A meta-analysis 5 of individual participant data included trials of more versus less intensive statin regimens (5 trials; n=39 612; median follow-up 5.1 years) and statin versus control (21 trials; n=129 526; median follow-up 4.8 years) (CTTC-study). Compared with less intensive regimens, more intensive regimens produced a highly significant 15% (95% CI 11 to 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 to 19; p<0.0001), in coronary revascularisation of 19% (95% CI 15 to 24; p<0.0001), and in ischaemic stroke of 16% (95% CI 5 to 26; p=0.005). Per 1.0 mmol/L reduction in LDL cholesterol (LDL-C), 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 (RR 0.78, 95% CI 0.76 to 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, largely reflecting significant reductions in deaths due to coronary heart disease and other cardiac causes. No significant effects were observed on deaths due to cancer or other non-vascular causes (RR 0.97, 95% CI 0.92 to 1.03; p=0.3) or on cancer incidence (RR 1.00, 95% CI 0.96 to 1.04; p=0.9), even at low LDL cholesterol concentrations. 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%.
Another meta-analysis 6 evaluated efficacy and safety of further lowering LDL-C levels in patient populations presenting with median LDL-C levels of 1.8 mmol/L (70 mg/dL) or less. There was a consistent relative risk reduction in major vascular events per change in LDL-C in patient populations starting as low as a median of 1.6 mmol/L (63 mg/dL) and achieving levels as low as a median of 0.5 mmol/L (21 mg/dL). LDL-C lowering was not associated with an increased risk of serious adverse events, myalgias and/or myositis, elevation in the level of aminotransferases, new-onset diabetes, hemorrhagic stroke, or cancer.
A prospective meta-analysis 1 included 14 RCTs with a total of 90 056 individuals of which 47% had pre-existing CHD, 24% were women, 21% had a history of diabetes and 55% a history of hypertension. Mean duration was 5 years. The mean pre-treatment LDL cholesterol was 3.79 mmol/l and decreased between 0.35 mmol/l to 1.77 mmol/l (mean 1.09) in one year. There was a 12% proportional reduction in all-cause mortality per mmol/l reduction in LDL cholesterol (rate ratio [RR] 0.88, 95% CI 0.84-0.91; p<0.0001). This reflected a 19% reduction in coronary mortality (0.81, 0.76-0.85; p<0.0001), and non-significant reductions in non-coronary vascular mortality (0.93, 0.83-1.03; p=0.2) and non-vascular mortality (0.95, 0.90-1.01; p=0.1). There were corresponding reductions in myocardial infarction or coronary death (0.77, 0.74-0.80; p<0.0001), in the need for coronary revascularisation (0.76, 0.73-0.80; p<0.0001), in fatal or non-fatal stroke (0.83, 0.78-0,88; p<0.0001), and, combining these, of 21% in any such major vascular event (0.79, 0.77-0.81; p<0.0001). Benefits were greater with longer treatment. 48 (95% CI 39-57) fewer participants suffered major vascular events per 1000 among those with pre-existing CHD at baseline, compared with 25 (19-31) per 1000 among participants with no such history. There was no evidence of increased incidence of cancer overall (1.00, 0.95-1.06; p=0.9) or at any particular site.
A systematic review 3 including 12 studies with a total of 80,862 subjects was abstracted in DARE. In primary prevention trials, the relative risk reduction for a major coronary event was 21% in diabetic patients (RR 0.79, 95% CI: 0.70 to 0.89, P<0.0001) and 23% in non-diabetic patients (RR 0.77, 95% CI: 0.67 to 0.88, P=0.0003) treated with either statins or gemfibrozil. Significant heterogeneity was shown in the primary prevention of a major coronary event for non-diabetic patients. In secondary prevention trials, the relative risk reduction for a major coronary event was 21% in diabetic patients (RR 0.79, 95% CI: 0.69 to 0.90, P=0.0005) and 23% in non-diabetic patients (RR 0.77, 95% CI: 0.74 to 0.81, P<0.00001) treated with either statins or gemfibrozil. Comment: The absolute benefit may be greater in diabetics because their absolute cardiovascular risk is higher.
A systematic review and individual patient data meta-analysis 4 included 61 prospective observational studies with a total of 892 337 subjects without previous stroke or heart disease (mean follow-up 13 y). 1 mmol/L lower total cholesterol was associated with about a half (HR 0.44, 95% CI 0.42-0.48), a third (0.66, 0.65-0.68), and a sixth (0.83, 0.81-0.85) lower ischemic heart disease mortality in both sexes at ages 40-49, 50-69, and 70-89 years, respectively. Total cholesterol was weakly positively related to ischemic and total stroke mortality only in early middle age (40-59 years) and only in those with lower blood pressure (systolic BP < 145 mmHg). At older ages (70-89 years) and, particularly, for those with systolic blood pressure over about 145 mm Hg, total cholesterol was negatively related to haemorrhagic and total stroke mortality. The absence of an independent positive association of cholesterol with stroke mortality remained unexplained. Nevertheless, there is conclusive evidence from randomised trials that statins substantially reduce not only coronary event rates but also total stroke rates in patients with a wide range of ages and blood pressures.
A meta-analysis of 26 RCTs with a total of 86,936 subjects 2 was abstracted in DARE. No evidence of increased cancer risk with statins was found (OR 1.02, 95% CI: 0.97, 1.07).
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