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

Abstract

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 12,064 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 statin 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 in 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.

Funding: Merck; The Clinical Trial Service Unit also receives funding from the UK Medical Research Council and the British Heart Foundation.

Figure 1

Trial profile Numbers lost to follow-up relate to those without information to the end of the scheduled treatment period for mortality (as well as morbidity) and for morbidity alone.

Figure 2

Effects of simvastatin dose allocation on first major vascular event Analyses are of the numbers of participants having a first event of each type during follow-up (with non-fatal and fatal events considered separately), so there is some non-additivity between different types of event. Risk ratios are plotted comparing outcomes in participants allocated 80 mg simvastatin with those in participants allocated 20 mg simvastatin, along with 95% CIs. The dashed vertical line shows the overall risk ratio. MI=myocardial infarction. CHD=coronary heart disease.

Figure 3

Effects of simvastatin dose allocation on first major vascular event by year of follow-up Risk ratios are plotted comparing outcomes in participants allocated 80 mg simvastatin with those in participants allocated 20 mg simvastatin, along with 95% CIs. The dashed vertical line shows the overall risk ratio. Analyses are of numbers of participants having a first event during each year of follow-up and of those still at risk of a first event at the start of each year.

Figure 4

Effects of simvastatin dose allocation on first major vascular event in different categories of participant Risk ratios are plotted comparing outcomes in participants allocated 80 mg simvastatin with those in participants allocated 20 mg simvastatin, along with 95% CIs. The dashed vertical line shows the overall risk ratio. p values of χ² tests are given for heterogeneity between RRs within dichotomous categories and for trend within other categories (except for previous disease categories since there is some overlap between them). Lipid categories relate to measured values at the randomisation visit after all participants had been taking 20 mg simvastatin daily for 2 months during the run-in. MI=myocardial infarction. CHD=coronary heart disease. GFR (MDRD)=glomerular filtration rate estimated with modification of diet in renal disease equation.

Figure 5

Effects of simvastatin dose allocation on cause-specific mortality Risk ratios are plotted comparing outcomes in participants allocated 80 mg simvastatin with those in participants allocated 20 mg simvastatin, along with 95% CIs. The dashed vertical line shows the overall risk ratio. MI=myocardial infarction. CHD=coronary heart disease.

Figure 6

Effect of simvastatin dose allocation on site-specific cancer incidence Risk ratios are plotted comparing outcomes in participants allocated 80 mg simvastatin with those in participants allocated 20 mg simvastatin, along with 95% CIs. The dashed vertical line shows the overall risk ratio. Analyses are of the numbers of participants developing cancer at each site (excluding recurrences or new cancers at the same site), so there is some non-additivity between cancers at different sites. Connective tissue includes breast, melanoma, skin, and other connective tissue cancers, but not non-melanoma skin cancer (which was prospectively to be considered separately).