Efficacy and safety of more intensive lowering of LDL cholesterol:

Cholesterol Treatment Trialists' (CTT) Collaboration; Lancet. 2010 November 13; 376(9753): 1670–1681


The Cholesterol Treatment Trialists' (CTT) Collaboration previously reported a meta-analysis1 of individual data from 90 000 individuals in 14 randomised trials2–15 of statin therapy versus control. Allocation to the statin regimens in those trials resulted in a weighted mean difference of about 1·0 mmol/L in LDL cholesterol and a proportional reduction of about a fifth in major vascular events (defined as coronary death, non-fatal myocardial infarction, coronary revascularisation, or stroke). Observational studies show that there is a continuous positive relation between coronary disease risk and blood cholesterol concentrations,16–18 so larger reductions in LDL cholesterol might well produce larger reductions in risk. This hypothesis is indirectly supported by the positive association identified in the previous meta-analysis between the absolute reduction in LDL cholesterol in a trial and the proportional reduction in major vascular events in that trial.1Standard statin regimens (eg, 20–40 mg simvastatin daily) typically reduce LDL cholesterol concentrations by about a third, but regimens involving higher doses or newer, more potent statins (eg, 40–80 mg atorvastatin or 10–20 mg rosuvastatin daily) can halve LDL cholesterol.19–22 To determine whether larger reductions in LDL cholesterol safely produce further reductions in major vascular events, several trials have compared more intensive versus standard statin regimens.23–27 Although their results tend to suggest further benefit,28 only two had significant results for their primary outcome.24,26 The present meta-analysis of individual data from all of these trials assesses the effects of more intensive statin therapy more reliably than before. Several recent trials of statin therapy in patients with renal failure29,30 or chronic heart failure31,32 have not shown clear evidence of benefit, and in our meta-analysis we also investigate those findings. Moreover, we address the question of whether lowering of LDL cholesterol to very low concentrations might have adverse consequences.18,33–35

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 lessintensive 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%.