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 SEARCH trial, the FDA announced new safety recommendations for high-dose simvastatin due to elevated risk of muscle injury or myopathy.
“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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OLSSON, A. G., McMurray, J. J. V., Thorgeirsson, G., Spaulding, C. M., Slattery, J., Pyörälà, K., Færgeman, O., Wright, R. S., Berg, K. M., Wilhelmsen, L., et al. (1994) · The Lancet · Cited by 8,467 · see citing works
Peto, R., Pike, M. C., Armitage, P., Breslow, N. E., Cox, D. R., Howard, S. V., Mantel, N., McPherson, K., Peto, J., & Smith, P. G. (1977) · British Journal of Cancer · doi:10.1038/bjc.1977.1 · Cited by 8,285 · see citing works
Sacks, F. M., Pfeffer, M. A., Moye, L. A., Rouleau, J. L., Rutherford, J. D., Cole, T. G., Brown, L., Warnica, J. W., Arnold, J. M. O., Wun, C.-C., et al. (1996) · New England Journal of Medicine · doi:10.1056/nejm199610033351401 · Cited by 7,439 · see citing works
Grundy, S. M., Cleeman, J. I., Merz, C. N. B., Brewer, H. B., Clark, L. T., Hunninghake, D. B., Pasternak, R. C., Smith, S. C., & Stone, N. J. (2004) · Circulation · doi:10.1161/01.cir.0000133317.49796.0e · Cited by 6,902 · see citing works
Cholesterol Treatment Trialists' (CTT) Collaboration (2010) · The Lancet · doi:10.1016/s0140-6736(10)61350-5 · Cited by 6,550 · see citing works
Intensive versus Moderate Lipid Lowering with Statins after Acute Coronary Syndromes
Cannon, C. P., Braunwald, E., McCabe, C. H., Rader, D. J., Rouleau, J. L., Belder, R., Joyal, S. V., Hill, K. A., Pfeffer, M. A., & Skene, A. M. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa040583 · Cited by 4,938 · see citing works
Stamler, J., Vaccaro, O., Neaton, J. D., Wentworth, D., & The Multiple Risk Factor Intervention Trial Research Group (1993) · Diabetes Care · doi:10.2337/diacare.16.2.434 · Cited by 4,063 · see citing works
SCANDINAVIANSIMVASTATINSURVIVAL (1994) · The Lancet · doi:10.1016/s0140-6736(94)90566-5 · Cited by 3,638 · see citing works
Intensive Lipid Lowering with Atorvastatin in Patients with Stable Coronary Disease
LaRosa, J. C., Grundy, S. M., Waters, D. D., Shear, C., Barter, P., Fruchart, J.-C., Gotto, A. M., Greten, H., Kastelein, J. J. P., Shepherd, J., et al. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa050461 · Cited by 3,489 · see citing works
Pedersen, T. R. (2004) · Atherosclerosis Supplements · doi:10.1016/j.atherosclerosissup.2004.08.027 · Cited by 3,098 · see citing works
Pocock, S. J., & Simon, R. (1975) · Biometrics · doi:10.2307/2529712 · Cited by 2,350 · see citing works
De Backer, G. (2003) · European Heart Journal · doi:10.1016/s0195-668x(03)00347-6 · Cited by 2,251 · see citing works
<i>SLCO1B1</i> Variants and Statin-Induced Myopathy — A Genomewide Study
(2008) · New England Journal of Medicine · doi:10.1056/nejmoa0801936 · Cited by 2,043 · see citing works
Grundy, S. M., Cleeman, J. I., Bairey Merz, C. N., Brewer, H. B., Clark, L. T., Hunninghake, D. B., Pasternak, R. C., Smith, S. C., & Stone, N. J. (2004) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2004.07.001 · Cited by 1,550 · see citing works
de Lemos, J. A., Blazing, M. A., Wiviott, S. D., Lewis, E. F., Fox, K. A. A., White, H. D., Rouleau, J.-L., Pedersen, T. R., Gardner, L. H., Mukherjee, R., et al. (2004) · JAMA · doi:10.1001/jama.292.11.1307 · Cited by 1,333 · see citing works
Prepared, B. (2005) · Heart · doi:10.1136/hrt.2005.079988 · Cited by 1,217 · see citing works
Second Joint Task Force of European (1998) · European Heart Journal · doi:10.1053/euhj.1998.1243 · Cited by 1,131 · see citing works
The safety of statins in clinical practice
Armitage, J. (2007) · The Lancet · doi:10.1016/s0140-6736(07)60716-8 · Cited by 833 · see citing works
Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy
Cannon, C. P., Steinberg, B. A., Murphy, S. A., Mega, J. L., & Braunwald, E. (2006) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2006.04.070 · Cited by 770 · see citing works
Ryan, T. J., Antman, E. M., Brooks, N. H., Califf, R. M., Hillis, L. D., Hiratzka, L. F., Rapaport, E., Riegel, B. J., Russell, R. O., Smith, E. E., et al. (1999) · Circulation · doi:10.1161/01.cir.100.9.1016 · Cited by 742 · see citing works
Chen, Z., Peto, R., Collins, R., MacMahon, S. W., Lu, J., & Li, W. (1991) · BMJ · doi:10.1136/bmj.303.6797.276 · Cited by 537 · see citing works
Bainbridge, K. E., Hoffman, H. J., & Cowie, C. C. (2008) · Annals of Internal Medicine · doi:10.7326/0003-4819-149-1-200807010-00231 · Cited by 388 · see citing works
Reliable assessment of the effects of treatment on mortality and major morbidity, I: clinical trials
Collins, R., & MacMahon, S. W. (2001) · The Lancet · doi:10.1016/s0140-6736(00)03651-5 · Cited by 337 · see citing works
(2010) · JAMA · doi:10.1001/jama.2010.840 · Cited by 327 · see citing works
Self-citationThe Effect of Diabetes on Sensorineural Hearing Loss
Kakarlapudi, V., Sawyer, R. G., & Staecker, H. (2003) · Otology & Neurotology · doi:10.1097/00129492-200305000-00006 · Cited by 280 · see citing works
Analyses of Cancer Data from Three Ezetimibe Trials
Peto, R., Emberson, J., Landray, M., Baigent, C., Collins, R., Clare, R. M., & Califf, R. M. (2008) · New England Journal of Medicine · doi:10.1056/nejmsa0806603 · Cited by 230 · see citing works
Recommended Procedures for Pure-tone Audiometry Using a Manually Operated Instrument
(1981) · British Journal of Audiology · doi:10.3109/03005368109081440 · Cited by 174 · see citing works
The Efficacy and Six-Week Tolerability of Simvastatin 80 and 160 mg/Day
Davidson, M., Stein, E. A., Dujovne, C. A., Hunninghake, D. B., Weiss, S. R., Knopp, R. H., Illingworth, D. R., Mitchel, Y., Melino, M. R., Zupkis, R. V., et al. (1997) · The American Journal of Cardiology · doi:10.1016/s0002-9149(96)00742-4 · Cited by 167 · see citing works
Bias in the one‐step method for pooling study results
Greenland, S., & Salván, A. (1990) · Statistics in Medicine · doi:10.1002/sim.4780090307 · Cited by 165 · see citing works
SEARCH Study Collaborative Group (2007) · American Heart Journal · doi:10.1016/j.ahj.2007.06.034 · Cited by 105 · see citing works
Self-citationPedersen, T. R., & Tobert, J. A. (1996) · Drug Safety · doi:10.2165/00002018-199614010-00003 · Cited by 103 · see citing works
Estimating the effect of the run‐in on the power of the physicians' health study
Lang, J. M., Buring, J. E., ROSNER, B. A., Cook, N. R., & Hennekens, C. H. (1991) · Statistics in Medicine · doi:10.1002/sim.4780101010 · Cited by 99 · see citing works
Hyperlipidemia in noise‐induced hearing loss
Chang, N., Yu, M., Ho, K., & Ho, C. (2007) · Otolaryngology · doi:10.1016/j.otohns.2007.04.022 · Cited by 45 · see citing works
Flagged first, then by citations
1 of the 38 references couldn’t be matched to a known paper.
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Stone, N. J., Robinson, J. G., Lichtenstein, A. H., Bairey Merz, C. N., Blum, C. B., Eckel, R. H., Goldberg, A. C., Gordon, D., Levy, D., Lloyd-Jones, D. M., et al. (2014) · Circulation · doi:10.1161/01.cir.0000437738.63853.7a · Cited by 7,081 · see citing works
Cholesterol Treatment Trialists' (CTT) Collaboration (2010) · The Lancet · doi:10.1016/s0140-6736(10)61350-5 · Cited by 6,550 · see citing works
Stone, N. J., Robinson, J. G., Lichtenstein, A. H., Bairey Merz, C. N., Blum, C. B., Eckel, R. H., Goldberg, A. C., Gordon, D., Levy, D., Lloyd-Jones, D. M., et al. (2014) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2013.11.002 · Cited by 3,845 · see citing works
Collaborators, C. T. T. (. (2012) · The Lancet · doi:10.1016/s0140-6736(12)60367-5 · Cited by 2,833 · see citing works
Baigent, C., Landray, M. J., Reith, C., Emberson, J., Wheeler, D. C., Tomson, C., Wanner, C., Krane, V., Cass, A., Craig, J., et al. (2011) · The Lancet · doi:10.1016/s0140-6736(11)60739-3 · Cited by 2,479 · see citing works
Interpretation of the evidence for the efficacy and safety of statin therapy
Collins, R., Reith, C., Emberson, J., Armitage, J., Baigent, C., Blackwell, L., Blumenthal, R., Danesh, J., Smith, G. D., DeMets, D., et al. (2016) · The Lancet · doi:10.1016/s0140-6736(16)31357-5 · Cited by 1,857 · see citing works
“in combination with certain antihypertensive drugs and in women, people aged over 80, and those with diabetes).(78)”
BackgroundEffects of extended-release niacin with laropiprant in high-risk patients
The HPS2-THRIVE Collaborative Group (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1300955 · Cited by 1,668 · see citing works
Silverman, M. G., Ference, B. A., Im, K., Wiviott, S. D., Giugliano, R. P., Grundy, S. M., Braunwald, E., & Sabatine, M. S. (2016) · JAMA · doi:10.1001/jama.2016.13985 · Cited by 1,483 · see citing works
Clinical Practice Guidelines for Multiple Endocrine Neoplasia Type 1 (MEN1)
Thakker, R. V., Newey, P. J., Walls, G. V., Bilezikian, J. P., Dralle, H., Ebeling, P. R., Melmed, S. K., Sakurai, A., Tonelli, F., & Brandi, M. L. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-1230 · Cited by 1,473 · see citing works
Preiss, D. (2011) · JAMA · doi:10.1001/jama.2011.860 · Cited by 1,390 · see citing works
KDOQI clinical practice guideline for diabetes and CKD: 2012 update
(2012) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2012.07.005 · Cited by 1,320 · see citing works
Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer
Francis, G. L., Waguespack, S. G., Bauer, A. J., Angelos, P., Benvenga, S., Cerutti, J. M., Dinauer, C., Hamilton, J. K., HAY, I. D., Luster, M., et al. (2015) · Thyroid · doi:10.1089/thy.2014.0460 · Cited by 1,252 · see citing works
Anderson, T. J., Grégoire, J. C., Hegele, R. A., Couture, P., Mancini, G. B. J., McPherson, R., Francis, G. A., Poirier, P., Lau, D. C. W., Grover, S. A., et al. (2013) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2012.11.032 · Cited by 762 · see citing works
Ward, N. C., Watts, G. F., & Eckel, R. H. (2019) · Circulation Research · doi:10.1161/circresaha.118.312782 · Cited by 772 · see citing works
Statin-Associated Side Effects
Thompson, P. D., Panza, G. A., Zaleski, A. L., & Taylor, B. A. (2016) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2016.02.071 · Cited by 756 · see citing works
Newman, C. B., Preiss, D., Tobert, J. A., Jacobson, T. A., Page, R. L., II, Goldstein, L. B., Chin, C. C., Tannock, L. R., Miller, M. J., Raghuveer, G., et al. (2019) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atv.0000000000000073 · Cited by 761 · see citing works
Navarese, E. P., Robinson, J. G., Kowalewski, M., Kolodziejczak, M., Andreotti, F., Bliden, K., Tantry, U., Kubica, J., Raggi, P., & Gurbel, P. A. (2018) · JAMA · doi:10.1001/jama.2018.2525 · Cited by 549 · see citing works
An assessment by the statin muscle safety task force: 2014 update
Rosenson, R. S., Baker, S. K., Jacobson, T. A., Kopecky, S. L., & Parker, B. A. (2014) · Journal of Clinical Lipidology · doi:10.1016/j.jacl.2014.03.004 · Cited by 485 · see citing works
Prevalence of statin intolerance: a meta-analysis
Bytyçi, I., Penson, P. E., Mikhailidis, D. P., Wong, N. D., Hernandez, A. V., Sahebkar, A., Thompson, P. D., Mazidi, M., Rysz, J., Pella, D., et al. (2022) · European Heart Journal · doi:10.1093/eurheartj/ehac015 · Cited by 481 · see citing works
Safety and efficacy of statin therapy
Adhyaru, B. B., & Jacobson, T. A. (2018) · Nature Reviews Cardiology · doi:10.1038/s41569-018-0098-5 · Cited by 424 · see citing works
Perspectives and opportunities for nanomedicine in the management of atherosclerosis
Lobatto, M. E., Fuster, V., Fayad, Z. A., & Mulder, W. J. M. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3578 · Cited by 423 · see citing works
Banach, M., Rizzo, M., Toth, P. P., Farnier, M., Davidson, M. H., Al‐Rasadi, K., Aronow, W. S., Athyros, V. G., Djuric, D. M., Владиславович, Е. М., et al. (2015) · Archives of Medical Science · doi:10.5114/aoms.2015.49807 · Cited by 381 · see citing works
Cholesterol Treatment Trialists' (CTT) Collaboration (2012) · PLoS ONE · doi:10.1371/journal.pone.0029849 · Cited by 351 · see citing works
High-density lipoproteins: A consensus statement from the National Lipid Association
Toth, P. P., Barter, P. J., Rosenson, R. S., Boden, W. E., Chapman, M. J., Cuchel, M., D'Agostino, R. B., Davidson, M. H., Davidson, W. S., Heinecke, J. W., et al. (2013) · Journal of Clinical Lipidology · doi:10.1016/j.jacl.2013.08.001 · Cited by 336 · see citing works
(2016) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(16)30156-5 · Cited by 338 · see citing works
Abraldes, J. G., Villanueva, C., Aracil, C., Turnes, J., Hernandez-Guerra, M., Genesca, J., Rodriguez, M., Castellote, J., García-Pagán, J. C., Torres, F., et al. (2016) · Gastroenterology · doi:10.1053/j.gastro.2016.01.004 · Cited by 339 · see citing works
“In addition, rhabdomyolysis has been particularly associated with higher doses of simvastatin (80 mg, which are no longer recommended) that the one used in this study (40 mg).(49,50) This suggests that patients with severely deteriorated liver function might develop rhabdomyolysis at lower doses than the general popul…”
BackgroundWiggins, B. S., Saseen, J. J., Page, R. L., II, Reed, B. N., Sneed, K., Kostis, J. B., Lanfear, D. E., Virani, S. S., & Morris, P. B. (2016) · Circulation · doi:10.1161/cir.0000000000000456 · Cited by 339 · see citing works
Relationship between Hyperlipidemia, Cardiovascular Disease and Stroke: A Systematic Review
Alloubani, A., Nimer, R. M., & Samara, R. (2020) · Current Cardiology Reviews · doi:10.2174/1573403x16999201210200342 · Cited by 352 · see citing works
Wadhera, R. K., Steen, D. L., Khan, I., Giugliano, R. P., & Foody, J. M. (2016) · Journal of Clinical Lipidology · doi:10.1016/j.jacl.2015.11.010 · Cited by 306 · see citing works
McKinney, J. S., & Kostis, W. J. (2012) · Stroke · doi:10.1161/strokeaha.112.655894 · Cited by 294 · see citing works
Dyslipidemia in Type 2 Diabetes: Prevalence, Pathophysiology, and Management
Chehade, J. M., Gladysz, M., & Mooradian, A. D. (2013) · Drugs · doi:10.1007/s40265-013-0023-5 · Cited by 299 · see citing works
Homocysteine-lowering interventions for preventing cardiovascular events
Martí-Carvajal, A. J., Solà, I., Lathyris, D., & Dayer, M. (2017) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd006612.pub5 · Cited by 284 · see citing works
Reith, C. A., Baigent, C., Blackwell, L. S., Emberson, J., Spata, E., Davies, K., Halls, H. J., Holland, L., Wilson, K., Armitage, J., et al. (2022) · The Lancet · doi:10.1016/s0140-6736(22)01545-8 · Cited by 288 · see citing works
A systematic review of statin-induced muscle problems in clinical trials
Ganga, H. V., Slim, H. B., & Thompson, P. D. (2014) · American Heart Journal · doi:10.1016/j.ahj.2014.03.019 · Cited by 253 · see citing works
Koskinas, K. C., Siontis, G. C. M., Piccolo, R., Mavridis, D., Räber, L., Mach, F., & Windecker, S. (2017) · European Heart Journal · doi:10.1093/eurheartj/ehx566 · Cited by 252 · see citing works
Meta-Analysis of Statin Effects in Women Versus Men
Kostis, W. J., Cheng, J., Dobrzynski, J. M., Cabrera, J., & Kostis, J. B. (2012) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2011.09.067 · Cited by 246 · see citing works
Ramos, R., Comas-Cufí, M., Martí-Lluch, R., Balló, E., Ponjoan, A., Alves-Cabratosa, L., Blanch, J., Marrugat, J., Elosua, R., Grau, M., et al. (2018) · BMJ · doi:10.1136/bmj.k3359 · Cited by 215 · see citing works
Karatasakis, A., Danek, B. A., Karacsonyi, J., Rangan, B. V., Roesle, M. K., Knickelbine, T., Miedema, M. D., Khalili, H., Ahmad, Z., Abdullah, S., et al. (2017) · Journal of the American Heart Association · doi:10.1161/jaha.117.006910 · Cited by 215 · see citing works
Gersh, B. (2011) · Yearbook of Medicine · doi:10.1016/s0084-3873(11)00278-1 · Cited by 2,768 · see citing works
Finegold, J. A., Manisty, C. H., Goldacre, B., Barron, A. J., & Francis, D. P. (2014) · European Journal of Preventive Cardiology · doi:10.1177/2047487314525531 · Cited by 214 · see citing works
Schneeweiß, S., Gagne, J. J., Glynn, R. J., Rühl, M., & Rassen, J. A. (2011) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2011.235 · Cited by 193 · see citing works
Visser, M. E., Wagener, G., Baker, B. F., Geary, R. S., Donovan, J. M., Beuers, U. H., Nederveen, A. J., Verheij, J., Trip, M. D., Basart, D. C. G., et al. (2012) · European Heart Journal · doi:10.1093/eurheartj/ehs023 · Cited by 191 · see citing works
“The incidence of statin ‘intolerance’ is rising, most likely reflecting the use of higher statin doses required to achieve more stringent LDL cholesterol (LDL-c) targets.(1,4) Available alternatives to lower LDL-c levels in statin-intolerant patients include switching to other statins, non-daily or low-dosing regimens…”
Wang, N., Fulcher, J., Abeysuriya, N., Park, L., Kumar, S., Di Tanna, G. L., Wilcox, I., Keech, A., Rodgers, A., & Lal, S. (2020) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(19)30388-2 · Cited by 187 · see citing works
Lipid-Modifying Therapies and Risk of Pancreatitis: A Meta-analysis
Preiss, D., Tikkanen, M. J., Welsh, P., Ford, I., Lovato, L. C., Elam, M. B., LaRosa, J. C., DeMicco, D. A., Colhoun, H. M., Goldenberg, I., et al. (2012) · JAMA · doi:10.1001/jama.2012.8439 · Cited by 181 · see citing works
Gaba, P., O’Donoghue, M. L., Park, J., Wiviott, S. D., Atar, D., Kuder, J., Im, K., Murphy, S. A., Ferrari, G. M. D., Gaciong, Z. A., et al. (2023) · Circulation · doi:10.1161/circulationaha.122.063399 · Cited by 186 · see citing works
The Current State of Niacin in Cardiovascular Disease Prevention
Lavigne, P. M., & Karas, R. H. (2013) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2012.10.030 · Cited by 185 · see citing works
Qaseem, A., HOPKINS, R. H., Sweet, D. E., Starkey, M., & Shekelle, P. (2013) · Annals of Internal Medicine · doi:10.7326/0003-4819-159-12-201312170-00726 · Cited by 179 · see citing works
Dormuth, C. R., Filion, K. B., Paterson, J. M., James, M. T., Teare, G. F., Raymond, C. B., Rahme, E., Tamim, H., Lipscombe, L. L., & for the Canadian Network for Observational Drug Effect Studies (CNODES) Investigators (2014) · BMJ · doi:10.1136/bmj.g3244 · Cited by 178 · see citing works
Statins: Old drugs as new therapy for liver diseases?
Pose, E., Trebicka, J., Mookerjee, R. P., Angeli, P., & Ginès, P. (2018) · Journal of Hepatology · doi:10.1016/j.jhep.2018.07.019 · Cited by 176 · see citing works
Newman, C. B., Blaha, M. J., Boord, J. B., Cariou, B., Chait, A., Fein, H. G., Ginsberg, H. N., Goldberg, I. J., Murad, M. H., Subramanian, S., et al. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa674 · Cited by 180 · see citing works
Statin-Associated Myopathy: Emphasis on Mechanisms and Targeted Therapy
Vinci, P., Panizon, E., Tosoni, L. M., Cerrato, C., Pellicori, F., Mearelli, F., Biasinutto, C., Fiotti, N., Girolamo, F. G. D., & Biolo, G. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222111687 · Cited by 180 · see citing works
“The Study of Effectiveness of Additional Reduction in Cholesterol and Homocysteine (SEARCH) reported a lower risk of statin-related myopathy with 20 mg of simvastatin compared to 80 mg of simvastatin [47].”
BackgroundNon-cardiovascular effects associated with statins
Desai, C. S., Martin, S. S., & Blumenthal, R. S. (2014) · BMJ · doi:10.1136/bmj.g3743 · Cited by 172 · see citing works
Long-Term Use of Cardiovascular Drugs
Rosselló, X., Pocock, S., & Julian, D. G. (2015) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2015.07.018 · Cited by 167 · see citing works
Tenenbaum, A., & Fisman, E. Z. (2012) · Cardiovascular Diabetology · doi:10.1186/1475-2840-11-125 · Cited by 166 · see citing works
Banach, M., Rizzo, M., Toth, P. P., Farnier, M., Davidson, M. H., Al-Rasadi, K., Aronow, W. S., Athyros, V., Djuric, D. M., Ezhov, M. V., et al. (2015) · Expert Opinion on Drug Safety · doi:10.1517/14740338.2015.1039980 · Cited by 162 · see citing works
Reith, C., Preiss, D., Blackwell, L., Emberson, J., Spata, E., Davies, K., Halls, H., Harper, C., Holland, L., Wilson, K., et al. (2024) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(24)00040-8 · Cited by 161 · see citing works
Preiss, D., Campbell, R. T., Murray, H. M., Ford, I., Packard, C. J., Sattar, N., Rahimi, K., Colhoun, H. M., Waters, D. D., LaRosa, J. C., et al. (2015) · European Heart Journal · doi:10.1093/eurheartj/ehv072 · Cited by 160 · see citing works
Fonarow, G. C., KEECH, A. C., Pedersen, T. R., Giugliano, R. P., Sever, P. S., Lindgren, P., van Hout, B., Villa, G., Qian, Y., Somaratne, R. M., et al. (2017) · JAMA Cardiology · doi:10.1001/jamacardio.2017.2762 · Cited by 153 · see citing works
Galicia-Garcia, U., Jebari, S., Larrea-Sebal, A., Uribe, K., Siddiqi, H., Ostolaza, H., Benito-Vicente, A., & Martín, C. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21134725 · Cited by 141 · see citing works
“9% in participants receiving 20 mg simvastatin [50].”
BackgroundMills, E. J., O’Regan, C., Eyawo, O., Wu, P., Mills, F. P., Berwanger, O. B., & Briel, M. (2011) · European Heart Journal · doi:10.1093/eurheartj/ehr035 · Cited by 147 · see citing works
“The concatenation of meta-analysis, and formal monitoring boundaries (or stopping rules), such as the Lan–DeMets alpha-spending monitoring boundary is analogous to group sequential analysis in single RCTs.39,40 For the outcome of CV death, we conducted a random effects cumulative meta-analysis assessing the effect of…”
BackgroundMethodInfluentialLDL-C does not cause cardiovascular disease: a comprehensive review of the current literature
Ravnskov, U., de Lorgeril, M., Diamond, D. M., Hama, R., Hamazaki, T., Hammarskjöld, B., Hynes, N., Kendrick, M. E., Langsjoen, P. H., Mascitelli, L., et al. (2018) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2018.1519391 · Cited by 148 · see citing works
Statin use and the risk of developing diabetes: a network meta‐analysis
Thakker, D., Nair, S., Pagada, A., Jamdade, V., & Malik, A. (2016) · Pharmacoepidemiology and Drug Safety · doi:10.1002/pds.4020 · Cited by 146 · see citing works
Cirrhosis as new indication for statins
Bosch, J., Gracia‐Sancho, J., & Abraldeṣ, J. G. (2020) · Gut · doi:10.1136/gutjnl-2019-318237 · Cited by 141 · see citing works
Natural approaches in metabolic syndrome management
Patti, A. M., Al‐Rasadi, K., Giglio, R. V., Nikolić, D., Mannina, C. M., Castellino, G., Chianetta, R., Banach, M., Cicero, A. F. G., Lippi, G., et al. (2017) · Archives of Medical Science · doi:10.5114/aoms.2017.68717 · Cited by 139 · see citing works
Robinson (2012) · doi:10.1016/j.amjcard.2012.07.007 · Cited by 137 · see citing works
Detection and treatment of atherosclerosis using nanoparticles
Zhang, J., Zu, Y., Dhanasekara, C. S., Li, J., Wu, D., Fan, Z., & Wang, S. F. (2016) · Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology · doi:10.1002/wnan.1412 · Cited by 131 · see citing works
van der Vaart, T., Plasschaert, E., Rietman, A. B., Renard, M., Oostenbrink, R., Vogels, A., de Wit, M. Y., Descheemaeker, M., Vergouwe, Y., Catsman‐Berrevoets, C. E., et al. (2013) · The Lancet Neurology · doi:10.1016/s1474-4422(13)70227-8 · Cited by 128 · see citing works
The nocebo effect in the context of statin intolerance
Tobert, J. A., & Newman, C. B. (2016) · Journal of clinical lipidology · doi:10.1016/j.jacl.2016.05.002 · Cited by 125 · see citing works
Hirsh, B. J., Smilowitz, N. R., Rosenson, R. S., Fuster, V., & Sperling, L. S. (2015) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2015.05.030 · Cited by 126 · see citing works
Myopathy in older people receiving statin therapy: a systematic review and meta‐analysis
Iwere, R. B., & Hewitt, J. (2015) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.12687 · Cited by 116 · see citing works
Bach, R. G., Cannon, C. P., Giugliano, R. P., White, J. A., Lokhnygina, Y. V., Bohula, E. A., Califf, R. M., D, E. B. M., & Blazing, M. A. (2019) · JAMA Cardiology · doi:10.1001/jamacardio.2019.2306 · Cited by 123 · see citing works
Gersh, B. J. (2011) · Yearbook of Cardiology · doi:10.1016/j.ycar.2010.12.014 · Cited by 117 · see citing works
Ramos, R., García-Gil, M., Comas‐Cufí, M., Quesada, M., Marrugat, J., Elosúa, R., Sala, J., Grau, M., Martí‐Lluch, R., Ponjoan, A., et al. (2016) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2015.11.052 · Cited by 116 · see citing works
Weighing the benefits of high-dose simvastatin against the risk of myopathy
Egan, A., & Colman, E. (2011) · New England Journal of Medicine · doi:10.1056/nejmp1106689 · Cited by 113 · see citing works
Robinson, J. G. (2013) · Journal of Managed Care Pharmacy · doi:10.18553/jmcp.2013.19.2.139 · Cited by 112 · see citing works
Mechanisms and assessment of statin‐related muscular adverse effects
Moßhammer, D., Schaeffeler, E., Schwab, M. G., & Mörike, K. (2014) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.12360 · Cited by 110 · see citing works
Statins and the risk of new-onset diabetes
Preiss, D., & Sattar, N. A. (2011) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e32834b4994 · Cited by 111 · see citing works
Hu, M., Cheung, B. M. Y., & Tomlinson, B. (2012) · Therapeutic Advances in Drug Safety · doi:10.1177/2042098612439884 · Cited by 103 · see citing works
“It was often the result of interactions with certain drugs and was frequently associated with a genetic predisposition toward simvastatin-related myopathy as discussed below [Armitage et al. 2010; Link et al. 2008].”
BackgroundResultInfluentialManaging the underestimated risk of statin-associated myopathy
Rallidis, L. S., Fountoulaki, K., & ANASTASIOU‐NANA, M. I. (2011) · International Journal of Cardiology · doi:10.1016/j.ijcard.2011.07.048 · Cited by 96 · see citing works
Rahimi, K., Bhala, N. B., Kamphuisen, P. W., Emberson, J., Biere‐Rafi, S., Krane, V., Robertson, M., Wikstrand, J., & McMurray, J. J. V. (2012) · PLoS Medicine · doi:10.1371/journal.pmed.1001310 · Cited by 96 · see citing works
Goldstein, L. B., Toth, P. P., Dearborn, J. L., Giugliano, R. P., Hirsh, B. J., Peña, J. M., Selim, M. H., & Woo, D. (2023) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atv.0000000000000164 · Cited by 95 · see citing works
Statins, inflammation and kidney disease
Krane, V., & Wanner, C. (2011) · Nature Reviews Nephrology · doi:10.1038/nrneph.2011.62 · Cited by 88 · see citing works
Statin drug interactions and related adverse reactions
Bellosta, S., & Corsini, A. (2012) · Expert Opinion on Drug Safety · doi:10.1517/14740338.2012.712959 · Cited by 111 · see citing works
“2% patients in the 80 mg group experienced rhabdomyolysis versus none of the patients taking simvastatin 20 mg [17].”
BackgroundTrends in Use of High-Intensity Statin Therapy After Myocardial Infarction, 2011 to 2014
Rosenson, R. S., Farkouh, M. E., Mefford, M. T., Bittner, V., Brown, T. M., Taylor, B., Monda, K. L., Zhao, H., Dai, Y., & Muntner, P. (2017) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2017.03.585 · Cited by 84 · see citing works
“Food and Drug Administration issued a black-box warning cautioning against new prescriptions for simvastatin 80 mg because of potential muscle toxicity, as reported in 2 clinical trials (15,16).”
BackgroundMuscle- and skeletal-related side-effects of statins: tip of the iceberg?
Auer, J., Sinzinger, H. F., Franklin, B., & Berent, R. (2014) · European Journal of Preventive Cardiology · doi:10.1177/2047487314550804 · Cited by 85 · see citing works
“Rhabdomyolysis occurred solely in the two trials of 80mg versus 20mg simvastatin daily, which also revealed an increased incidence of myopathy with the higher dosage.(29) In contrast, in two cohort studies it was reported that the incidence of rhabdomyolysis among patients taking statins was 3.”
BackgroundDyslipidemia and its therapeutic challenges in renal transplantation
Riella, L. V., Gabardi, S., & Chandraker, A. (2012) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2012.04084.x · Cited by 82 · see citing works
Muntean, D. M., Thompson, P. D., Catapano, A. L., Stasiolek, M., Fabis, J., Muntner, P., Serban, M.-C., & Banach, M. (2017) · Drug Discovery Today · doi:10.1016/j.drudis.2016.09.001 · Cited by 82 · see citing works
Yu, J., Shah, B. M., Ip, E. J., & Chan, J. (2013) · Journal of Managed Care Pharmacy · doi:10.18553/jmcp.2013.19.2.102 · Cited by 81 · see citing works
Risk identification and possible countermeasures for muscle adverse effects during statin therapy
Magni, P., Macchi, C., Morlotti, B., Sirtori, C. R., & Ruscica, M. (2015) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2015.01.002 · Cited by 81 · see citing works
“Rhabdomyolysis was diagnosed in seven patients allocated only at simvastatin 80 mg [54], which prompted in 2011 the FDA to release a warning issue regarding 80 mg simvastatin and a subsequent change in the approved dosing regimen for this drug.”
BackgroundManagement of Cardiovascular Risk: The Importance of Meeting Lipid Targets
Gotto, A. M., & Moon, J. E. (2012) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2012.04.002 · Cited by 78 · see citing works
Statins for Primary Prevention of Cardiovascular Disease
Kazi, D. S., Penko, J. M., & Bibbins-Domingo, K. B. (2017) · Medical Clinics of North America · doi:10.1016/j.mcna.2017.03.001 · Cited by 76 · see citing works
High-Dose Simvastatin for Aneurysmal Subarachnoid Hemorrhage
Wong, G. K. C., Chan, D., Siu, D. Y. W., Zee, B. C.-Y., Poon, W. S., Chan, M. T. V., Gin, T., Leung, M., Zhu, X., Liang, M., et al. (2014) · Stroke · doi:10.1161/strokeaha.114.007006 · Cited by 73 · see citing works
Khan, S. U., Rahman, H., Okunrintemi, V., Riaz, H., Khan, M. S., Sattur, S., Kaluski, E., Lincoff, A. M., Martin, S. S., & Blaha, M. J. (2019) · Journal of the American Heart Association · doi:10.1161/jaha.118.011581 · Cited by 70 · see citing works
Khan, S. U., Khan, M. U., Valavoor, S., Khan, M. S., Okunrintemi, V., Mamas, M. A., Leucker, T. M., Blaha, M. J., & Michos, E. D. (2020) · European Journal of Preventive Cardiology · doi:10.1177/2047487319871733 · Cited by 67 · see citing works
Pitt, B., Loscalzo, J., Monyak, J. T., Miller, E., & Raichlen, J. S. (2012) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2011.12.015 · Cited by 70 · see citing works
Brunham, L. R., Baker, S. K., Mammen, A. L., Mancini, G. B. J., & Rosenson, R. S. (2018) · Cardiovascular Research · doi:10.1093/cvr/cvy119 · Cited by 71 · see citing works
Gudzune, K. A., Monroe, A. K., Sharma, R., Ranasinghe, P. D., Chelladurai, Y., & Robinson, K. A. (2014) · Annals of Internal Medicine · doi:10.7326/m13-2526 · Cited by 70 · see citing works
Karalis, D. G., Victor, B. M., Ahedor, L., & Liu, L. (2012) · Cholesterol · doi:10.1155/2012/861924 · Cited by 68 · see citing works
“Hindawi Publishing Corporation Cholesterol Volume 2012, Article ID 861924, 7 pages doi:10.1155/2012/861924”
BackgroundInfluentialThe Therapeutic Role of Niacin in Dyslipidemia Management
Boden, W. E., Sidhu, M. S., & Toth, P. P. (2013) · Journal of Cardiovascular Pharmacology and Therapeutics · doi:10.1177/1074248413514481 · Cited by 67 · see citing works
Statins for acute coronary syndrome
Vale, N., Nordmann, A. J., Schwartz, G. G., de Lemos, J. A., Colivicchi, F., den Hartog, F., Ošťádal, P., Macin, S. M., Liem, A. H., Mills, E. J., et al. (2014) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd006870.pub3 · Cited by 67 · see citing works
- 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 › Surgery › 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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