Ivan J. Perry

Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial

BACKGROUND Although statins reduce coronary and cerebrovascular morbidity and mortality in middle-aged individuals, their efficacy and safety in elderly people is not fully established. Our aim was to test the benefits of pravastatin treatment in an elderly cohort of men and women with, or at high risk of developing, cardiovascular disease and stroke. METHODS We did a randomised controlled trial in which we assigned 5804 men (n=2804) and women (n=3000) aged 70-82 years with a history of, or risk factors for, vascular disease to pravastatin (40 mg per day; n=2891) or placebo (n=2913). Baseline cholesterol concentrations ranged from 4.0 mmol/L to 9.0 mmol/L. Follow-up was 3.2 years on average and our primary endpoint was a composite of coronary death, non-fatal myocardial infarction, and fatal or non-fatal stroke. Analysis was by intention-to-treat. FINDINGS Pravastatin lowered LDL cholesterol concentrations by 34% and reduced the incidence of the primary endpoint to 408 events compared with 473 on placebo (hazard ratio 0.85, 95% CI 0.74-0.97, p=0.014). Coronary heart disease death and non-fatal myocardial infarction risk was also reduced (0.81, 0.69-0.94, p=0.006). Stroke risk was unaffected (1.03, 0.81-1.31, p=0.8), but the hazard ratio for transient ischaemic attack was 0.75 (0.55-1.00, p=0.051). New cancer diagnoses were more frequent on pravastatin than on placebo (1.25, 1.04-1.51, p=0.020). However, incorporation of this finding in a meta-analysis of all pravastatin and all statin trials showed no overall increase in risk. Mortality from coronary disease fell by 24% (p=0.043) in the pravastatin group. Pravastatin had no significant effect on cognitive function or disability. INTERPRETATION Pravastatin given for 3 years reduced the risk of coronary disease in elderly individuals. PROSPER therefore extends to elderly individuals the treatment strategy currently used in middle aged people.

Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men

Moderate hyperhomocysteinaemia is common in the general population and has been linked with cardiovascular disease. However, there are no data from prospective, population-based studies. We examined the association between serum total homocysteine (tHcy) concentration and stroke in a nested case-control study within the British Regional Heart Study cohort. Between 1978 and 1980 serum was saved from 5661 men, aged 40-59 years, randomly selected from the population of one general practice in each of 18 towns in the UK. During follow-up to December, 1991, there were 141 incident cases of stroke among men with no history of stroke at screening. Serum tHcy was measured in 107 cases and 118 control men (matched for age-group and town, without a history of stroke at screening, who did not develop a stroke or myocardial infarction during follow-up). tHcy concentrations were significantly higher in cases than controls (geometric mean 13.7 [95% CI 12.7-14.8] vs 11.9 [11.3-12.6] mumol/L; p = 0.004). There was a graded increase in the relative risk of stroke in the second, third, and fourth quarters of the tHcy distribution (odds ratios 1.3, 1.9, 2.8; trend p = 0.005) relative to the first. Adjustment for age-group, town, social class, body-mass index, hypertensive status, cigarette smoking, forced expiratory volume, packed-cell volume, alcohol intake, diabetes, high-density-lipoprotein cholesterol, and serum creatinine did not attenuate the association. These findings suggest that tHcy is a strong and independent risk factor for stroke.

Prospective study of risk factors for development of non-insulin dependent diabetes in middle aged British men.

Abstract Objective: To determine the risk factors for non-insulin dependent diabetes in a cohort representative of middle aged British men. Design: Prospective study. Subjects and setting: 7735 men aged 40-59, drawn from one group practice in each of 24 towns in Britain. Known and probable cases of diabetes at screening (n=158) were excluded. Main outcome measures: Non-insulin dependent diabetes (doctor diagnosed) over a mean follow up period of 12.8 years. Results: There were 194 new cases of non-insulin dependent diabetes. Body mass index was the dominant risk factor for diabetes, with an age adjusted relative risk (upper fifth to lower fifth) of 11.6; 95% confidence interval 5.4 to 16.8. Men engaged in moderate levels of physical activity had a substantially reduced risk of diabetes, relative to the physically inactive men, after adjustment for age and body mass index (0.4; 0.2 to 0.7), an association which persisted in full multivariate analysis. A non-linear relation between alcohol intake and diabetes was observed, with the lowest risk among moderate drinkers (16-42 units/week) relative to the baseline group of occasional drinkers (0.6; 0.4 to 1.0). Additional significant predictors of diabetes in multivariate analysis included serum triglyceride concentration, high density lipoprotein cholesterol concentration (inverse association), heart rate, uric acid concentration, and prevalent coronary heart disease. Conclusion: These findings emphasise the interrelations between risk factors for non-insulin dependent diabetes and coronary heart disease and the potential value of an integrated approach to the prevention of these conditions based on the prevention of obesity and the promotion of physical activity. Key messages Key messages This study shows a strong, graded association between body mass index and risk of diabetes in middle aged men, with no evidence of a threshold effect The risk of diabetes is reduced by more than 50% among men who take moderately vigorous exercise Cardiovascular disease risk factors that are linked with insulin resistance, such as hypertriglyceridaemia and hyperuricaemia, predict non-insulin dependent diabetes These findings support an integrated approach to the prevention of non-insulin dependent diabetes and cardiovascular disease based on the prevention of obesity and the promotion of physical activity

The design of a prospective study of pravastatin in the elderly at risk (PROSPER)

The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) is a randomized, double-blind, placebo-controlled trial designed to test the hypothesis that treatment with pravastatin will diminish risk of subsequent major vascular events in a cohort of men and women (70 to 82 years old) with preexisting vascular disease or significant risk of developing this condition. Five thousand eight hundred four men and women in addition to receiving advice on diet and smoking, have been randomized equally to treatment with 40 mg pravastatin/day or matching placebo in 3 centers (Cork, Ireland, Glasgow, Scotland, and Leiden, The Netherlands). Following an average 3.5-year intervention period, a primary assessment will be made of the influence of this therapy on major vascular events (a combination of coronary heart disease, death, nonfatal myocardial infarction, and fatal and nonfatal stroke). A number of additional analyses will also be conducted on the individual components of the primary end point, on men, on women, and on subjects with and without previous evidence of vascular disease. Finally, an assessment will be made of the effects of treatment on cognitive function, disability, hospitalization or institutionalization, vascular mortality, and all-cause mortality.

Prospective Study of Serum γ-Glutamyltransferase and Risk of NIDDM

OBJECTIVE Serum γ-glutamyltransferase (GGT) levels are raised inobese individuals, and a particularly strong association with central obesity has been described. We hypothesized that elevated GGT levels are a marker for visceral fat, and specifically for hepatic steatosis (fatty liver), and that hepatic steatosis leads to hepatic insulin resistance. To test this hypothesis, we examined the association between GGT levels and risk of NIDDM. RESEARCH DESIGN AND METHODS We carried out a prospective cohort study of incident cases of doctor-diagnosed NIDDM in a group of 7,458 nondiabetic men (aged 40–59 years) followed for a mean of 12.8 years (range 11.5–13.0). The men were randomly selected from general practice lists in 24 British towns. Cases of NIDDM were ascertained by repeated postal questionnaires to the men and by regular systematic review of primary care records. RESULTS A total of 194 men developed NIDDM during follow-up. Mean serum GGT at baseline (geometric mean [95% Cl]) was significantly higher in the NIDDM patients than in the rest of the cohort (20.9 [19.3–22.6] vs. 15.3 U/l [15.0–15.6], P < 0.0001). There was a smooth, graded increase in the age-adjusted risk of NIDDM with increasing GGT levels, with a relative risk in the top fifth of the distribution of 6.8 (3.5–12.9) relative to the bottom fifth (trend P < 0.0001). This association was independent of serum glucose and BMI and of other predictors of NIDDM with which GGT is associated, including alcohol intake and physical activity level (adjusted upper to lower fifth relative risk: 4.8 [2.0–11.8], trend P < 0.0001]). CONCLUSIONS These findings suggest that a raised serum GGT levelis an independent risk factor for NIDDM. Serum GGT level may be a simple andreliable marker of visceral and hepatic fat and, by inference, of hepatic insulin resistance.

Serum Creatinine Concentration and Risk of Cardiovascular Disease A Possible Marker for Increased Risk of Stroke

BACKGROUND AND PURPOSE Elevated serum creatinine has been associated with increased mortality in hypertensive persons, the elderly, and patients with myocardial infarction or stroke in whom cardiovascular disease is the major cause of death. We have examined the relationship between serum creatinine concentration and the risk of major ischemic heart disease and stroke events and all-cause mortality in a general population of middle-aged men. METHODS We present a prospective study of middle-aged men (aged 40 to 59 years) drawn from 24 British towns who have been followed up for an average of 14.75 years. Data on serum creatinine were available for 7690 men in whom there were 287 major stroke events, 967 major ischemic heart disease events, and 1259 deaths from all causes during follow-up. RESULTS The median serum creatinine concentration was 98 micromol/L (95% range, 76 to 129 micromol/L). Stroke risk was significantly increased at levels above 116 micromol/L (90th percentile) even after adjustment for a wide range of cardiovascular risk factors (relative risk [RR], 1.6; 95% CI, 1.1 to 2.1; > 116 micromol/L versus the rest). Risk of a major ischemic heart disease event was significantly increased at or above 130 micromol/L (97.5 percentile), but this was attenuated after adjustment (RR, 1.2; 95% CI, 0.8 to 1.7; > or = 130 micromol/L versus the rest). There was a weak but significant positive association between diastolic blood pressure and creatinine concentration. However, elevated creatinine concentration (> or = 116 micromol/L) was associated with a significant increase in stroke in both normotensive and hypertensive men. All-cause mortality and overall cardiovascular mortality were significantly increased only above the 97.5 percentile, and no significant association was seen with cancer or other noncardiovascular mortality. CONCLUSIONS A high serum creatinine concentration within the normal range is a marker for increased risk of cerebrovascular disease in both normotensive and hypertensive subjects. These findings support the evidence indicating that subtle impairment of renal function is a factor for increased risk of stroke and suggest mechanisms in the pathogenesis of stroke that warrant further investigation.

Anxiety and depression symptoms in patients with diabetes

Aims  To identify the prevalence and major determinants of anxiety and depression symptoms in patients with diabetes.

Legislation for smoke-free workplaces and health of bar workers in Ireland: before and after study.

Abstract Objectives To compare exposure to secondhand smoke and respiratory health in bar staff in the Republic of Ireland and Northern Ireland before and after the introduction of legislation for smoke-free workplaces in the Republic. Design Comparisons before and after the legislation in intervention and control regions. Setting Public houses in three areas in the Republic (intervention) and one area in Northern Ireland (control). Participants 329 bar staff enrolled in baseline survey; 249 (76%) followed up one year later. Of these, 158 were non-smokers both at baseline and follow-up. Main outcome measures Salivary cotinine concentration, self reported exposure to secondhand smoke, and respiratory and sensory irritation symptoms. Results In bar staff in the Republic who did not themselves smoke, salivary cotinine concentrations dropped by 80% after the smoke-free law (from median 29.0 nmol/l (95% confidence interval 18.2 to 43.2 nmol/l)) to 5.1 nmol/l (2.8 to 13.1 nmol/l) in contrast with a 20% decline in Northern Ireland over the same period (from median 25.3 nmol/l (10.4 to 59.2 nmol/l) to 20.4 nmol/l (13.2 to 33.8 nmol/l)). Changes in self reported exposure to secondhand smoke were consistent with the changes in cotinine concentrations. Reporting any respiratory symptom declined significantly in the Republic (down 16.7%, −26.1% to −7.3%) but not in Northern Ireland (0% difference, −32.7% to 32.7%). After adjustment for confounding, respiratory symptoms declined significantly more in the Republic than in Northern Ireland and the decline in cotinine concentration was twice as great. Conclusion The smoke-free law in the Republic of Ireland protects non-smoking bar workers from exposure to secondhand smoke.

Prospective relations between Helicobacter pylori infection, coronary heart disease, and stroke in middle aged men.

OBJECTIVE: To determine whether Helicobacter pylori, a chronic bacterial infection often acquired in childhood, is associated with increased risk of coronary heart disease and stroke later in life. DESIGN: Nested case-control study. SETTING: Prospective study of cardiovascular disease in men aged 40-59 years at entry (1978-1980) in 24 British towns. SUBJECTS: 135 cases of myocardial infarction and 137 cases of stroke occurring before December 1991; 136 controls were identified, frequency matched to cases by town and age group. METHODS: Serum samples stored at entry were analysed by an enzyme linked immunosorbent assay for the presence of H pylori specific IgG antibodies. RESULTS: 95 of the myocardial infarction cases (70%) and 93 (68%) of the stroke cases were seropositive for H pylori compared with 78 (57%) of the controls (odds ratio for myocardial infarction 1.77, 95% confidence interval (CI) 1.06 to 2.95, P = 0.03; odds ratio for stroke 1.57, 95% CI 0.95 to 2.60, P = 0.07). Helicobacter pylori infection was associated with manual social class, residence in Northern England or Scotland, cigarette smoking, higher systolic pressure and blood glucose, and a lower height-standardised forced expiratory volume in one second. Adjustment for these factors attenuated the relation between H pylori and myocardial infarction (odds ratio = 1.31, 95% CI 0.70 to 2.43, P = 0.40) and effectively abolished the relation with stroke (odds ratio = 0.96, 0.46 to 2.02, P = 0.92). The relation between helicobacter infection and fatal myocardial infarction was slightly stronger (odds ratio 2.41, 95% CI 1.13 to 5.12) but was also markedly attenuated after adjustment (1.56, 95% CI 0.68 to 3.61). CONCLUSION: In this prospective study the association between Helicobacter pylori infection and increased risk of myocardial infarction and stroke was substantially confounded by the relation between this infection, adult social class, and major cardiovascular risk factors.

Does Inflammation Determine Metabolic Health Status in Obese and Nonobese Adults

CONTEXT Inflammation is a potential mechanism linking obesity and cardiometabolic risk. Limited data on inflammatory markers in metabolically healthy obese and nonobese individuals exist. OBJECTIVE The aim of the study was to investigate the extent to which differences between metabolically healthy and unhealthy obese and nonobese adults, defined using a range of metabolic health definitions, are correlated with a range of inflammatory markers. DESIGN A cross-sectional sample of 2047 men and women aged 45-74 years participated in the study. Participants were classified as obese (body mass index ≥ 30 kg/m(2)) and nonobese (body mass index < 30 kg/m(2)). Metabolic health status was defined using 5 existing metabolic health definitions based on a range of cardiometabolic abnormalities. Serum acute-phase reactants, adipocytokines, proinflammatory cytokines, and white blood cell counts were determined. RESULTS According to most definitions, metabolically healthy obese and nonobese individuals presented with lower concentrations of complement component 3, C-reactive protein, TNF-α, IL-6, and plasminogen activator inhibitor-1; higher adiponectin levels; and reduced white blood cell count compared to their metabolically unhealthy counterparts. Logistic regression analysis identified greater likelihood of metabolically healthy obesity among individuals with lower levels of complement component 3 (odds ratios [ORs], 2-3.5), IL-6 (ORs, 1.7-2.9), plasminogen activator inhibitor-1 (ORs, 1.7-2.9), and white blood cells (ORs, 2.1-2.5) and higher adiponectin concentrations (ORs, 2.6-4.0). CONCLUSIONS Favorable inflammatory status is positively associated with metabolic health in obese and nonobese individuals. These findings are of public health and clinical significance in terms of screening and stratification based on metabolic health phenotype to identify those at greatest cardiometabolic risk for whom appropriate therapeutic or intervention strategies should be developed.