Cited by 558Lipoproteins and Cardiovascular HealthAcute Myocardial Infarction ResearchCancer, Lipids, and Metabolism

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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

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Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group·2010·The Lancet

DOI 10.1016/s0140-6736(10)60310-8PMC PMC2988223

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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.

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Background
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Liu, Z., Xu, Y., Hao, H., Yin, C., Xu, J., Li, J., Wang, Y., & Xu, D. (2016) · International Journal of Cardiology · doi:10.1016/j.ijcard.2016.07.140 · Cited by 16
Patent landscape for discovery of promising acyltransferase DGAT and MGAT inhibitors
Zambre, V. P., Khamkar, S. M., Gavhane, D. D., Khedkar, S. C., Chavan, M. R., Pandey, M. M., Sanap, S. B., Patil, R. B., & Sawant, S. D. (2020) · Expert Opinion on Therapeutic Patents · doi:10.1080/13543776.2020.1815707 · Cited by 16
The Incidence of Kidney Injury for Patients Treated With a High‐Potency Versus Moderate‐Potency Statin Regimen After an Acute Coronary Syndrome
Sarma, A. A., Cannon, C. P., de Lemos, J. A., Rouleau, J. L., Lewis, E. F., Guo, J., Mega, J. L., Sabatine, M. S., & O’Donoghue, M. L. (2014) · Journal of the American Heart Association · doi:10.1161/jaha.114.000784 · Cited by 16
Statins plus ezetimibe in the era of proprotein convertase subtilisin/ kexin type 9 inhibitors
Luca, L. D., Corsini, A., Uguccioni, M., & Colivicchi, F. (2020) · Kardiologia Polska · doi:10.33963/kp.15529 · Cited by 17
Pharmacological approaches of refractory angina
Giannopoulos, A. A., Giannoglou, G. D., & Chatzizisis, Y. S. (2016) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2016.03.008 · Cited by 16
Evidence for more intensive cholesterol lowering
Soran, H., Kwok, S., Adam, S., Ho, J. H., & Durrington, P. N. (2017) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000433 · Cited by 16
Cardiovascular outcomes trials with statins in diabetes
Naeem, F., McKay, G. A., & Fisher, M. (2018) · British Journal of Diabetes · doi:10.15277/bjd.2018.161 · Cited by 16
Executive Summary of the 2020 Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines: 2020 Dyslipidemia CPG
Santos, L. E. G., Jimeno, C., Gonzales, E. M., Balabagno, M. M., Ona, D. I. D., Cinco, J. E., Baston, A., Caoile, I., Fojas, M., Hernandez, R. F., et al. (2021) · Journal of the ASEAN Federation of Endocrine Societies · doi:10.15605/jafes.036.01.01 · Cited by 15
Prevalence and Effects of High-Intensity Statins for Japanese Patients Presenting With Acute Coronary Syndrome ― A Post Hoc Secondary Analysis of STOPDAPT-2 ACS ―
Watanabe, H., Morimoto, T., Yamamoto, K., Obayashi, Y., Natsuaki, M., Yamaji, K., Ogita, M., Suwa, S., Isawa, T., Domei, T., et al. (2022) · Circulation Journal · doi:10.1253/circj.cj-22-0650 · Cited by 15
Counterpoint: Low-Density Lipoprotein Cholesterol Targets Are Not Needed in Lipid Treatment Guidelines
Robinson, J. G., & Ray, K. K. (2016) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.116.306887 · Cited by 15
The Application of the LDL Principle
Schade, D. S., Cavanaugh, B., Ramo, B. W., & Eaton, R. P. (2016) · World Journal of Cardiovascular Diseases · doi:10.4236/wjcd.2016.65012 · Cited by 15
Statins and new-onset atrial fibrillation in a cohort of patients with hypertension. Analysis of electronic health records, 2006–2015
Alves‐Cabratosa, L., García-Gil, M., Comas‐Cufí, M., Ponjoan, A., Martí‐Lluch, R., Parramon, D., Blanch, J., Elosua-Bayés, M., & Ramos, R. (2017) · PLoS ONE · doi:10.1371/journal.pone.0186972 · Cited by 15
Projected Real‐World Effectiveness of Using Aggressive Low‐Density Lipoprotein Cholesterol Targets Among Elderly Statin Users Following Acute Coronary Syndromes in Canada
Alter, D. A., Tu, J. V., Koh, M., Jackevicius, C. A., Austin, P. C., Rezai, M. R., Bhatia, R. S., Johnston, S., Udell, J. A., & Ko, D. T. (2018) · Journal of the American Heart Association · doi:10.1161/jaha.117.007535 · Cited by 15
Hyperlipidemia: An Evidence-based Review of Current Guidelines
Clebak, K. T., & Dambro, A. B. (2020) · Cureus · doi:10.7759/cureus.7326 · Cited by 15
Effect of Rosuvastatin on Fatigue in Patients With Heart Failure
Moreno, A. C. P., Jhund, P. S., Preiss, D., KJEKSHUS, J. K., & McMurray, J. J. V. (2013) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2012.12.004 · Cited by 14
Statins and Anti-Inflammatory Therapies for Subarachnoid Hemorrhage
Dhar, R., & Diringer, M. N. (2012) · Current Treatment Options in Neurology · doi:10.1007/s11940-012-0163-z · Cited by 14
Common Statin Intolerance Variants in ABCB1 and LILRB5 Show Synergistic Effects on Statin Response: An Observational Study Using Electronic Health Records
Melhem, A. L., Chourasia, M. K., Bigossi, M., Maroteau, C., Taylor, A., Pola, R., Dawed, A. Y., Tornio, A., Palmer, C. N. A., & Siddiqui, M. K. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.713181 · Cited by 14
Effect of Golimumab on Carotid Atherosclerotic Disease Measures and Cardiovascular Events in Inflammatory Arthritides
Wasko, M. C., Hsia, E. C., Kirkham, B. W., Touboul, P., Fleischmann, R., Genovese, M. C., Matteson, E. L., Lu, J., Xu, W., & Rahman, M. U. (2013) · JCR Journal of Clinical Rheumatology · doi:10.1097/rhu.0000000000000053 · Cited by 14
Low-Density Lipoprotein Cholesterol: How Low Can We Go?
Sherbet, D. P., Garg, P., Brilakis, E. S., & Banerjee, S. (2013) · American Journal of Cardiovascular Drugs · doi:10.1007/s40256-013-0013-8 · Cited by 14
“In contrast, 80 mg atorvastatin does not appear to be associated with a markedly increased rate of myopathy or a rise in creatine kinase levels in randomized trials; however, the numbers of such reports are small [17, 18, 20].”
Background
Increasing Doses of Simvastatin Versus Combined Ezetimibe/Simvastatin
Pesaro, A. E. P., Junior, C. V. S., Katz, M., Marti, L. C., Fernandes, J. L., Parra, P. R. G., & Campos, A. H. (2013) · Journal of Cardiovascular Pharmacology and Therapeutics · doi:10.1177/1074248413489771 · Cited by 15
Statin Use and the Risk for Incident Diabetes Mellitus in Patients with Acute Coronary Syndrome after Percutaneous Coronary Intervention: A Population-Based Retrospective Cohort Study in Taiwan
Lin, Z., Wang, C., Shen, L., Hsiao, F., & Wu, F. L. (2016) · Canadian Journal of Diabetes · doi:10.1016/j.jcjd.2015.12.006 · Cited by 14
Acute-onset rhabdomyolysis secondary to sitagliptin and atorvastatin interaction
Khan, M., Kurian, S., & Bishnoi, R. (2016) · International Journal of General Medicine · doi:10.2147/ijgm.s98543 · Cited by 14
Use of Statins in Patients With and Without Liver Disease
Francis, P., & Forman, L. (2020) · Clinical Liver Disease · doi:10.1002/cld.866 · Cited by 14
Is HPS2-THRIVE the death knell for niacin?
Toth, P. P., Murthy, A., Sidhu, M. S., & Boden, W. E. (2015) · Journal of clinical lipidology · doi:10.1016/j.jacl.2015.01.008 · Cited by 13
Statin therapy across the lifespan: evidence in major age groups
Stone, N. J., Turin, A., Spitz, J. A., Valle, C. W., & Kazmi, S. (2015) · Expert Review of Cardiovascular Therapy · doi:10.1586/14779072.2016.1128825 · Cited by 13
Riesgo cardiovascular residual de origen lipídico. Componentes y aspectos fisiopatológicos
Hernández‐Mijares, A., Ascaso, J. F., Blasco, M., Brea, Á., Rodríguez, Á. D., Mantilla, T., Pedro‐Botet, J., Pintó, X., & Millán, J. (2018) · Clínica e Investigación en Arteriosclerosis · doi:10.1016/j.arteri.2018.06.007 · Cited by 14
Comparison of statins for primary prevention of cardiovascular disease and persistent physical disability in older adults
Zhou, Z., Curtis, A. J., Ernst, M. E., Ryan, J. L., Zoungas, S., Wolfe, R. S., McNeil, J. J., Murray, A. M., Reid, C. M., Chowdhury, E., et al. (2021) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-021-03239-1 · Cited by 14
Standard and intensive lipid-lowering therapy with statins for the primary prevention of vascular diseases: a population-based study
Saint-Gerons, D. M., Honrubia, C. D. L. F., Corominas, D. M., Gil, M., Andres-Trelles, F., & Catalá-López, F. (2013) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-013-1586-5 · Cited by 13
Patterns and Predictors of Intensive Statin Therapy Among Patients With Diabetes Mellitus After Acute Myocardial Infarction
Abdallah, M., Kosiborod, M., Tang, F., Karrowni, W., Maddox, T. M., McGuire, D. K., Spertus, J. A., & Arnold, S. V. (2014) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2013.12.040 · Cited by 13
Low-density lipoprotein apheresis is effective in reducing lipoprotein(a) levels and in improving symptoms in a patient with refractory angina secondary to accelerated coronary artery disease
Ibrahim, M., Ussen, B., Pottle, A., & Barbir, M. (2011) · Journal of clinical lipidology · doi:10.1016/j.jacl.2011.11.003 · Cited by 13
The ezetimibe controversy – can this be resolved by comparing the clinical trials with simvastatin and ezetimibe alone and together?
Doggrell, S. A. (2012) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.2012.696098 · Cited by 12
Cardiovascular Aspects of Kidney Disease
Wheeler, D. C., Haynes, R., Landray, M., & Baigent, C. (2012) · Elsevier eBooks · doi:10.1016/b978-1-4160-6193-9.10055-7 · Cited by 12
Statin Intensity and Clinical Outcome in Patients with Stable Coronary Artery Disease and Very Low LDL-Cholesterol
Lee, S. Y., Oh, S.-J., Kim, E. J., Oum, C.-Y., Park, S. H., Oh, J., Kim, J., Kim, B., Park, S., Chang, H., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0166246 · Cited by 13
Validation of a pharmacological model for mitochondrial dysfunction in healthy subjects using simvastatin: A randomized placebo-controlled proof-of-pharmacology study
van Diemen, M. P. J., Berends, C. L., Akram, N., Wezel, J., Teeuwisse, W. M., Mik, B., Kan, H. E., Webb, A., Beenakker, J. M., & Groeneveld, G. J. (2017) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2017.09.031 · Cited by 13
“The dose was chosen to keep adverse effects, most notably statin-associated myopathy, at a minimum based on a large clinical trial comparing simvastatin 20–80 mg (Armitage et al., 2010).”
Background
Is intensive LDL-cholesterol lowering beneficial and safe?
Cheung, B. M. Y., & Lam, K. S. (2010) · The Lancet · doi:10.1016/s0140-6736(10)61545-0 · Cited by 13
Attainment of optional low-density lipoprotein cholesterol goal of less than 70 mg/dl and impact on prognosis of very high risk stable coronary patients: a 3-year follow-up
Rallidis, L. S., Kotakos, C., Sourides, V., Varounis, C., Charalampopoulos, A. F., Zolindaki, M., Dagres, N., Papadopoulos, C., & ANASTASIOU‐NANA, M. I. (2011) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.2011.591379 · Cited by 13
The relationship of low-density lipoprotein cholesterol and all-cause or cardiovascular mortality in patients with type 2 diabetes: a retrospective study
Chang, C.-H., Yeh, S., Ooi, S.-W., Li, C., & Chen, H.-F. (2023) · PeerJ · doi:10.7717/peerj.14609 · Cited by 12
Statin therapy after elective abdominal aortic aneurysm repair improves long-term survival
Lilja, F., Wanhainen, A., & Mani, K. (2024) · British journal of surgery · doi:10.1093/bjs/znad383 · Cited by 12
Simvastatin Exerts Favourable Effects on Neointimal Formation in a Mouse Model of Vein Graft
Zhang, L., Lu, H.-H., Huang, J., Guan, Y., & Sun, H. (2011) · European Journal of Vascular and Endovascular Surgery · doi:10.1016/j.ejvs.2011.05.016 · Cited by 12

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
DOI: 10.1016/s0140-6736(10)60310-8
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
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
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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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

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