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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
Open accessAbstract
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.
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“based on the results of the SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) trial the US Food and Drug Administration has announced new safety recommendations for high-dose simvastatin treatment owing to an associated elevated risk of muscle injury or myopathy75.”
From Perspectives and opportunities for nanomedicine in the management of atherosclerosis (2011) · cites this paper as [75]
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Metadata
- Authors
- Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group
- Corresponding author
- Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2010-11
- Volume
- 376
- Issue
- 9753
- Pages
- 1658-1669
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- PMC
- PMC2988223
- OpenAlex
- W1523152575
- Cited by
- 558
- References
- 38
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 20 · 2023: 23 · 2022: 28 · 2021: 22 · 2020: 29 · 2019: 31 · 2018: 33 · 2017: 35 · 2016: 40 · 2015: 47 · 2014: 52 · 2013: 50 · 2012: 68
- FWCI
- 61.00
- Type
- journal article
- Language
- en
- Update notices
- erratum (2011-01-08)
- Open access
- bronze
- doi.org
- Locations
- The Lancet (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Funders
- British Heart Foundation (PG/12/32/29544)
- University of Southampton
- University of Oxford
- Medical Research Council (MC_EX_G0801669)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Acute Myocardial Infarction Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- simvastatin, LDL cholesterol lowering, high-intensity statin therapy, myocardial infarction survivors, major vascular events, coronary artery disease, stroke, cardiovascular mortality, statin safety, lipid-lowering therapy, high cardiovascular risk patients, dose comparison, hemorrhagic stroke, coronary death, myocardial infarction recurrence, secondary prevention
- MeSH terms
- Adult, Aged, Aged, 80 and over, Anticholesteremic Agents, Double-Blind Method, Female, Humans, Hypercholesterolemia, Cholesterol, HDL, Cholesterol, LDL, Male, Middle Aged, Myocardial Infarction, Triglycerides, Simvastatin, Young Adult
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