The effects of cholesterol-lowering treatment with statins on mortality and risk of cancer beyond the usual 5–6-year trial periods are unknown. We extended post-trial follow-up of participants in the ...Scandinavian Simvastatin Survival Study (4S) to investigate cause-specific mortality and incidence of cancer 5 years after closure of the trial.
4S was a randomised double-blind trial of simvastatin or placebo in patients with coronary heart disease, serum total cholesterol 5·5–8·0 mmol/L, and serum triglycerides 2·5 mmol/L or lower. The double-blind period lasted for a median of 5·4 years (range for survivors 4·9–6·3) and ended in 1994. After the trial, most patients in both groups received open-label lipid-lowering treatment. National registers were used to assess mortality and causes of death and cancer incidence in the original treatment groups for a median total follow-up time of 10·4 years (range for survivors 9·9–11·3). Analysis was by intention to treat.
414 patients originally allocated simvastatin and 468 assigned placebo died during the 10·4-year follow-up (relative risk 0·85 95% CI 0·74–0·97, p=0·02), a difference largely attributable to lower coronary mortality in the simvastatin group (238 vs 300 deaths; 0·76 0·64–0.90, p=0·0018). 85 cancer deaths arose in the simvastatin group versus 100 in the placebo group (0·81 0·60–1·08, p=0·14), and 227 incident cancers were reported in the simvastin group versus 248 in the placebo group (0·88 0·73–1·05, p=0·15). Incidence of any specific type of cancer did not rise in the simvastatin group.
Simvastatin treatment for 5 years in a placebo-controlled trial, followed by open-label statin therapy, was associated with survival benefit over 10 years of follow-up compared with open-label statin therapy for the past 5 years only. No difference was noted in mortality from and incidence of cancer between the original simvastatin group and placebo group.
Options for the prevention of cardiovascular disease, the greatest global cause of death, include population preventive measures (the Rose approach), or specifically seeking out and managing ...high-risk cases. However, the likely benefit of a population approach has been recently questioned.
To compare the estimated effects of population strategies at varying levels of population-wide risk factor reduction and high-risk strategies at varying rates of screening uptake on cardiovascular disease mortality.
Data (of 109 954 participants) were pooled from six European general population cohort studies the high-risk cohorts from the SCORE (Systematic COronary Risk Evaluation) dataset. The effects of various population and high-risk strategies for the reduction of risk factors were estimated by calculating the change in 10-year risk of cardiovascular disease mortality (SCORE risk) before and after the particular intervention. Risk factors studied were: total cholesterol, blood pressure and smoking.
At population level, if a 10-year reduction of blood cholesterol level of 10%, a BP reduction of 10% and a 10% reduction in the prevalence of smoking is considered possible, then 9125 lives per million of the population would be saved over 10 years. In contrast, an approach that treats all high-risk individuals with a polypill containing statin, three half-dose antihypertensives and aspirin, with a 20-80% uptake, would save 1861-7452 lives per million. However, the high-risk estimates are very optimistic, as their achievement would require complete compliance.
High-risk and population strategies are complementary. These estimates of the benefits of each may be useful to health planners, when combined with their local knowledge. Recently, benefits of population strategies have been underestimated.
Turner syndrome (TS) is caused by a sex chromosome aberration. The aim was to study the prevalence and incidence of thyroid disease in adults with TS.
Women with TS (n = 91; mean age, 37.7 ± 11 yr) ...were compared with an age-matched female random population sample (n = 228). At baseline, 15 (16%) TS women were treated for hypothyroidism, and elevated serum TSH was found in another eight (9%). As a result, hypothyroidism was more common in women with TS (25%) than in controls (2%; P < 0.0001). Serum free T4 was lower (P = 0.02), and serum TSH was higher (P < 0.0001) in TS women than in age-matched controls. Of all TS women with hypothyroidism, 10 (43%) had an elevated thyroid peroxidase antibody titer vs. 15 (22%) of those without hypothyroidism (P < 0.05), evenly distributed between the karyotype 45,X and mosaicism. A high body mass index, but not a family history or blood lipids, was associated with hypothyroidism in TS. After the 5-yr follow-up, an additional 11 (16%) developed hypothyroidism, of whom four (36%) had elevated thyroid peroxidase. Altogether, 34 (37%) TS women had hypothyroidism after the 5-yr follow-up.
Autoimmune hypothyroidism was common, with an annual incidence of 3.2% in TS. Thyroid function should be checked regularly in TS.
Analysis of insulin-like growth factor I in serum (S-IGF-I) is an integral component in the diagnosis of GH-related disorders and is going to be of interest in the diagnosis and follow-up of many ...disorders. The objective of the present study was to develop cross-sectional reference values for S-IGF-I measured by an automated chemiluminescence immunoassay (Nichols Advantage).
The study included samples from 3,961 healthy subjects (2,201 males, 1,760 females) aged 1 month to 88 years. Six laboratories were involved in this study and the samples were analyzed by one of seven automated immunoassay systems run in these laboratories. For data analysis, polynomial age and sex-specific models were fitted after transformation of S-IGF-I values.
The results show the well-known age dependency of S-IGF-I levels. At ages <20, higher S-IGF-I levels were seen in girls with an estimated mean peak of 410 microg/l at age 14 and an estimated mean peak of 382 microg/l at age 16 in boys. Thereafter, a rapid decrease was seen to approximately 25 years of age, followed by a slow age-dependent decrease. In adulthood, S-IGF-I in males were slightly, but significantly higher than in females. It could be shown that the mean values of some reference sample subgroups differed significantly from the total mean. However, the multicenter approach used in this study reduces the impact of systematic population, sample handling and laboratory differences on the calculated reference mean.
The present study establishes age- and sex-specific reference values for a fully automated immunoassay system based on a large population of healthy subjects. The established reference values may be used for this immunoassay system in different laboratories provided that the systematic difference between systems is low.
The link between type 2 diabetes and hypertension is well established and the conditions often coexist. High normal blood pressure, defined by WHO-ISH as systolic blood pressure (SBP) 130-139 mm Hg ...or diastolic blood pressure (DBP) 85-89 mm Hg, has been found to be an independent predictor for type 2 diabetes in studies, although with relatively limited follow-up periods of approximately 10 years. The aim of this study was to investigate whether hypertension, including mildly elevated blood pressure within the normal range, predicted subsequent development of type 2 diabetes in men over an extended follow-up of 35 years.
Data were derived from the Gothenburg Primary Prevention Study where a random sample of 7 494 men aged 47-55 years underwent a baseline screening investigation in the period 1970-1973. A total of 7 333 men were free from previous history of diabetes at baseline. During a 35-year follow-up diabetes was identified through the Swedish hospital discharge and death registries. The cumulative risk of diabetes adjusted for age and competing risk of death was calculated. Using Cox proportional hazard models we calculated the multiple adjusted hazard ratios (HR) (95% confidence interval (CI)) for diabetes at different blood pressure levels.
During a 35-year follow-up, 956 men (13%) were identified with diabetes. The 35-year cumulative risk of diabetes after adjusting for age and competing risk of death in men with SBP levels <130 mm Hg, 130-139 mm Hg, 140-159 mm Hg and ≥160 mm Hg were 19%, 30%, 31% and 49%, respectively. The HR for diabetes adjusted for age, body mass index (BMI), cholesterol, antihypertensive treatment, smoking, physical activity and occupation were 1.43 (95% CI 1.12-1.84), 1.43 (95% CI 1.14-1.79) and 1.95 (95% CI 1.55-2.46) for men with SBP 130-139 mm Hg, 140-159 mm Hg, and ≥ 160 mm Hg, respectively (reference; SBP<130 mm Hg).
In this population, at mid-life, even high-normal SBP levels were shown to be a significant predictor of type 2 diabetes, independently of BMI and other conventional type 2 diabetes risk factors over an extended follow-up.
This study examined variations in stroke incidence across occupational classes over a 35-year follow-up period. We analyzed a random population-based sample of 6,994 men aged 47–56 years at baseline ...without prior history of stroke. Standardized incidence rates, subdistribution hazard ratios (SHRs) from competing risk regressions and cumulative incidence were calculated, after accounting for risk of death attributed to causes other than stroke. A total of 1,442 strokes were identified over the 35-year period with crude incidences of 5.50 (ischemic) and 1.16 (hemorrhagic) per 1,000 person-years. In the whole group, occupational class was not associated with either ischemic or hemorrhagic stroke. However, older men (≥51 years at baseline) with unskilled manual occupations had a significantly lower risk of ischemic stroke than those with high officials (referent). No association between occupation and stroke of either type was detected for men younger than 51 years. There was an inverse and graded risk of death from causes other than stroke; men in high official positions had the lowest cumulative risk and unskilled manual workers had the highest risk (
P
< 0.0001). The association between occupation and ischemic stroke in older men persisted after accounting for competing risks of death (SHR 0.62; 95 % CI 0.46–0.84). In conclusion, low socioeconomic status was not associated with an increased risk of incident hemorrhagic or ischemic stroke. Older men with the lowest occupational status i.e. unskilled manual had a significantly lower risk of ischemic stroke, even after controlling for other risk factors and competing risks of death.
The Scandinavian Simvastatin Survival Study (4S) and other randomized clinical trials have demonstrated that cholesterol-lowering treatment with statins improves prognosis in patients with coronary ...atherosclerosis compared with placebo. The effect of therapy with statins beyond the typical 5 to 6 years’ duration of the trials, in particular regarding the risk of cancer, has not been investigated. This study examines the long-term effects of simvastatin for up to 8 years on cause-specific mortality in patients with coronary heart disease (CHD). We performed an observational, government registry-based study of mortality in the groups originally randomized to simvastatin or placebo in the 4S over an additional 2-year follow-up period, so that the median total follow-up period was 7.4 years (range 6.9 to 8.3 in surviving patients). Randomization took place at outpatient clinics at 94 clinical centers in Denmark, Finland, Iceland, Norway, and Sweden from 1988 to 1989. Of 4,444 patients with CHD, 2,223 and 2,221 were randomized to treatment with placebo or simvastatin therapy, respectively. Patients received treatment with simvastatin, starting at 20 mg/day, with titration to 40 mg/day at 12 or 24 weeks if total cholesterol was >5.2 mmol/L (200 mg/dl), or placebo. After the double-blind period, most patients in both treatment groups received simvastatin as open-label prescription. Of the 1,967 patients originally treated with placebo and surviving the double-blind period, 97 (4.9%) died during the following 2 years. In the group randomized to simvastatin the corresponding number was 74 of the 2,039 survivors (3.6%). Adding these deaths to those occurring during the original trial, the total was 353 (15.9%) and 256 (11.5%) deaths in the groups originally randomized to placebo and simvastatin, respectively. The relative risk was 0.70 (95% confidence interval 0.60 to 0.82, p = 0.00002). The total number of cancer deaths was 68 (3.1%) in the placebo group and 52 (2.3%) in the simvastatin group (relative risk 0.73, 95% confidence interval 0.51 to 0.05, p = 0.087), and the numbers of noncardiovascular and other deaths were similar in both groups. We therefore conclude that treatment with simvastatin for up to 8 years in patients with CHD is safe and yields continued survival benefit.
The Scandinavian Simvastatin Survival Study (4S) randomized 4444 patients with coronary heart disease (CHD) and serum cholesterol 5.5 to 8.0 mmol/L (213 to 310 mg/dL) with triglycerides < or =2.5 ...mmol/L (220 mg/dL) to simvastatin 20 to 40 mg or placebo once daily. Over the median follow-up period of 5.4 years, one or more major coronary events (MCEs) occurred in 622 (28%) of the 2223 patients in the placebo group and 431 (19%) of the 2221 patients in the simvastatin group (34% risk reduction, P<.00001). Simvastatin produced substantial changes in several lipoprotein components, which we have attempted to relate to the beneficial effects observed.
The Cox proportional hazards model was used to assess the relationship between lipid values (baseline, year 1, and percent change from baseline at year 1) and MCEs. The reduction in MCEs within the simvastatin group was highly correlated with on-treatment levels and changes from baseline in total and LDL cholesterol, apolipoprotein B, and less so with HDL cholesterol, but there was no clear relationship with triglycerides. We estimate that each additional 1% reduction in LDL cholesterol reduces MCE risk by 1.7% (95% CI, 1.0% to 2.4%; P<.00001).
These analyses suggest that the beneficial effect of simvastatin in individual patients in 4S was determined mainly by the magnitude of the change in LDL cholesterol, and they are consistent with current guidelines that emphasize aggressive reduction of this lipid in CHD patients.
Aims To compare incidence and mortality of coronary and stroke events, and risk factors for non-fatal and fatal events, respectively. Methods and results Incidence and mortality were compared in all ...coronary (n=559 341) and stroke (n=530 689) events in Sweden from 1987 to 2001. Data from 28 years of follow-up of a random sample of 7400 men aged 47–55 and free of disease at baseline were used to compare risk factors. Incidence and 28 days of case fatality were considerably higher for coronary disease than for stroke, especially for men. Incidence of coronary disease decreased, especially for men (P=0.0001 for both sexes), and mortality declined for both men and women during 1987–2001 (P=0.0001 for both sexes). Stroke incidence declined slightly (P=0.0001 for both sexes), and there was a decline of mortality (P=0.0001 for both sexes). Out-of-hospital mortality during the first 28 days was higher than in-hospital mortality for coronary events, whereas for stroke, in-hospital mortality was higher (in men) or the same (in women) as out-of-hospital mortality. High serum cholesterol was a strong risk factor for coronary events, but not for stroke. High blood pressure was a stronger risk factor for stroke. About 50% of men with both stroke and coronary disease died from coronary disease. Conclusion Several differences regarding incidence, mortality, prognosis, and risk factors for stroke and coronary disease point towards different pathologies.
Low social class is associated with higher mortality from cancer at several sites and in patients with cancer low social class is known to be associated with a poorer chance of survival. Social ...differences in cancer incidence are less consistent. The present study was undertaken to assess the relation between occupational class and cancer incidence, mortality and survival from cancer in a large population of 7001 men aged 51-59, free of diagnosed cancer at baseline in 1970-1972. The main outcome measures were cancer incidence and cancer mortality until 1992 according to the Swedish national cancer and cause-specific death registries. Cancer survival was analysed in a subgroup of 904 men diagnosed with cancer before 1990. There were 1329 incident cases of cancer including 620 deaths from cancer. Overall cancer incidence during follow-up did not vary significantly by occupational class, but respiratory cancers were significantly more common among men with manual occupations; p = 0.0004. This was not be explained by differences in tobacco smoking, which were minor at the start of the study and did not increase much during follow-up. Overall mortality from cancer was significantly higher among men with manual occupations. Among professionals and higher officials 336 per 100,000 observation years died from cancer, compared to 391 among intermediate officials, 509 among lower officials, 474 among skilled and 548 among non-skilled workers; p for trend = 0.0003. This difference was mainly due to mortality from respiratory cancer, with a threefold difference between manual workers and professionals; this did not change after adjustment for smoking. Among the 904 men diagnosed before 1990 with cancer at any site (except non-melanoma skin cancer) the adjusted relative risk of dying from cancer was 1.75 (95% confidence interval 1.22-2.50) in unskilled workers compared to higher officials (p for trend 0.015).
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