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

SEARCH Study, Clinical Trial Service Unit and Epidemiological Studies Unit, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, UK.
The Lancet (Impact Factor: 45.22). 11/2010; 376(9753):1658-69. DOI: 10.1016/S0140-6736(10)60310-8
Source: PubMed


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

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Available from: Richard Bulbulia, Apr 09, 2014
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    • "However, even in patients treated with statins, the risk of complications and death from cardiovascular events is reduced by only 30% (Libby, 2005). Statin treatment, in fact, is not always effective to lower LDL cholesterol to the recommended level, and can cause side effects such as an increased risk of muscle injury (myopathy and rhabdomyolysis) and hepatic dysfunction (rise of γ-glutamyltransferase (γ-GTP) and alanine transaminase (ALT)) (Armitage et al., 2010; Egan and Colman, 2011). Recently, two antibodies, alirocumab and evolocumab, were reported as a new type of cholesterol-lowering drug. "
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    ABSTRACT: Sterol O-acyltransferase 2 (SOAT2, also known as ACAT2) is considered as a new therapeutic target for the treatment or prevention of hypercholesterolemia and atherosclerosis. Fungal pyripyropene A (PPPA:1-, 7-, 11-triacyl type), the first SOAT2-selective inhibitor, proved orally active in vivo using atherogenic mouse models. The purpose of the present study was to demonstrate that the PPPA derivatives (PRDs) prove more effective in the mouse models than PPPA. Among 196 semi-synthetic PPPA, potent, SOAT2-selective and stable PRDs were selected. In vivo anti-atherosclerotic activity of selected PRDs was tested in apolipoprotein E knockout (Apoe(-/-)) mice or low density lipoprotein receptor knockout (Ldlr(-/-)) mice fed a cholesterol-enriched diet (0.2% cholesterol and 21% fat) for 12 weeks. During the PRD treatments, no detrimental side effects were observed. Among three PRDs, Apoe(-/-) mice treated with PRD125 (1-, 11-O<-benzylidene type) at 1 mg/kg/day had significantly lower total plasma cholesterol concentration by 57.9±9.3%;further, the ratio of cholesteryl oleate to cholesteryl linoleate in LDL was lower by 55.6±7.5%, respectively. The hepatic cholesteryl ester levels and SOAT2 activity in the small intestines and livers of the PRD-treated mice were selectively lowered. The atherosclerotic lesion areas in the aortae of PRD125-treated mice were significantly lower at 62.2±13.1%, respectively. Furthermore, both PRDs were also orally active in atherogenic Ldlr(-/-) mice. Among the PRDs tested, PRD125 was the most potent in both mouse models. These results suggest that SOAT2-selective inhibitors like PRD125 have a high potential as post-statin agents for the treatment and/or prevention in patients with atherosclerosis and hypercholesterolemia. The American Society for Pharmacology and Experimental Therapeutics.
    Full-text · Article · Sep 2015 · Journal of Pharmacology and Experimental Therapeutics
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    • "None of the longer-term randomised controlled trials involving simvastatin [8] [9] [10] [11] [12] directly compared outcomes in users of 40 mg versus 20 mg daily, hence no trial-based estimates of relative or excess absolute risk of rhabdomyolysis exist for these doses. Moreover, the very small number of exposed cases in the 40 mg (5 cases in the Heart Protection Study [11]) and 20 mg (3 cases in IDEAL [12], 1 in 4S [10], none in SEARCH [8] or A to Z [9]) groups of these trials did not permit the estimation of stable incidence rates. However, our results are consistent with the findings of an observational study which used data from the Group Health Cooperative [13]. "
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    ABSTRACT: Two randomised controlled trials have found a higher risk of rhabdomyolysis in users of 80mg versus 20mg simvastatin, but there is very limited information about the risk associated with other doses. We undertook a nested case-control study, using routinely collected national health and drug dispensing data, to estimate the relative and absolute risks of rhabdomyolysis resulting in hospital admission or death according to simvastatin dose. The underlying study cohort comprised all patients (n=313,552) who initiated a new episode of simvastatin use in New Zealand between 1 May 2005 and 31 December 2009. Cases (n=29) were patients with a diagnosis of rhabdomyolysis after cohort entry, confirmed by hospital discharge letter or death records. Ten controls, matched by year of birth and sex, were randomly selected from the study cohort using risk set sampling. Current users of 40mg simvastatin daily were about five times as likely to develop rhabdomyolysis as those taking 20mg; the adjusted odds ratio was 5.3 (95% CI 1.9-15.0). The absolute excess risk of rhabdomyolysis associated with the use of 40mg versus 20mg was about 10 per 100,000 person-years; the crude incidence rates were 11.5 (95% CI 7.1-17.5) and 2.1 (95% CI 0.7-4.8) per 100,000 person-years respectively. These findings provide reassurance that the absolute risk of rhabdomyolysis in a general population of simvastatin users is very low. Nonetheless, they also raise questions about the optimal simvastatin regimen to maximise cardiovascular benefits and minimise the risk of serious muscle injury.
    Full-text · Article · Mar 2014 · International journal of cardiology
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    • "However, in this study, the percent reduction in LDL-C and increases in HDL-C were associated with improved secondary prevention of CV disease outcome in ACS patients in a Japanese population; these parameters were superior to the absolute values of cholesterol profile parameters. This finding adds support to the results of previous large studies from Western countries showing that baseline cholesterol profiles were not associated with CV disease outcome [4] [6] [13]. Why does the percent change better relate with the outcome than the absolute value? "
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    ABSTRACT: Background: Although increased attention is given to assess absolute values of serum cholesterol profiles as optimal markers for preventing future cardiovascular (CV) events, changes in cholesterol profiles also have the potential to be associated with CV disease outcome in Japanese patients with acute coronary syndrome (ACS). Methods: From the database of the Japanese Coronary Artery Disease (JCAD) study, 2664 patients with ACS who had serial measurements of serum cholesterol profile parameters were enrolled. These patients were followed-up for a mean period of 2.7 years. The endpoint was all CV events. Baseline clinical characteristics of patients with and without CV events were adjusted by the propensity score matching analysis. Results: None of the serum absolute cholesterol profiles at baseline and 6 months later was associated with CV events, except for baseline serum total cholesterol level. However, large improvements in cholesterol profiles correlated with better CV disease outcome. Conclusions: This subanalysis of JCAD demonstrated the importance of serial assessment of serum cholesterol profiles for secondary prevention of CV events in Japanese patients with ACS. Changes in serum cholesterol profiles, rather than their absolute values, correlated with future CV events.
    Full-text · Article · Mar 2013 · Journal of Cardiology
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