In the Cholesterol Treatment Trialists Collaboration (CTT) meta-analysis all those trials were eligible for inclusion if: the main effect of the intervention was to lower LDL cholesterol; no other differences in risk factor modification were intended; and at least 1000 participants were to be recruited with at least 2 years' scheduled treatment duration. Five trials comparing more intensive with less intensive LDL-C lowering were taken and 21 trials were of comparison of statin therapy with control.
Overall, among the 39 612 participants in five trials, the weighted mean baseline LDL cholesterol concentration was estimated to be 2·53 mmol/L, the weighted mean difference at one year was 0·51 mmol/L, and the weighted median follow-up duration among survivors was 5·1 years (2·1 years for patients with acute coronary syndrome and 5·8 years for those with stable disease).
First major vascular events were recorded in the five trials of more versus less intensive statin therapy in 3837 (4·5% per annum) of 19 829 participants allocated more intensive versus 4416 (5·3% per annum) of 19 783 allocated less intensive therapy, corresponding to a highly significant further proportional risk reduction of 15% (95% CI 11—18; p<0·0001) associated with the mean 0·51 mmol/L further LDL cholesterol reduction.
In the updated meta-analysis of 21 trials of statin versus control, 7136 (2·8% per annum) of 64 744 participants allocated statin therapy had first major vascular events versus 8934 (3·6% per annum) of 64 782 allocated control, corresponding to a highly significant 22% (95% CI 19—24; p<0·0001) risk reduction with a 1·07 mmol/L LDL cholesterol reduction. Overall, the weighted average reduction in major vascular events was 21% (95% CI 19—23; p<0·0001) per 1·0 mmol/L reduction in LDL cholesterol.
Taking all 26 trials together, the risk reduction was 22% (95% CI 20—24; p<0·0001) per 1·0 mmol/L reduction in LDL cholesterol at 1 year, with a significant 12% reduction during the first year after randomisation (p<0·0001) and highly significant reductions of about a quarter during each subsequent year (all p<0·0001).
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.
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.
Overall, there was a 22% proportional reduction in the risk of major vascular events for each 1 mmol/L reduction in LDL cholesterol, which implies that, at least within the range of LDL cholesterol studied to date, a 2 mmol/L reduction would reduce the risk by about 40% (since the combination of risk ratios of 0·78×0·78 yields a risk ratio of about 0·6), and a 3 mmol/L reduction could reduce the risk by about 50%.
In the combined meta-analysis coronary mortality was reduced by about a fifth per 1·0 mmol/L LDL cholesterol reduction, but the reduction in cardiac deaths that were not attributed to coronary disease was only about half as large.
There was no evidence in the analyses of an increase in incidence of cancer.The lowering of LDL cholesterol with statin therapy was associated with a non-significant excess (257 vs 220; p=0·2 of incidence of haemorrhagic strokes
These findings suggest that the primary goal for patients at high risk of occlusive vascular events should be to achieve the largest LDL cholesterol reduction possible without materially increasing myopathy risk.
Current therapeutic guidelines tend to emphasise the need to reach a particular LDL cholesterol target—for example, US National Cholesterol Education Program guidelines suggest that the objective in high-risk patients should generally be to reduce LDL cholesterol to below 100 mg/dL (2·6 mmol/L) or, optionally, for very high risk patients, to below 70 mg/dL (1·8 mmol/L).
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