Lifetime and 10-year risks of cardiovascular mortality in relation to risk factors in middle and old age: 50-year follow-up of the Whitehall study of London Civil Servants.

BACKGROUND: Cardiovascular disease (CVD)-related mortality has declined substantially in the United Kingdom (UK) in recent decades, but the continued relevance of conventional risk factors for prediction of CVD mortality throughout the life-course is uncertain. We compared the 10-year risks and lifetime risks of CVD mortality associated with conventional risk factors recorded in middle and old age. METHODS: The Whitehall study was a prospective study of 19,019 male London civil servants (mean age 52 years) when enrolled in 1967-1970 and followed-up for 50 years for cause-specific mortality. In 1997, 7044 (83%) survivors (mean age 77 years) were re-surveyed. The 10-year and lifetime risks of CVD mortality were estimated by levels of CVD risk factors recorded in middle-age and old-age, respectively. RESULTS: By July 2020, 97% had died (22%, 51% and 80% before age 70, 80 and 90 years, respectively) and 7944 of 17,673 deaths (45%) were from CVD. The 10-year and lifetime risks of CVD death increased linearly with higher levels of CVD risk factors recorded in middle-age and in old-age. Individuals in the top versus bottom 5% of CVD risk scores in middle age had a 10.3% (95% CI:7.2-13.4) vs 0.6% (0.1-1.2) 10-year risk of CVD mortality, a 61.4% (59.4-65.3) vs 31.3% (24.1-34.5) lifetime risk of CVD mortality and a 12-year difference in life expectancy from age 50 years. The corresponding differences using a CVD risk score in old-age were 11.0% (4.4-17.5) vs 0.8% (0.0-2.2) for 10-year risk and 42.1% (28.2-50.0) vs 30.3% (6.0-38.0) for lifetime risk of CVD mortality and a 6-year difference in life expectancy from age 70 years. CONCLUSIONS: Conventional risk factors remained highly predictive of CVD mortality and life expectancy through the life-course. The findings highlight the relevance of estimation of both lifetime risks of CVD and 10-year risks of CVD for primary prevention of CVD.

Effect on non-vascular outcomes of lowering LDL cholesterol in patients with chronic kidney disease: results from the Study of Heart and Renal Protection.

BACKGROUND: Reducing LDL cholesterol (LDL-C) with statin-based therapy reduces the risk of major atherosclerotic events among patients with chronic kidney disease (CKD), with no evidence of an excess risk of cancer or death from any non-vascular cause. However, non-randomized data have suggested that statin therapy may have effects (both adverse and beneficial) on particular non-vascular conditions that do not cause death. METHODS: The Study of Heart and Renal Protection (SHARP) randomized patients with CKD to simvastatin 20 mg plus ezetimibe 10 mg (simvastatin/ezetimibe) daily versus matching placebo. Participants were followed up at least 6 monthly and all post-randomization serious adverse events (SAEs) were recorded. This supplementary analysis reports the effects of treatment on non-vascular SAEs, overall, by system of disease, by baseline characteristics, and by duration of follow-up. RESULTS: During a median of 4.9 years follow-up, similar numbers of participants in the two groups experienced at least one non-vascular SAE (3551 [76.4%] simvastatin/ezetimibe vs 3537 [76.6%] placebo; risk ratio [RR] 0.99, 95% confidence interval [CI] 0.95-1.04). There was no good evidence of any significant effect of simvastatin/ezetimibe on SAEs attributed to any particular nonvascular disease system (of 43 comparisons, only 3 yielded an uncorrected p value < 0.05, of which the smallest was p = 0.02). The relative risk of any nonvascular SAE did not vary significantly among particular prognostic subgroups or by duration of follow-up. CONCLUSIONS: In the SHARP trial, allocation to simvastatin/ezetimibe combination therapy was not associated with any significant non-vascular hazard. TRIALS REGISTRATION: SHARP was retrospectively registered after the first participant was enrolled in 2003 at ISRCTN (ISRCTN54137607 on 31 January 2005: http://www.isrctn.com/ISRCTN54137607) and ClinicalTrials.gov (NCT00125593 on 29 July 2005: https://clinicaltrials.gov/ct2/show/NCT00125593).

Optimum dose of vitamin D for disease prevention in older people: BEST-D trial of vitamin D in primary care.

This trial compared the effects of daily treatment with vitamin D or placebo for 1 year on blood tests of vitamin D status. The results demonstrated that daily 4000 IU vitamin D3 is required to achieve blood levels associated with lowest disease risks, and this dose should be tested in future trials for fracture prevention. INTRODUCTION: The aim of this trial was to assess the effects of daily supplementation with vitamin D3 4000 IU (100 µg), 2000 IU (50 µg) or placebo for 1 year on biochemical markers of vitamin D status in preparation for a large trial for prevention of fractures and other outcomes. METHODS: This is a randomized placebo-controlled trial in 305 community-dwelling people aged 65 years or older in Oxfordshire, UK. Outcomes included biochemical markers of vitamin D status (plasma 25-hydroxy-vitamin D [25[OH]D], parathyroid hormone [PTH], calcium and alkaline phosphatase), cardiovascular risk factors and tests of physical function. RESULTS: Mean (SD) plasma 25(OH)D levels were 50 (18) nmol/L at baseline and increased to 137 (39), 102 (25) and 53 (16) nmol/L after 12 months in those allocated 4000 IU, 2000 IU or placebo, respectively (with 88%, 70% and 1% of these groups achieving the pre-specified level of >90 nmol/L). Neither dose of vitamin D3 was associated with significant deviation outside the normal range of PTH or albumin-corrected calcium. The additional effect on 25(OH)D levels of 4000 versus 2000 IU was similar in all subgroups except for body mass index, for which the further increase was smaller in overweight and obese participants compared with normal-weight participants. Supplementation with vitamin D had no significant effects on cardiovascular risk factors or on measures of physical function. CONCLUSIONS: After accounting for average 70% compliance in long-term trials, doses of 4000 IU vitamin D3 daily may be required to achieve plasma 25(OH)D levels associated with lowest disease risk in observational studies.

Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials.

BACKGROUND: The vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials. METHODS: We undertook meta-analyses of 280 trials of NSAIDs versus placebo (124,513 participants, 68,342 person-years) and 474 trials of one NSAID versus another NSAID (229,296 participants, 165,456 person-years). The main outcomes were major vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, obstruction, or bleed). FINDINGS: Major vascular events were increased by about a third by a coxib (rate ratio [RR] 1·37, 95% CI 1·14-1·66; p=0·0009) or diclofenac (1·41, 1·12-1·78; p=0·0036), chiefly due to an increase in major coronary events (coxibs 1·76, 1·31-2·37; p=0·0001; diclofenac 1·70, 1·19-2·41; p=0·0032). Ibuprofen also significantly increased major coronary events (2·22, 1·10-4·48; p=0·0253), but not major vascular events (1·44, 0·89-2·33). Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (0·93, 0·69-1·27). Vascular death was increased significantly by coxibs (1·58, 99% CI 1·00-2·49; p=0·0103) and diclofenac (1·65, 0·95-2·85, p=0·0187), non-significantly by ibuprofen (1·90, 0·56-6·41; p=0·17), but not by naproxen (1·08, 0·48-2·47, p=0·80). The proportional effects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (coxibs 1·81, 1·17-2·81, p=0·0070; diclofenac 1·89, 1·16-3·09, p=0·0106; ibuprofen 3·97, 2·22-7·10, p<0·0001; and naproxen 4·22, 2·71-6·56, p<0·0001). INTERPRETATION: The vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted, which could help guide clinical decision making. FUNDING: UK Medical Research Council and British Heart Foundation.

The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials.

BACKGROUND: Statins reduce LDL cholesterol and prevent vascular events, but their net effects in people at low risk of vascular events remain uncertain. METHODS: This meta-analysis included individual participant data from 22 trials of statin versus control (n=134,537; mean LDL cholesterol difference 1·08 mmol/L; median follow-up 4·8 years) and five trials of more versus less statin (n=39,612; difference 0·51 mmol/L; 5·1 years). Major vascular events were major coronary events (ie, non-fatal myocardial infarction or coronary death), strokes, or coronary revascularisations. Participants were separated into five categories of baseline 5-year major vascular event risk on control therapy (no statin or low-intensity statin) (<5%, ≥5% to <10%, ≥10% to <20%, ≥20% to <30%, ≥30%); in each, the rate ratio (RR) per 1·0 mmol/L LDL cholesterol reduction was estimated. FINDINGS: Reduction of LDL cholesterol with a statin reduced the risk of major vascular events (RR 0·79, 95% CI 0·77-0·81, per 1·0 mmol/L reduction), largely irrespective of age, sex, baseline LDL cholesterol or previous vascular disease, and of vascular and all-cause mortality. The proportional reduction in major vascular events was at least as big in the two lowest risk categories as in the higher risk categories (RR per 1·0 mmol/L reduction from lowest to highest risk: 0·62 [99% CI 0·47-0·81], 0·69 [99% CI 0·60-0·79], 0·79 [99% CI 0·74-0·85], 0·81 [99% CI 0·77-0·86], and 0·79 [99% CI 0·74-0·84]; trend p=0·04), which reflected significant reductions in these two lowest risk categories in major coronary events (RR 0·57, 99% CI 0·36-0·89, p=0·0012, and 0·61, 99% CI 0·50-0·74, p<0·0001) and in coronary revascularisations (RR 0·52, 99% CI 0·35-0·75, and 0·63, 99% CI 0·51-0·79; both p<0·0001). For stroke, the reduction in risk in participants with 5-year risk of major vascular events lower than 10% (RR per 1·0 mmol/L LDL cholesterol reduction 0·76, 99% CI 0·61-0·95, p=0·0012) was also similar to that seen in higher risk categories (trend p=0·3). In participants without a history of vascular disease, statins reduced the risks of vascular (RR per 1·0 mmol/L LDL cholesterol reduction 0·85, 95% CI 0·77-0·95) and all-cause mortality (RR 0·91, 95% CI 0·85-0·97), and the proportional reductions were similar by baseline risk. There was no evidence that reduction of LDL cholesterol with a statin increased cancer incidence (RR per 1·0 mmol/L LDL cholesterol reduction 1·00, 95% CI 0·96-1·04), cancer mortality (RR 0·99, 95% CI 0·93-1·06), or other non-vascular mortality. INTERPRETATION: In individuals with 5-year risk of major vascular events lower than 10%, each 1 mmol/L reduction in LDL cholesterol produced an absolute reduction in major vascular events of about 11 per 1000 over 5 years. This benefit greatly exceeds any known hazards of statin therapy. Under present guidelines, such individuals would not typically be regarded as suitable for LDL-lowering statin therapy. The present report suggests, therefore, that these guidelines might need to be reconsidered. FUNDING: British Heart Foundation; UK Medical Research Council; Cancer Research UK; European Community Biomed Programme; Australian National Health and Medical Research Council; National Heart Foundation, Australia.

Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.

BACKGROUND: Lowering of LDL cholesterol with standard statin regimens reduces the risk of occlusive vascular events in a wide range of individuals. We aimed to assess the safety and efficacy of more intensive lowering of LDL cholesterol with statin therapy. METHODS: We undertook meta-analyses of individual participant data from randomised trials involving at least 1000 participants and at least 2 years' treatment duration of more versus less intensive statin regimens (five trials; 39 612 individuals; median follow-up 5·1 years) and of statin versus control (21 trials; 129 526 individuals; median follow-up 4·8 years). For each type of trial, we calculated not only the average risk reduction, but also the average risk reduction per 1·0 mmol/L LDL cholesterol reduction at 1 year after randomisation. FINDINGS: In the trials of more versus less intensive statin therapy, the weighted mean further reduction in LDL cholesterol at 1 year was 0·51 mmol/L. Compared with less intensive regimens, more intensive regimens produced a highly significant 15% (95% CI 11-18; p<0·0001) further reduction in major vascular events, consisting of separately significant reductions in coronary death or non-fatal myocardial infarction of 13% (95% CI 7-19; p<0·0001), in coronary revascularisation of 19% (95% CI 15-24; p<0·0001), and in ischaemic stroke of 16% (95% CI 5-26; p=0·005). Per 1·0 mmol/L reduction in LDL cholesterol, these further reductions in risk were similar to the proportional reductions in the trials of statin versus control. When both types of trial were combined, similar proportional reductions in major vascular events per 1·0 mmol/L LDL cholesterol reduction were found in all types of patient studied (rate ratio [RR] 0·78, 95% CI 0·76-0·80; p<0·0001), including those with LDL cholesterol lower than 2 mmol/L on the less intensive or control regimen. Across all 26 trials, all-cause mortality was reduced by 10% per 1·0 mmol/L LDL reduction (RR 0·90, 95% CI 0·87-0·93; p<0·0001), largely reflecting significant reductions in deaths due to coronary heart disease (RR 0·80, 99% CI 0·74-0·87; p<0·0001) and other cardiac causes (RR 0·89, 99% CI 0·81-0·98; p=0·002), with no significant effect on deaths due to stroke (RR 0·96, 95% CI 0·84-1·09; p=0·5) or other vascular causes (RR 0·98, 99% CI 0·81-1·18; p=0·8). No significant effects were observed on deaths due to cancer or other non-vascular causes (RR 0·97, 95% CI 0·92-1·03; p=0·3) or on cancer incidence (RR 1·00, 95% CI 0·96-1·04; p=0·9), even at low LDL cholesterol concentrations. INTERPRETATION: Further reductions in LDL cholesterol safely produce definite further reductions in the incidence of heart attack, of revascularisation, and of ischaemic stroke, with each 1·0 mmol/L reduction reducing the annual rate of these major vascular events by just over a fifth. There was no evidence of any threshold within the cholesterol range studied, suggesting that reduction of LDL cholesterol by 2-3 mmol/L would reduce risk by about 40-50%. FUNDING: UK Medical Research Council, British Heart Foundation, European Community Biomed Programme, Australian National Health and Medical Research Council, and National Heart Foundation.

Cystatin C and risk of vascular and nonvascular mortality: a prospective cohort study of older men.

OBJECTIVE: To assess the relevance of cystatin C, as a marker of mild-to-moderate renal impairment, for vascular and nonvascular mortality in older people. DESIGN: Prospective cohort study. SETTING: Re-survey in 1997 to 1998 of survivors in the 1970 Whitehall study of London civil servants. SUBJECTS: Five thousand three hundred and seventy-one men (mean age at resurvey: 77 years) who took part in the resurvey and had plasma cystatin C concentration measured. MAIN OUTCOME MEASURES: Cause-specific mortality over subsequent 11 years (1997 to 2008). METHODS: Cox regression was used to estimate the associations of cystatin C with vascular and nonvascular mortality, before and after adjustment for prior disease and other risk factors (including lifetime blood pressure). RESULTS: During an 11.0-year follow-up period, there were 1171 deaths from vascular causes [26 per 1000 per year (py)] and 1615 deaths from nonvascular causes (36 per 1000 py). Compared with men with cystatin C in the bottom fifth of the distribution, men in the top 10th had about two-fold higher mortality rates from vascular and nonvascular mortality (fully adjusted P both <0.001) even after adjustment for prior disease and all measured confounders, including lifetime blood pressure. The fully adjusted relative risks per 50% higher cystatin C concentrations were 1.66 [95% CI 1.48 to 1.85] for vascular mortality, 1.92 [95% CI 1.66 to 2.22] for ischaemic heart disease mortality and 1.46 [95% CI 1.31 to 1.61] for nonvascular mortality. CONCLUSIONS: In older men, plasma concentration of cystatin C, probably as a marker of mild renal disease, is a strong independent predictor of both vascular and nonvascular mortality.

Effects of older age on fibrin D-dimer, C-reactive protein, and other hemostatic and inflammatory variables in men aged 60-79 years.

BACKGROUND: Previous studies have suggested that several hemostatic and inflammatory variables, which are risk predictors for arterial or venous thrombosis, increase with age. However, there is a lack of data from large population studies for reliable estimates of reference ranges. OBJECTIVES: To establish reliable reference ranges of hemostatic and inflammatory variables for 5-year age groups in older men and their implications for pathogenesis and diagnosis. PATIENTS AND METHODS: A total of 3861 men aged 60-79 years at the 20 years follow-up of the British Regional Heart Study. RESULTS: Several variables increased with age. The greatest median increases between 60-64 and 75-79 years age groups were observed for fibrin D-dimer (91%) and C-reactive protein (CRP) (57%). Significant median increases were also observed for von Willebrand factor antigen (23%), tissue plasminogen activator antigen (11%), factor VIII (10%), and fibrinogen (8%). In contrast, levels of classical cardiovascular risk factors neither decreased nor increased substantially with age, with the exception of systolic blood pressure (median increase 10%). CONCLUSIONS: The exponential increases in risk of arterial and venous thrombotic events in men between age 60 and 79 years (when most such events occur) may be related in part to increasing activation of blood coagulation, fibrinolysis, and inflammation; possibly related to the increasing inflammatory burden of both atherosclerotic and non-vascular disease. These increases also have implications for diagnosis of suspected acute venous thromboembolism (D-dimer), and recently proposed screening for prediction of coronary heart disease risk and detection of occult disease (CRP).

Early experiences and their relationship to maternal eating disorder symptoms, both lifetime and during pregnancy.

BACKGROUND: There is some evidence that early sexual abuse is an aetiological factor for eating disorder. However, there is sparse information from large-scale, non-clinical studies. AIMS: This study was designed to explore which early experiences, recalled during pregnancy, were associated with both lifetime and antenatal eating disorder symptoms in a community sample. METHOD: Univariate and multivariate analyses were conducted of data from questionnaires administered during pregnancy to a community sample of pregnant women. RESULTS: Recall of parental mental health problems and of early unwanted sexual experiences were independently associated with both lifetime eating problems, laxative use and vomiting during pregnancy, and marked concern during pregnancy over shape and weight. CONCLUSIONS: There are public health implications for these results. Eating disorders in mothers represent a risk for child development. It may be important to enquire during pregnancy about a history of eating problems and to provide the opportunity for early experiences to be discussed.

Prevalence of undiagnosed Type 2 diabetes and impaired fasting glucose in older British men and women.

AIM: To estimate the prevalence of undiagnosed diabetes and impaired fasting glucose in older British men and women, using the 1999 World Health Organization (WHO) thresholds based on fasting glucose measurements. METHODS: Participants in the British Regional Heart Study and the British Women's Heart and Health Study were selected from one socially representative general practice in 24 British towns. Included in this analysis were 3736 men and 3642 women aged 60-79 years (predominantly white), who provided a single fasting blood sample at a clinical examination between 1998 and 2001, and who had no previous diagnosis of diabetes. RESULTS: Two hundred and eleven men (5.7%) and 190 women (5.2%) had a fasting blood glucose level consistent with the WHO threshold for a diagnosis of diabetes (> or = 7.0 mmol/l), whilst a further 667 men (17.9%) and 642 women (17.6%) had impaired fasting glucose levels (6.1 < or = 7 mmol/l). When analyses were restricted to subjects who had fasted for at least 8 h, and whose blood sample was taken before 12.00 h, the predicted prevalence of undiagnosed diabetes (based on two separate measurements) was 6.7% in men and 6.0% in women. The predicted prevalence of impaired fasting glucose (based on two separate measurements) was approximately 20% in both sexes. CONCLUSIONS: More than one-fifth of older white British men and women have either undiagnosed diabetes or impaired fasting glucose according to new WHO criteria. Strategies for the primary and secondary prevention of Type 2 diabetes among older individuals are urgently needed.

Alcohol intake in middle age and risk of cardiovascular disease and mortality: accounting for intake variation over time.

Moderate alcohol consumption is associated with a decreased risk of cardiovascular disease. However, the impact of variation in alcohol intake over time on estimated risk relations has not been adequately addressed. In this study, 6,544 middle-aged British men without previous cardiovascular disease were followed for cardiovascular events and all-cause mortality over 20 years from 1978/1980 to 1998/2000. Alcohol intake was ascertained at regular points throughout the study. A total of 922 men had a major coronary event within 20 years, 352 men had a stroke, and 1,552 men died of all causes. Baseline alcohol intake displayed U-shaped relations with cardiovascular disease and all-cause mortality, with light drinkers having the lowest risks and nondrinkers and heavy drinkers having similarly high risks. However, the nature of these relations changed after adjustment for intake variation; risks associated with nondrinking were lowered, and risks associated with moderate and heavy drinking increased. Regular heavy drinkers had a 74% higher risk of a major coronary event, a 133% higher risk of stroke, and a 127% higher risk of all-cause mortality than did occasional drinkers (these estimates were 8%, 54%, and 44% before adjustment for intake variation). The findings suggest that considerable caution may be needed before any recommendations regarding acceptable limits of alcohol consumption are made.

Coronary heart disease prevention in clinical practice: are patients with diabetes special? Evidence from two studies of older men and women.

OBJECTIVE: To assess whether the extent of primary and secondary coronary heart disease (CHD) prevention in older British men and women differs between patients with and without diabetes. DESIGN: Two prospective cardiovascular cohort studies. SETTING: 24 British towns. PATIENTS: 4252 men and 4286 women aged 60-79 years examined between 1998 and 2001. MAIN OUTCOME MEASURES: Use of aspirin, statin, and blood pressure lowering treatment and risk factor control, examined by diabetic status and history of established CHD. RESULTS: About 20% of the men and 12% of the women had established CHD at age 60-79 years and 7% of the men and 5% of the women had diabetes. In primary CHD prevention, patients with diabetes were more likely to receive CHD risk reducing medications than those without diabetes, but the proportions receiving preventive treatments in both groups were low. In secondary prevention, diabetic and non-diabetic patients received similar levels of treatment, with the exception of angiotensin converting enzyme inhibitors and (for women only) blood pressure lowering treatment, which were more widely used among diabetic patients. There were no clear differences in blood pressure control or cigarette smoking by diabetic status in primary or secondary prevention. Mean total cholesterol concentrations were lower in diabetic patients independently of treatment with statins. CONCLUSIONS: Despite their exceptionally high CHD risk, many opportunities to reduce CHD risk among patients with diabetes have not been taken.

A multi-centre cohort study of the physical health of 5-year-old children conceived after intracytoplasmic sperm injection, in vitro fertilization and natural conception.

BACKGROUND: Over a million children have been born from assisted conception worldwide. Newer techniques being introduced appear less and less 'natural', such as intracytoplasmic sperm injection (ICSI), but there is little information on these children beyond the neonatal period. METHODS: 540 ICSI conceived 5-year-old children from five European countries were comprehensively assessed, along with 538 matched naturally conceived children and 437 children conceived with standard IVF. RESULTS: Of the 540 ICSI children examined, 63 (4.2%) had experienced a major congenital malformation. Compared with naturally conceived children, the odds of a major malformation were 2.77 (95% CI 1.41-5.46) for ICSI children and 1.80 (95% CI 0.85-3.81) for IVF children; these estimates were little affected by adjustment for socio-demographic factors. The higher rate observed in the ICSI group was due partially to an excess of malformations in the (boys') urogenital system. In addition, ICSI and IVF children were more likely than naturally conceived children to have had a significant childhood illness, to have had a surgical operation, to require medical therapy and to be admitted to hospital. A detailed physical examination revealed no further substantial differences between the groups, however. CONCLUSIONS: Singleton ICSI and IVF 5-year-olds are more likely to need health care resources than naturally conceived children. Assessment of singleton ICSI and IVF children at 5 years of age was generally reassuring, however, we found that ICSI children presented with more major congenital malformations and both ICSI and IVF children were more likely to need health care resources than naturally conceived children. Ongoing monitoring of these children is therefore required.

North-south gradients in Britain for stroke and CHD: are they explained by the same factors?

BACKGROUND AND PURPOSE: The geographic variation in CHD and stroke within Great Britain is well known. We aimed to quantify these variations and to determine the contribution of established risk factors. METHODS: This prospective study consisted of 7735 men 40 to 59 years of age in 24 British towns who were followed up for 20 years from screening in 1978 to 1980. We compared age-adjusted incidences of major stroke and CHD events in southern England and the rest of Britain before and after adjustment for established cardiovascular risk factors. RESULTS: At least 1 episode of stroke occurred in 467 men (3.54 per 1000 person-years, age standardized) and of CHD in 1299 men (10.05 per 1000 person-years). Event rates varied between towns, from 2.00 to 5.45 per 1000 person-years for stroke and from 6.16 to 12.21 per 1000 person-years for CHD. Incidence for both diseases was highest in Scottish towns and lowest in southern English towns ("north-south gradient"). The hazard ratio for stroke in the rest of Britain compared with southern England was 1.44 (95% confidence interval [CI], 1.16 to 1.78); for CHD, it was 1.32 (95% CI, 1.14 to 1.53). After adjustment for baseline systolic blood pressure, smoking status, physical activity, social class, and height, the hazard ratio was 1.24 (95% CI, 1.00 to 1.54) for stroke and 1.17 (95% CI, 1.02 to 1.35) for CHD. CONCLUSIONS: Similar north-south gradients were observed for major stroke and major CHD events. The magnitude of these gradients was considerably diminished when individual risk variables were taken into account.

Biochemical measures in a population-based study: effect of fasting duration and time of day.

BACKGROUND: Epidemiological studies generally aim to make simple but unbiased measurements of individuals. For this reason measurements of metabolic variables (including blood lipids, glucose and insulin) are usually carried out after a period of fasting. Few studies have examined the extent to which the use of a defined protocol for fasting in epidemiological studies abolishes the influence of fasting duration and time of day on biochemical measurements. METHODS: Cross-sectional survey of British Regional Heart Study participants (4,252 men aged 60-79 years), in which men without diabetes were asked to provide a blood sample after fasting for at least 6 h. Serum total, HDL and LDL cholesterol, triglyceride and insulin, and plasma glucose concentrations were measured between 08:00 h and 18:00 h. RESULTS: Non-fasting men had lower mean LDL cholesterol and higher glucose, insulin and triglyceride levels than fasting men; these differences were more marked among diabetics. Among fasting men without diabetes, insulin and glucose levels were strongly related to time of day, falling gradually throughout the morning and remaining stable in the afternoon. Because of these relationships and the dependence of fasting duration on time of day, insulin and glucose displayed a periodic relation with fasting duration above 6 h. These associations were largely abolished by adjustment for time of day; associations with time of day were unaffected by adjustment for fasting duration. Triglyceride concentrations fell with increasing fasting duration. This relationship was also mediated through a gradual increase in triglyceride levels throughout the day. Adjustments to compensate for these variations are described. DISCUSSION: Even after fasting, biochemical measurements may still differ in relation to fasting duration and time of day. In epidemiological studies, it is important to standardize both the period of fasting and the time of day as much as possible, and make adjustments where necessary.

Low prevalence of lipid lowering drug use in older men with established coronary heart disease.

OBJECTIVE: To determine the prevalence and correlates of lipid lowering drug use among older British men with established coronary heart disease (CHD). DESIGN: Cross sectional survey within a cohort study (British regional heart study) carried out at 20 years of follow up in 1998-2000. SETTING: General practices in 24 British towns. PARTICIPANTS: 3689 men aged 60-75 years (response rate 76%). MAIN OUTCOME MEASURES: Diagnoses of myocardial infarction and angina based on detailed review of general practice records. Lipid lowering drug use and blood cholesterol concentrations ascertained at 20 year follow up examination. RESULTS: Among 286 men with definite myocardial infarction, 102 (36%) were taking a lipid lowering drug (93 (33%) a statin); among 360 men with definite angina without myocardial infarction, 84 (23%) were taking a lipid lowering drug (78 (21%) a statin). Most men with documented CHD who were not receiving a lipid lowering drug had a total cholesterol concentration of 5.0 mmol/l or more (87% of those with myocardial infarction, 82% with angina). Fewer than half of men with CHD receiving a statin had a total cholesterol concentration below 5.0 mmol/l (45% of those with myocardial infarction and 47% of those with angina). Only one third of the men taking a statin were receiving trial validated dosages. Among men with CHD, a history of revascularisation, more recent diagnosis, and younger age at diagnosis were associated with a higher probability of receiving lipid lowering drug treatment. CONCLUSION: Among patients with established CHD, the prevalence of lipid lowering drug use remains low and statin regimens suboptimal. Major improvements in secondary prevention are essential if the benefits of statins are to be realised.

Effect of pravastatin on frequency of fracture in the LIPID study: secondary analysis of a randomised controlled trial. Long-term Intervention with Pravastatin in Ischaemic Disease.

BACKGROUND: Statins inhibit the same biochemical pathway as aminobisphosphonates, therefore these cholesterol-lowering agents may have a beneficial effect on osteoporosis. This possibility has been supported by the finding that some statins also stimulate bone formation, and by observational studies suggesting that patients using statins have higher bone densities and lower fracture rates than controls. To assess whether statins have clinically significant effects on bone, we studied the frequency of fractures in a large randomised controlled trial of these agents. METHODS: 9014 patients (17% women, median age 62 years) with ischaemic heart disease were randomly assigned pravastatin 40 mg daily or placebo and followed up for a mean of 6.0 years. Fractures were ascertained from adverse-event reports. FINDINGS: 101 patients in the placebo group were admitted to hospital for fracture compared with 107 in the pravastatin group (hazard ratio 1.05 [95% CI 0.80-1.37]). When patients with fractures not necessitating hospital admission were added, the total number of patients having a fracture was 183 in the placebo group and 175 in the pravastatin group (0.94 [0.77-1.16]). Separate analyses for women alone and for individuals aged 65 years and over gave similar results. INTERPRETATION: These findings offer no support for the hypothesis that statins have a significant effect on fracture risk. However, this study was not of an osteoporotic population, and fracture rate, although clinically important, is an insensitive index of effects on bone. Statins should not be used to prevent osteoporosis until there is evidence for their efficacy based on randomised controlled trials.

Effects of pravastatin in 3260 patients with unstable angina: results from the LIPID study.

BACKGROUND: The LIPID study is a major trial of secondary prevention of coronary-heart-disease events that includes hospital admission with unstable angina (as well as myocardial infarction) as a qualifying event. In this substudy of LIPID, we compared subsequent cardiovascular risks and the effects of pravastatin in patients with previous unstable angina or previous myocardial infarction. METHODS: 3260 patients diagnosed with unstable angina and 5754 with acute myocardial infarction 3-36 months previously were randomly assigned 40 mg pravastatin daily or placebo over a mean of 6.0 years. The risk reduction of a range of cardiovascular events was estimated by means of the hazard ratio in Cox's proportional hazards model. FINDINGS: Among patients assigned placebo, survival in the two diagnosis groups was similar. The relative risk reduction for mortality with pravastatin was 20.6% in the myocardial infarction group and 26.3% in the unstable angina group (p=0.55). Pravastatin significantly reduced the rates of all prespecified coronary endpoints in the myocardial infarction group. In patients with previous unstable angina, coronary heart disease mortality, total mortality, myocardial infarction, a need for coronary revascularisation, the number of admissions to hospital, and the number of days in hospital were significantly lower with pravastatin. Overall, hospital admission for unstable angina was the most common endpoint (24.6% of the placebo group; 22.3% of the pravastatin group). INTERPRETATION: Patients who have survived acute myocardial infarction or unstable angina have a similar long-term prognosis, a high occurrence of subsequent unstable angina, and benefit similarly from therapy with pravastatin.