Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12 064 survivors of myocardial infarction: a double-blind randomised trial

Background Lowering of LDL cholesterol reduces major vascular events, but whether more intensive therapy safely produces extra benefits is uncertain We aimed to establish efficacy and safety of more intensive statin treatment in patients at high cardiovascular risk Methods We undertook a double-blind randomised trial in 12064 men and women aged 18-80 years with a history of myocardial infarction Participants were either currently on or had clear indication for statin therapy, and had a total cholesterol concentration of at least 3 5 mmol/L if already on a stain or 4 5 mmol/L. if not Randomisation to either 80 mg or 20 mg simvastatin daily was done centrally using a minimisation algorithm Participants were assessed at 2 4 8, and 12 months after randomisation and then every 6 months until final follow up The primary endpoint was major vascular events, defined as coronary death, myocardial infarction, stroke or arterial revascularisation Analysis was by intention to treat This study is registered number ISRCTN74348595 Findings 6031 participants were allocated 80 mg simvastatin daily, and 6033 allocated 20 mg simvastatin daily During a mean follow up of 6 7 (SD 1 5) years allocation to 80 mg simvastatin produced an average 0 35 (SE 0 01) mmol/L greater reduction in LDL cholesterol compared with allocation to 20 mg Major vascular events occurred m 1477 (24 5%) participants allocated 80 mg simvastatin versus 1553 (25 7%) of those allocated 20 mg, corresponding to a 6% proportional reduction (risk ratio 0 94 95% CI 0 88-1 01, p=0 10) There were no apparent differences in numbers of haemorrhagic strokes (24 [0 4%] vs 25 [0 4%]) or deaths attributed to vascular (565 [9 4%] vs 572 [9 5%]) or non vascular (399 [6 6%] vs 398 [6 6%]) causes Compared with two (0 03%) cases of myopathy in patients taking 20 mg simvastatin daily there were 53 (0 9%) cases in the 80 mg group Interpretation The 6% (SE 3 5%) reduction in major vascular events with a further 0 35 mmol/L reduction in LDL cholesterol in our trial is consistent with previous trials Myopathy was increased with 80 mg simvastatin daily, but intensive lowering of LDL cholesterol can be achieved safely with other regimens