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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    • "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.
    International journal of cardiology 03/2014; 174(1). DOI:10.1016/j.ijcard.2014.03.150 · 4.04 Impact Factor
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    • "Patients with known CAD are considered at high or very high cardiovascular risk and require aggressive modification of all their risk factors [2]. Several major clinical trials with statin therapy in patients with CAD have shown that lowering low-density lipoprotein (LDL) cholesterol can reduce cardiovascular events and the lower the LDLcholesterol achieved the lower the cardiovascular risk [3] [4] [5] [6] [7]. "
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    ABSTRACT: Background. In clinical practice, most coronary artery disease patients are not achieving their recommend LDL-cholesterol goal of <70 mg/dL. Methods. We conducted a retrospective analysis of outpatient electronic health records and the most recent lipid profile, lipid-lowering medications and doses were collected. Results. We identified 9950 coronary artery disease patients. Only 37% on a statin alone achieved an LDL-cholesterol of <70 mg/dL, and most were on moderate-to-high-potency statins. The intensity of statin therapy did not improve LDL-cholesterol goal attainment. Among patients on combination therapy, 41% on statin plus ezetimibe and 46% on statin plus niacin achieved an LDL-cholesterol of <70 mg/dL (P = 0.01 and <0.0001 versus statin alone). If patients were switched to a high-potency statin LDL-cholesterol goal attainment of <70 mg/dL would increase to 46% and would increase up to 72% with combination therapy. Conclusions. Most coronary artery disease patients in clinical practice do not attain an LDL-cholesterol of <70 mg/dL, even among patients on high potency statins. The combination of statin plus either ezetimibe or niacin is the most effective regimen to achieve an LDL-cholesterol of <70 mg/dL, however, these drug combinations are used infrequently in clinical practice.
    Cholesterol 07/2012; 2012(3):861924. DOI:10.1155/2012/861924
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    • "When atherosclerosis blocks arteries that supply blood to the brain, it can cause an ischemic stroke. Atherosclerotic heart disease is the leading cause of death, accounting for one-third of all deaths and atherosclerotic interference with blood supply to the brain (ischemic stroke) is the third most common cause of death after cancer [6-9]. The biosynthetic pathway for cholesterol involves more than 25 different enzymes and the major rate-limiting step in this pathway is regulated by the 3-hydroxy- 3-methylglutaryl Coenzyme A (HMG-CoA) reductase. "
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    ABSTRACT: Background Coronary heart disease continues to be the leading cause of mortality and a significant cause of morbidity and account for nearly 30% of all deaths each year worldwide. High levels of cholesterol are an important risk factor for coronary heart disease. The blockage of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity by small molecule inhibitors has been shown to inhibit hypercholesterolemia. Herein, we describe the development of effective and robust pharmacophore model and the structure–activity relationship studies of 43N-iso-propyl pyrrole-based derivatives previously reported for HMG-CoA reductase inhibition. Results A 5-point pharmacophore model was developed and the generated pharmacophore model was used to derive a predictive atom-based 3D quantitative structure–activity relationship analysis (3D-QSAR) model for the studied dataset. The obtained 3D-QSAR model has an excellent correlation coefficient value (r 2 = 0.96) along with good statistical significance as shown by high Fisher ratio (F = 143.2). The model also exhibited good predictive power confirmed by the high value of cross validated correlation coefficient (q 2 = 0.672). Further, pharmacophoric model was employed for virtual screening to identify four potential HMG-CoA reductase inhibitors. Conclusions The QSAR model suggests that electron-withdrawing character is crucial for the HMG-CoA reductase inhibitory activity. In addition to the electron-withdrawing character, hydrogen bond--donating groups, hydrophobic and negative ionic groups positively contribute to the HMG-CoA reductase inhibition. These findings provide a set of guidelines for designing compounds with better HMG-CoA reductase inhibitory potential.
    07/2012; 2(1). DOI:10.1186/2191-2858-2-25
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