared with that from linear extrapolation of the risk in smokers using seven studies of biochemical markers of tobacco smoke intake. MAIN OUTCOME MEASURE: Relative risk of lung cancer in lifelong non-smokers according to whether the spouse currently smoked or had never smoked. RESULTS: The excess risk of lung cancer was 24% (95% confidence interval 13% to 36%) in non-smokers who lived with a smoker (P < 0.001). Adjustment for the effects of bias (positive and negative) and dietary confounding had little overall effect; the adjusted excess risk was 26% (7% to 47%). The dose-response relation of the risk of lung cancer with both the number of cigarettes smoked by the spouse and the duration of exposure was significant. The excess risk derived by linear extrapolation from that in smokers was 19%, similar to the direct estimate of 26%. CONCLUSION: The epidemiological and biochemical evidence on exposure to environmental tobacco smoke, with the supporting evidence of tobacco specific carcinogens in the blood and urine of non-smokers exposed to environmental tobacco smoke, provides compelling confirmation that breathing other people's tobacco smoke is a cause of lung cancer.
PMCID: PMC2127653  PMID: 9365295
15.  A meta-analysis of cigarette smoking, bone mineral density and risk of hip fracture: recognition of a major effect. 
BMJ : British Medical Journal  1997;315(7112):841-846.
OBJECTIVE: To determine the magnitude and importance of the relation between smoking, bone mineral density, and risk of hip fracture according to age. DESIGN: Meta-analysis of 29 published cross sectional studies reporting the difference in bone density in 2156 smokers and 9705 non-smokers according to age, and of 19 cohort and case-control studies recording 3889 hip fractures reporting risk in smokers relative to non-smokers. RESULTS: In premenopausal women bone density was similar in smokers and non-smokers. Postmenopausal bone loss was greater in current smokers than non-smokers, bone density diminishing by about an additional 2% for every 10 year increase in age, with a difference of 6% at age 80. In current smokers relative to non-smokers the risk of hip fracture was similar at age 50 but greater thereafter by an estimated 17% at age 60, 41% at 70, 71% at 80, and 108% at 90. These estimates of relative risk by age, derived directly from a regression analysis of the studies of smoking and hip fracture, were close to estimates using the difference in bone density between smokers and non-smokers and the association between bone density and risk of hip fracture. The estimated cumulative risk of hip fracture in women in England was 19% in smokers and 12% in non-smokers to age 85; 37% and 22% to age 90. Among all women, one hip fracture in eight is attributable to smoking. Limited data in men suggest a similar proportionate effect of smoking as in women. The association was not explained by smokers being thinner, younger at menopause, and exercising less nor by actions of smoking on oestrogen, but smoking may have a direct action on bone. CONCLUSIONS: Hip fracture in old age is a major adverse effect of smoking after the menopause. The cumulative excess bone loss over decades is substantial, increasing the lifetime risk of hip fracture by about half.
PMCID: PMC2127590  PMID: 9353503
16.  Increasing incidence of tuberculosis in England and Wales: a study of the likely causes. 
BMJ : British Medical Journal  1995;310(6985):967-969.
OBJECTIVE--To examine factors responsible for the recent increase in tuberculosis in England and Wales. DESIGN--Study of the incidence of tuberculosis (a) in the 403 local authority districts in England and Wales, ranked according to Jarman score, and (b) in one deprived inner city district, according to ethnic origin and other factors. SETTING--(a) England and Wales 1980-92, and (b) the London borough of Hackney 1986-93. MAIN OUTCOME MEASURE--Age and sex adjusted rate of tuberculosis. RESULTS--In England and Wales notifications of tuberculosis increased by 12% between 1988 and 1992. The increase was 35% in the poorest 10th of the population and 13% in the next two; and in the remaining 70% there was no increase. In Hackney the increase affected traditionally high risk and low risk ethnic groups to a similar extent. In the "low risk" white and West Indian communities the incidence increased by 58% from 1986-8 (78 cases) to 1991-3 (123), whereas in residents of Indian subcontinent origin the increase was 41% (from 51 cases to 72). Tuberculosis in recently arrived immigrants--refugees (11% of the Hackney population) and Africans (6%)--accounted for less than half of the overall increase, and the proportion of such residents was much higher than in most socioeconomically deprived districts. The local increase was not due to an increase in the proportion of cases notified, to HIV infection, nor to an increase in homeless people. CONCLUSIONS--The national rise in tuberculosis affects only the poorest areas. Within one such area all residents (white and established ethnic minorities) were affected to a similar extent. The evidence indicates a major role for socioeconomic factors in the increase in tuberculosis and only a minor role for recent immigration from endemic areas.
PMCID: PMC2549357  PMID: 7728031
17.  Assessing possible hazards of reducing serum cholesterol. 
BMJ : British Medical Journal  1994;308(6925):373-379.
OBJECTIVE--To assess whether low serum cholesterol concentration increases mortality from any cause. DESIGN--Systematic review of published data on mortality from causes other than ischaemic heart disease derived from the 10 largest cohort studies, two international studies, and 28 randomised trials, supplemented by unpublished data on causes of death obtained when necessary. MAIN OUTCOME MEASURES--Excess cause specific mortality associated with low or lowered serum cholesterol concentration. RESULTS--The only cause of death attributable to low serum cholesterol concentration was haemorrhagic stroke. The excess risk was associated only with concentrations below about 5 mmol/l (relative risk 1.9, 95% confidence interval 1.4 to 2.5), affecting about 6% of people in Western populations. For noncirculatory causes of death there was a pronounced difference between cohort studies of employed men, likely to be healthy at recruitment, and cohort studies of subjects in community settings, necessarily including some with existing disease. The employed cohorts showed no excess mortality. The community cohorts showed associations between low cholesterol concentration and lung cancer, haemopoietic cancers, suicide, chronic bronchitis, and chronic liver and bowel disease; these were most satisfactorily explained by early disease or by factors that cause the disease lowering serum cholesterol concentration (depression causes suicide and lowers cholesterol concentration, for example). In the randomised trials nine deaths (from a total of 687 deaths not due to ischaemic heart disease in treated subjects) were attributed to known adverse effects of the specific treatments, but otherwise there was no evidence of an increased mortality from any cause arising from reduction in cholesterol concentration. CONCLUSIONS--There is no evidence that low or reduced serum cholesterol concentration increases mortality from any cause other than haemorrhagic stroke. This risk affects only those people with a very low concentration and even in these will be outweighed by the benefits from the low risk of ischaemic heart disease.
PMCID: PMC2539477  PMID: 8124144
18.  Serum cholesterol and cancer. 
British Journal of Cancer  1992;65(3):307-308.
PMCID: PMC1977593  PMID: 1558781
20.  By how much does dietary salt reduction lower blood pressure? II--Analysis of observational data within populations. 
BMJ : British Medical Journal  1991;302(6780):815-818.
OBJECTIVE--To determine whether the estimates of the size of the association between blood pressure and sodium intake derived from studies of individuals within populations can be quantitatively reconciled with our estimates derived from comparisons of the average blood pressure and sodium intake between different populations. DESIGN--Examination of data from 14 published studies that correlated blood pressure recordings in individuals against measurements of their 24 hour sodium intake (within population studies). MAIN OUTCOME MEASURE--Comparison of observed differences in blood pressure per 100 mmol/24 h difference in sodium intake in each within population study with predicted differences calculated from the between population data, after allowing for the underestimation of the true association of blood pressure with sodium intake caused by the large day to day variation in 24 hour sodium intake within individuals. RESULTS--The underestimation bias inherent in the within populations studies reduced the regression slope of blood pressure on single measures of 24 hour sodium intake to between a half and a quarter of the true value (for example, in one study from 6.0 to 2.4 mm Hg/100 mmol/24 h). Estimates from between population comparisons of the regression slope of blood pressure on sodium intake, after adjustment to take this underestimation bias into account, were similar to the values actually observed in the within population studies. CONCLUSION--The within population studies confirm our estimates from between population comparisons of the magnitude of the association between blood pressure and sodium intake.
PMCID: PMC1669173  PMID: 2025704
21.  By how much does dietary salt reduction lower blood pressure? III--Analysis of data from trials of salt reduction. 
BMJ : British Medical Journal  1991;302(6780):819-824.
OBJECTIVE--To determine whether the reduction in blood pressure achieved in trials of dietary salt reduction is quantitatively consistent with estimates derived from blood pressure and sodium intake in different populations, and, if so, to estimate the impact of reducing dietary salt on mortality from stroke and ischaemic heart disease. DESIGN--Analysis of the results of 68 crossover trials and 10 randomised controlled trials of dietary salt reduction. MAIN OUTCOME MEASURE--Comparison of observed reductions in systolic blood pressure for each trial with predicted values calculated from between population analysis. RESULTS--In the 45 trials in which salt reduction lasted four weeks or less the observed reductions in blood pressure were less than those predicted, with the difference between observed and predicted reductions being greatest in the trials of shortest duration. In the 33 trials lasting five weeks or longer the predicted reductions in individual trials closely matched a wide range of observed reductions. This applied for all age groups and for people with both high and normal levels of blood pressure. In people aged 50-59 years a reduction in daily sodium intake of 50 mmol (about 3 g of salt), attainable by moderate dietary salt reduction would, after a few weeks, lower systolic blood pressure by an average of 5 mm Hg, and by 7 mm Hg in those with high blood pressure (170 mm Hg); diastolic blood pressure would be lowered by about half as much. It is estimated that such a reduction in salt intake by a whole Western population would reduce the incidence of stroke by 22% and of ischaemic heart disease by 16% [corrected]. CONCLUSIONS--The results from the trials support the estimates from the observational data in the accompanying two papers. The effect of universal moderate dietary salt reduction on mortality from stroke and ischaemic heart disease would be substantial--larger, indeed, than could be achieved by fully implementing recommended policy for treating high blood pressure with drugs. However, reduction also in the amount of salt added to processed foods would lower blood pressure by at least twice as much and prevent some 75,000 [corrected] deaths a year in Britain as well as much disability.
PMCID: PMC1669188  PMID: 1827353
22.  Genetic predisposition to lung cancer. 
British Journal of Cancer  1990;61(2):195-206.
PMCID: PMC1971391  PMID: 2178665
23.  Hospital-acquired infection with methicillin-resistant and methicillin-sensitive staphylococci. 
Epidemiology and Infection  1988;101(3):623-629.
In-patients at a London hospital over one year from whom the south-east England strain of 'epidemic' methicillin-resistant Staphylococcus aureus (MRSA) was isolated were compared with in-patients with strains of methicillin-sensitive Staphylococcus aureus (MSSA). MRSA were virtually entirely hospital-acquired; isolates before 10 days were uncommon and related to recent previous admission. Thereafter first isolates occurred at a fairly constant daily rate of about 1.9 per 1,000 in-patients. Acquisition of MSSA after more than 4 days in hospital occurred at a similar constant rate. Such strains were less likely to be penicillin-sensitive than strains isolated in the first 4 days after admission (11 vs. 22%) and were considered to be hospital-acquired. The single MRSA strain caused 40 infections in a year, about half of all hospital-acquired staphylococcal infections. Patients prescribed anti-staphylococcal antibiotics and patients with indwelling cannulae both had about a ninefold increased risk of acquiring MRSA. There was no reciprocal increase in MSSA infections after control measures had substantially reduced the number of MRSA infections.
PMCID: PMC2249421  PMID: 3215291
24.  Methicillin-resistant Staphylococcus aureus: associated morbidity and effectiveness of control measures. 
Epidemiology and Infection  1988;101(2):301-309.
The strain of methicillin-resistant Staphylococcus aureus (MRSA) prevalent in south-east England produced in one acute hospital in a year 40 infections (bacteraemia, pneumonia and surgical wound, skin and urinary tract infections) with three attributable deaths. Rigorous measures succeeded in controlling the outbreak despite its extent, but our results suggest that less stringent measures could fail to control outbreaks of this scale. Several subsequent localized outbreaks within the hospital, probably caused by separate re-introductions of MRSA from other hospitals, were controlled by re-instigation of control measures on individual wards. The overall success of the intervention was shown by the decline in the incidence of MRSA infections from 27 in the 6 months beforehand to 2 in the most recent 6 months, and by the decline in the prevalence of colonization among patients 10 or more days in hospital from 52% immediately before the intervention to 3% 7 months after it. The incidence of attributable morbidity and death without control measures warrants a concerted effort to tackle the epidemic in all affected hospitals in Britain.
PMCID: PMC2249399  PMID: 3181314
25.  Serum cholesterol and subsequent risk of cancer: results from the BUPA study. 
British Journal of Cancer  1989;59(6):936-938.
In the BUPA study, a prospective study of 22,000 men attending a screening centre in London, the mean serum cholesterol level of the 267 men who developed cancer was 6.66 mmol l-1, not significantly different from the mean level of 6.72 mmol l-1 among the 525 unaffected controls matched for age, smoking history and the calendar quarter of their attendance at the screening centre. There was, however, a significant difference in serum cholesterol levels among men who were diagnosed as having cancer less than 2 years after the date of blood collection (6.49 mmol l-1 for the 116 cancer subjects and 6.78 mmol l-1 for the 224 controls (P = 0.02)) but not in men who developed cancer 2-11 years after blood collection (6.79 mmol l-1 for the 151 cancer subjects and 6.68 mmol l-1 for the 301 controls). The observation that the association between low serum cholesterol and cancer was confined to men in whom a diagnosis of cancer was made within 2 years after the date of blood collection suggests that the low serum cholesterol is a metabolic consequence rather than a precursor of the cancer. Our results, which are consistent with the majority of other published studies, indicate that a low serum cholesterol is not a cause of cancer.
PMCID: PMC2246723  PMID: 2736230

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