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Meta-Analysis
. 2018 Nov 19;11(11):CD012502.
doi: 10.1002/14651858.CD012502.pub2.

Ezetimibe for the prevention of cardiovascular disease and all-cause mortality events

Shipeng Zhan  1 , Min Tang, Fang Liu, Peiyuan Xia, Maoqin Shu, Xiaojiao Wu
Affiliations
Meta-Analysis

Ezetimibe for the prevention of cardiovascular disease and all-cause mortality events

Shipeng Zhan et al. Cochrane Database Syst Rev. .

Abstract

Background: Cardiovascular disease (CVD) remains an important cause of mortality and morbidity, and high levels of blood cholesterol are thought to be the major modifiable risk factors for CVD. The use of statins is the preferred treatment strategy for the prevention of CVD, but some people at high-risk for CVD are intolerant to statin therapy or unable to achieve their treatment goals with the maximal recommended doses of statin. Ezetimibe is a selective cholesterol absorption inhibitor, whether it has a positive effect on CVD events remains uncertain. Results from clinical studies are inconsistent and a thorough evaluation of its efficacy and safety for the prevention of CVD and mortality is necessary.

Objectives: To assess the efficacy and safety of ezetimibe for the prevention of CVD and all-cause mortality.

Search methods: We searched the CENTRAL, MEDLINE, Embase and Web of Science on 27 June 2018, and two clinical trial registry platforms on 11 July 2018. We checked reference lists from primary studies and review articles for additional studies. No language restrictions were applied.

Selection criteria: We included randomised controlled trials (RCTs) that compared ezetimibe versus placebo or ezetimibe plus other lipid-modifying drugs versus other lipid-modifying drugs alone in adults, with or without CVD, and which had a follow-up of at least 12 months.

Data collection and analysis: Two review authors independently selected studies for inclusion, extracted data, assessed risk of bias and contacted trialists to obtain missing data. We performed statistical analyses according to the Cochrane Handbook for Systematic Reviews of Interventions and used the GRADE to assess the quality of evidence.

Main results: We included 26 RCTs randomising 23,499 participants. All included studies assessed effects of ezetimibe plus other lipid-modifying drugs compared with other lipid-modifying drugs alone or plus placebo. Our findings were driven by the largest study (IMPROVE-IT), which had weights ranging from 41.5% to 98.4% in the different meta-analyses.Ezetimibe with statins probably reduces the risk of major adverse cardiovascular events compared with statins alone (risk ratio (RR) 0.94, 95% confidence interval (CI) 0.90 to 0.98; a decrease from 284/1000 to 267/1000, 95% CI 256 to 278; 21,727 participants; 10 studies; moderate-quality evidence). Trials reporting all-cause mortality used ezetimibe with statin or fenofibrate and found they have little or no effect on this outcome (RR 0.98, 95% CI 0.91 to 1.05; 21,222 participants; 8 studies; high-quality evidence). Adding ezetimibe to statins probably reduces the risk of non-fatal myocardial infarction (MI) (RR 0.88, 95% CI 0.81 to 0.95; a decrease from 105/1000 to 92/1000, 95% CI 85 to 100; 21,145 participants; 6 studies; moderate-quality evidence) and non-fatal stroke (RR 0.83, 95% CI 0.71 to 0.97; a decrease 32/1000 to 27/1000, 95% CI 23 to 31; 21,205 participants; 6 studies; moderate-quality evidence). Trials reporting cardiovascular mortality added ezetimibe to statin or fenofibrate, probably having little or no effect on this outcome (RR 1.00, 95% CI 0.89 to 1.12; 19457 participants; 6 studies; moderate-quality evidence). The need for coronary revascularisation might be reduced by adding ezetimibe to statin (RR 0.94, 95% CI 0.89 to 0.99; a decrease from 196/1000 to 184/1000, 95% 175 to 194; 21,323 participants; 7 studies); however, no difference in coronary revascularisation rate was observed when a sensitivity analysis was limited to studies with a low risk of bias.In terms of safety, adding ezetimibe to statins may make little or no difference in the risk of hepatopathy (RR 1.14, 95% CI 0.96 to 1.35; 20,687 participants; 4 studies; low-quality evidence). It is uncertain whether ezetimibe increase or decrease the risk of myopathy (RR 1.31, 95% CI 0.72 to 2.38; 20,581 participants; 3 studies; very low-quality evidence) and rhabdomyolysis, given the wide CIs and low event rate. Little or no difference in the risk of cancer, gallbladder-related disease and discontinuation due to adverse events were observed between treatment groups. For serum lipids, adding ezetimibe to statin or fenofibrate might further reduce the low-density lipoprotein cholesterol (LDL-C), total cholesterol and triglyceride levels and likely increase the high-density lipoprotein cholesterol levels; however, substantial heterogeneity was detected in most analyses.None of the included studies reported on health-related quality of life.

Authors' conclusions: Moderate- to high-quality evidence suggests that ezetimibe has modest beneficial effects on the risk of CVD endpoints, primarily driven by a reduction in non-fatal MI and non-fatal stroke, but it has little or no effect on clinical fatal endpoints. The cardiovascular benefit of ezetimibe might involve the reduction of LDL-C, total cholesterol and triglycerides. There is insufficient evidence to determine whether ezetimibe increases the risk of adverse events due to the low and very low quality of the evidence. The evidence for beneficial effects was mainly obtained from individuals with established atherosclerotic cardiovascular disease (ASCVD, predominantly with acute coronary syndrome) administered ezetimibe plus statins. However, there is limited evidence regarding the role of ezetimibe in primary prevention and the effects of ezetimibe monotherapy in the prevention of CVD, and these topics thus requires further investigation.

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Conflict of interest statement

Zhan Shipeng: no conflict of interest

Xia Peiyuan: no conflict of interest

Tang Min: no conflict of interest

Liu Fang: no conflict of interest

Shu Maoqin: no conflict of interest

Wu Xiaojiao: no conflict of interest

Figures

1
1
Study flow diagram.
2
2
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
4
4
Funnel plot of comparison: 1 Ezetimibe plus other lipid‐modifying drugs vs other lipid‐modifying drugs alone or plus placebo, outcome: 1.1 MACE (subgroup analysis: duration of follow‐up).
5
5
Funnel plot of comparison: 1 Ezetimibe plus other lipid‐modifying drugs vs other lipid‐modifying drugs alone or plus placebo, outcome: 1.34 Discontinuation due to adverse event.
6
6
Funnel plot of comparison: 1 Ezetimibe plus other lipid‐modifying drugs vs other lipid‐modifying drugs alone or plus placebo, outcome: 1.37 LDL‐C (end of follow up).
7
7
Funnel plot of comparison: 1 Ezetimibe plus other lipid‐modifying drugs vs other lipid‐modifying drugs alone or plus placebo, outcome: 1.40 TC (end of follow up).
8
8
Funnel plot of comparison: 1 Ezetimibe plus other lipid‐modifying drugs vs other lipid‐modifying drugs alone or plus placebo, outcome: 1.43 HDL‐C (end of follow up).
9
9
Funnel plot of comparison: 1 Ezetimibe plus other lipid‐modifying drugs vs other lipid‐modifying drugs alone or plus placebo, outcome: 1.46 TG (end of follow up).
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References

References to studies included in this review

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    1. Auscher S, Heinsen L, Nieman K, Vinther KH, Logstrup B, Moller JE, et al. Effects of intensive lipid‐lowering therapy on coronary plaques composition in patients with acute myocardial infarction: Assessment with serial coronary CT angiography. Atherosclerosis 2015;241(2):579‐87. - PubMed
Bays 2008 {published data only}
    1. Bays H, Sapre A, Taggart W, Liu J, Capece R, Tershakovec A. Long‐term (48‐week) safety of ezetimibe 10 mg/day coadministered with simvastatin compared to simvastatin alone in patients with primary hypercholesterolemia. Current Medical Research and Opinion 2008;24(10):2953‐66. - PubMed
Crespo‐Leiro 2008 {published data only}
    1. Crespo‐Leiro MG, Paniagua MJ, Marzoa R, Grille Z, Naya C, Flores X, et al. The efficacy and safety of ezetimibe for treatment of dyslipidemia after heart transplantation. Transplantation Proceedings 2008;40(9):3060‐2. - PubMed
Dagli 2007 {published data only}
    1. Dagli N, Yavuzkir M, Karaca I. The effects of high dose pravastatin and low dose pravastatin and ezetimibe combination therapy on lipid, glucose metabolism and inflammation. Inflammation 2007;30(6):230‐5. - PubMed
DESCARTES 2014 {published data only}
    1. Blom DJ, Hala T, Bolognese M, Lillestol MJ, Toth PD, Burgess L, et al. A 52‐week placebo‐controlled trial of evolocumab in hyperlipidemia. New England Journal of Medicine 2014;370(19):1809‐19. - PubMed
Dujovne 2008 {published data only}
    1. Dujovne CA, Suresh R, McCrary Sisk C, Maccubbin D, Strony J, Veltri E. Safety and efficacy of ezetimibe monotherapy in 1624 primary hypercholesterolaemic patients for up to 2 years. International Journal of Clinical Practice 2008;62(9):1332‐6. - PubMed
EASEGO 2008 {published data only}
    1. Roeters van Lennep HW, Liem AH, Dunselman PH, Dallinga‐Thie GM, Zwinderman AH, Jukema JW. The efficacy of statin monotherapy uptitration versus switching to ezetimibe/simvastatin: results of the EASEGO study. Current Medical Research and Opinion 2008;24(3):685‐94. - PubMed
ELIMIT 2013 {published data only}
    1. Brunner G, Yang EY, Kumar A, Sun W, Virani SS, Negi SI, et al. The Effect of Lipid Modification on Peripheral Artery Disease after Endovascular Intervention Trial (ELIMIT). Atherosclerosis 2013;231(2):371‐7. - PMC - PubMed
Enajat 2009 {published data only}
    1. Enajat M, Teerenstra S, Kuilenburg JT, Sorge‐Greve AH, Albers‐Akkers MT, Verheugt FW, et al. Safety of the combination of intensive cholesterol‐lowering therapy with oral anticoagulation medication in elderly patients with atrial fibrillation: a randomized, double‐blind, placebo‐controlled study. Drugs and Aging 2009;26(7):585‐93. - PubMed
Ferrieres 2016 {published data only}
    1. Ferrieres J, Dallongeville J, Rossignol M, Benichou J, Caro JJ, Getsios D, et al. Model‐observational bridging study on the effectiveness of ezetimibe on cardiovascular morbidity and mortality in France: A population‐based study. Journal of Clinical Lipidology 2016;10(6):1379‐88. - PubMed
Foody 2013 {published data only}
    1. Foody JM, Toth PP, Tomassini JE, Sajjan S, Ramey DR, Neff D, et al. Changes in LDL‐C levels and goal attainment associated with addition of ezetimibe to simvastatin, atorvastatin, or rosuvastatin compared with titrating statin monotherapy. Vascular Health and Risk Management 2013;9:719‐27. - PMC - PubMed
Habara 2014 {published data only}
    1. Habara M, Nasu K, Terashima M, Ko E, Yokota D, Ito T, et al. Impact on optical coherence tomographic coronary findings of fluvastatin alone versus fluvastatin + ezetimibe. American Journal of Cardiology 2014;113(4):580‐7. - PubMed
Hayek 2013 {published data only}
    1. Hayek S, Canepa Escaro F, Sattar A, Gamalski S, Wells KE, Divine G, et al. Effect of ezetimibe on major atherosclerotic disease events and all‐cause mortality. American Journal of Cardiology 2013;111(4):532‐9. - PMC - PubMed
HEAVEN 2012 {published data only}
    1. Kovarnik T. Changes of plaque volume and plaque composition during dual lipid‐lowering therapy (atorvastatin+ezetimibe) compared to standard therapy. Study with intravascular ultrasound and virtual histology. EuroIntervention 2013;9 EuroPCR Abstracts 2013:no pagination.
    1. Kovarnik T, Horak J, Sonka M, Uhrova J, Skalicka H, Simek S, et al. Virtual histology evaluation of atherosclerosis regression during atorvastatin and ezetimibe administration ‐ HEAVEN study (ongoing). American Journal of Cardiology 2009;104(6 SUPPL 1):60D‐61D. - PubMed
    1. Kovarnik T, Mintz GS, Skalicka H, Kral A, Horak J, Skulec R, et al. Virtual histology evaluation of atherosclerosis regression during atorvastatin and ezetimibeadministration: HEAVEN study. Circulation Journal 2012;76(1):176‐83. - PubMed
Hiro 2014 {published data only}
    1. Hiro T, Hirayama A, Ueda Y, Komatsu S, Matsuoka H, Takayama T, et al. Rationale and design of a randomized clinical study to investigate the effect of ezetimibe, a cholesterol absorption inhibitor, on the regression of intracoronary plaque evaluated by non‐obstructive angioscopy and ultrasound: The ZIPANGU study. Journal of Cardiology 2014;64(6):501‐7. - PubMed
Jackowska 2016 {published data only}
    1. Jackowska P, Pytel E, Koter‐Michalak M, Olszewska‐Banaszczyk M, Legeza A, Broncel M. The effect of combined ezetimibe/atorvastatin therapy vs. atorvastatin monotherapy on the erythrocyte membrane structure in patients with coronary artery disease: A pilot study. Advances in Clinical & Experimental Medicine 2016;25(3):433‐9. - PubMed
Japaridze 2017 {published data only}
    1. Japaridze L, Sadunishvili M. The short‐term effect of atorvastatin plus ezetimibe therapy versus atorvastatin monotherapy on clinical outcome in acute coronary syndrome patients by gender. Kardiologia Polska 2017;75(8):770‐8. - PubMed
    1. Japaridze L, Sadunishvili M, Megreladze I. Combination therapy effectiveness of ezetimibe and atorvastatin in patients with acute coronary syndrome. Georgian Medical News 2016;252:15‐22. - PubMed
Koren 2014 {published data only}
    1. Koren MJ, Lundqvist P, Bolognese M, Neutel JM, Monsalvo ML, Yang J, et al. Anti‐PCSK9 monotherapy for hypercholesterolemia: the MENDEL‐2 randomized, controlled phase III clinical trial of evolocumab. Journal of the American College of Cardiology 2014;63(23):2531‐40. - PubMed
Kral 2011 {published data only}
    1. Kral A, Kovarnik T, Kralik L, Skalicka H, Horak J, Mintz GS, et al. Genetic variants in haem oxygenase‐1 and endothelial nitric oxide synthase influence the extent and evolution of coronary artery atherosclerosis. Folia Biologica (Czech Republic) 2011;57(5):182‐90. - PubMed
Le 2015 {published data only}
    1. Le NA, Tomassini JE, Tershakovec AM, Neff DR, Wilson PW. Effect of switching from statin monotherapy to ezetimibe/simvastatin combination therapy compared with other intensified lipid‐lowering strategies on lipoprotein subclasses in diabetic patients with symptomatic cardiovascular disease. Journal of the American Heart Association 2015;4(10):e001675. - PMC - PubMed
Lopez 2008 {published data only}
    1. Lopez V, Gutierrez C, Gutierrez E, Sola E, Cabello M, Burgos D, et al. Treatment with ezetimibe in kidney transplant recipients with uncontrolled dyslipidemia. Transplantation Proceedings 2008;40(9):2925‐6. - PubMed
Masana 2005 {published data only}
    1. Masana L, Mata P, Gagne C, Sirah W, Cho M, Johnson‐Levonas AO, et al. Long‐term safety and, tolerability profiles and lipid‐modifying efficacy of ezetimibe coadministered with ongoing simvastatin treatment: a multicenter, randomized, double‐blind, placebo‐controlled, 48‐week extension study. Clinical Therapeutics 2005;27(2):174‐84. - PubMed
Masia 2009 {published data only}
    1. Masia M, Bernal E, Padilla S, Garcia N, Escribano JC, Martanez E, et al. A pilot randomized trial comparing an intensive versus a standard intervention in stable HIV‐infected patients with moderate ‐ High cardiovascular risk. Journal of Antimicrobial Chemotherapy 2009;64(3):589‐98. - PubMed
Masuda 2015 {published data only}
    1. Masuda J, Tanigawa T, Yamada T, Nishimura Y, Sasou T, Nakata T, et al. Effect of combination therapy of ezetimibe and rosuvastatin on regression of coronary atherosclerosis in patients with coronary artery disease. International Heart Journal 2015;56(3):278‐85. - PubMed
McKenney 2006 {published data only}
    1. McKenney JM, Farnier M, Lo KW, Bays HE, Perevozkaya I, Carlson G, et al. Safety and efficacy of long‐term co‐administration of fenofibrate and ezetimibe in patients with mixed hyperlipidemia. Journal of the American College of Cardiology 2006;47(8):1584‐7. - PubMed
Nicholls 2016 {published data only}
    1. Nicholls S, Ray K, Ballantyne C, Beacham L, Miller D, Ruotolo G, et al. Workshop 3.1: Novel Therapies. Comparative effects of cholesteryl ester transfer protein inhibiton, statin and ezetimibe therapy on atherogenic and protective lipid factors: The ACCENTUATE Trial. Atherosclerosis 2016;252:E237‐8. - PubMed
ODYSSEY COMBO II {published data only}
    1. Cannon CP, Cariou B, Blom D, McKenney JM, Lorenzato C, Pordy R, et al. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. European Heart Journal 2015;36(19):1186‐94. - PMC - PubMed
Okada 2010 {published data only}
    1. Okada K, Fukuoka T, Saitoh T, Endo T, Uchino K, Fukui K, et al. Measuring the baseline cholesterol absorption and synthesis marker can predict the LDL‐C lowering response to ezetimibe‐statin combination therapy in patients with coronary artery disease: A multi‐center prospective randomized trial. Circulation 2010;122(21):2.
Okuyama 2012 {published data only}
    1. Okuyama Y, Kuramoto Y, Kawasaki M, Iwasaki Y, Tanaka K, Furukawa Y, et al. Assessment of atrial late potentials in patients with hypercholesteremia, to investigate the preventive effect of pitavastatin on atrial fibrillation (Alpina study). Journal of the American College of Cardiology 2012;59(13 SUPPL 1):E687.
Palacio 2016 {published data only}
    1. Palacio E, Viadero‐Cervera R, Revilla M, Larrosa‐Campo D, Acha‐Salazar O, Novo‐Robledo F, et al. Utility of treatment with atorvastatin 40 mg plus ezetimibe 10 mg versus atorvastatin 80 mg in reducing the levels of LDL cholesterol in patients with ischaemic stroke or transient ischaemic attack. Revista De Neurologia 2016;62(5):203‐10. - PubMed
Pandey 2008 {published data only}
    1. Pandey AS, Bissonnette S, Boukas S, Sampalis JS. Effectiveness and tolerability of ezetimibe 10 mg/d coadministered with statins vs statin dose‐doubling in patients at high coronary artery disease risk who are not at target LDL‐C on statin monotherapy: The EZE (STAT)(2) trial. Arteriosclerosis Thrombosis and Vascular Biology 2008;28(6):E132.
Patel 2013 {published data only}
    1. Patel AY, Pillarisetti J, Marr J, Vacek JL. Ezetimibe in combination with a statin does not reduce all‐cause mortality. Journal of Clinical Medicine Research 2013;5(4):275‐80. - PMC - PubMed
Pauriah 2014 {published data only}
    1. Pauriah M, Elder DH, Ogston S, Noman AY, Majeed A, Wyatt JC, et al. High‐potency statin and ezetimibe use and mortality in survivors of an acute myocardial infarction: a population‐based study. Heart 2014;100(11):867‐72. - PubMed
Pesaro 2010 {published data only}
    1. Pesaro AE, Serrano CV, Fernandes JL, Cavalcanti AB, Campos AH, Martins HS, et al. A randomized trial comparing the pleotropic effects of ezetimibe plus moderate dose statin versus high dose statin monotherapy. Circulation 2010;122(21):2.
Pop‐Purceleanu 2009 {published data only}
    1. Pop‐Purceleanu M, Wezenberg E, Enajat M, Zwiers M, Urner M, Leeuw FE, et al. Cholesterol lowering treatment in atrial fibrillation (AF) reduces MTL atrophy. Biological Psychiatry 2009;65(8 SUPPL 1):152S.
Pytel 2017 {published data only}
    1. Pytel E, Bukowska B, Koter‐Michalak M, Olszewska‐Banaszczyk M, Gorzelak‐Pabi P, Broncel M. Effect of intensive lipid‐lowering therapies on cholinesterase activity in patients with coronary artery disease. Pharmacological Reports 2017; Vol. 69, issue 1:150‐5. - PubMed
Ran 2017 {published data only}
    1. Ran D, Nie HJ, Gao YL, Deng SB, Du JL, Liu YJ, et al. A randomized, controlled comparison of different intensive lipid‐lowering therapies in Chinese patients with non‐ST‐elevation acute coronary syndrome (NSTE‐ACS): Ezetimibe and rosuvastatin versus high‐dose rosuvastatin. International Journal of Cardiology 2017;235:49‐55. - PubMed
REMEDY 2016 {published data only}
    1. Briguori C, Madonna R, Zimarino M, Calabro P, Quintavalle C, Salomone M, et al. Rosuvastatin for reduction of myocardial damage during coronary angioplasty ‐ the REMEDY trial. Cardiovascular Drugs and Therapy 2016;30(5):465‐72. - PubMed
    1. Briguori C, Quintavalle C, D'Alessio F, Donahue M, Roscigno G, Micco F, et al. Impact of statin therapy intensity on endothelial progenitor cells after percutaneous coronary intervention in diabetic patients. The REMEDY‐EPC late study. International Journal of Cardiology 2017; Vol. 244:112‐8. - PubMed
    1. Madonna R, Renna FV, Lanuti P, Pertetti M, Marchisio M, Briguori C, et al. The acute impact of high‐dose lipid‐lowering treatment on endothelial progenitor cells in patients with coronary artery disease‐The REMEDY‐EPC early substudy. PLOS One 2017;12(4):e0172800. - PMC - PubMed
SANDS 2008 {published data only}
    1. Fleg J, Meta M, Howard B, Roman M, Howard W. The SANDS trial: the effect of statins with versus without ezetimibe on carotid atherosclerosis in type 2 diabetes. Atherosclerosis Supplements 2009;10(2):e165.
    1. Fleg JL, Mete M, Howard BV, Umans JG, Roman MJ, Ratner RE, et al. Effect of statins alone versus statins plus ezetimibe on carotid atherosclerosis in type 2 diabetes: the SANDS (Stop Atherosclerosis in Native Diabetics Study) trial. Journal of the American College of Cardiology 2008;52(25):2198‐205. - PMC - PubMed
    1. Howard BV, Roman MJ, Devereux RB, Fleg JL, Galloway JM, Henderson JA, et al. Effect of lower targets for blood pressure and LDL cholesterol on atherosclerosis in diabetes: the SANDS randomized trial. JAMA: Journal of the American Medical Association 2008;299(14):1678‐89. - PMC - PubMed
    1. Mete M, Wilson C, Lee ET, Silverman A, Russell M, Stylianou M, et al. Relationship of glycemia control to lipid and blood pressure lowering and atherosclerosis: The SANDS experience. Journal of Diabetes and its Complications 2011;25(6):362‐7. - PMC - PubMed
    1. Russell M, Silverman A, Fleg JL, Lee ET, Mete M, Weir M, et al. Achieving lipid targets in adults with type 2 diabetes: the Stop Atherosclerosis in Native Diabetics Study. Journal of Clinical Lipidology 2010;4(5):435‐43. - PMC - PubMed
Santos 2014 {published data only}
    1. Santos PC, Morgan AC, Jannes CE, Krieger JE, Santos RD, Pereira AC. The MYLIP p.N342S polymorphism is associated with response to lipid‐lowering therapy in Brazilian patients with familial hypercholesterolemia. Pharmacogenetics and Genomics 2014;24(11):548‐55. - PMC - PubMed
SEAS 2008 {published data only}
    1. Rossebo AB, Pedersen TR, Allen C, Boman K, Chambers J, Egstrup K, et al. Design and baseline characteristics of the simvastatin and ezetimibe in aortic stenosis (SEAS) study. American Journal of Cardiology 2007;99(7):970‐3. - PubMed
    1. Rossebo AB, Pedersen TR, Boman K, Brudi P, Chambers JB, Egstrup K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. New England Journal of Medicine 2008;359(13):1343‐56. - PubMed
Sertbas 2010 {published data only}
    1. Sertbas Y, Ersoy U, Ayter M, Gultekin Tirtil F, Kucukkaya B. Ezetimibe effect on bone mineral density and markers of bone formation and resorption. Journal of Investigative Medicine 2010;58(2):295‐7. - PubMed
SHARP 2011 {published data only}
    1. Baigent C, Landray M, Reith C, Dasgupta T, Emberson J, Herrington W, et al. Study of Heart and Renal Protection (SHARP): Randomized trial to assess the effects of lowering low‐density lipoprotein cholesterol among 9,438 patients with chronic kidney disease. American Heart Journal 2010;160(5):785‐U28. - PubMed
    1. Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo‐controlled trial. Lancet 2011;377(9784):2181‐92. - PMC - PubMed
    1. Baigent C, Landry M. Study of Heart and Renal Protection (SHARP). Kidney International, Supplement 2003;63(84):S207‐10. - PubMed
Steg 2008 {published data only}
    1. Steg PG, Verdier JC, Carre F, Darne B, Ducardonnet A, Jullien G, et al. A randomised trial of three counselling strategies for lifestyle changes in patients with hypercholesterolemia treated with ezetimibe on top of statin therapy (TWICE). Archives of Cardiovascular Diseases 2008;101(11‐12):723‐35. - PubMed
    1. Steg PG, Verdier JC, Carre F, Ducardonnet A, Farnier M, Giral P, et al. Does patient counseling enhance the lipid‐lowering efficacy of ezetimibe in hypercholesterolemic patients uncontrolled with a statin? The TWICE randomized trial. European Heart Journal 2007;28:589‐90.
Stein 2008 {published data only}
    1. Stein EA, Ballantyne CM, Engelhardt M, Gimpelewicz CR, Ghani S, Lescol XL: Myalgia Study Grp. Treating patients with a prior history of statin related muscle side effects to LDL‐C goals using fluvastatin XL alone, or in combination with ezetimibe: A randomized, double blind multicentre study. European Heart Journal 2007;28:209.
    1. Stein EA, Ballantyne CM, Gimplewicz C, Seper C, Ghani S. A randomized, double‐blind, double‐dummy, comparison of efficacy and tolerability of fluvastatin XL alone, ezetimibe alone and the combination, in patients with a history of muscle related side effects with other statins. Circulation 2006;114(18):905.
    1. Stein EA, Ballantyne CM, Windler E, Sirnes PA, Sussekov A, Yigit Z, et al. Efficacy and tolerability of fluvastatin XL 80 mg alone, ezetimibe alone, and the combination of fluvastatin XL 80 mg with ezetimibe in patients with a history of muscle‐related side effects with other statins. American Journal of Cardiology 2008;101(4):490‐6. - PubMed
Strony 2008 {published data only}
    1. Strony J, Yang B, Hanson ME, Veltri EP. Long‐term safety and tolerability of ezetimibe coadministered with simvastatin in hypercholesterolemic patients: a randomized, 12‐month double‐blind extension study. Current Medical Research and Opinion 2008;24(11):3149‐57. - PubMed
Strony 2008a {published data only}
    1. Strony J, Hoffman R, Hanson M, Veltri E. Tolerability and effects on lipids of ezetimibe coadministered with pravastatin or simvastatin for twelve months: results from two open‐label extension studies in hypercholesterolemic patients. Clinical Therapeutics 2008;30(12):2280‐97. - PubMed
Suzuki 2010 {published data only}
    1. Suzuki H, Inoue T, Watanabe Y, Kikuta T, Sato T, Tsuda M. Efficacy and safety of ezetimibe and low‐dose simvastatin as primary treatment for dyslipidemia in peritoneal dialysis patients. Advances in Peritoneal Dialysis 2010;26:53‐7. - PubMed
Takase 2017 {published data only}
    1. Takase S, Matoba T, Nakashiro S, Mukai Y, Inoue S, Oi K, et al. Ezetimibe in combination with statins ameliorates endothelial dysfunction in coronary arteries after stenting: The CuVIC Trial (Effect of Cholesterol Absorption Inhibitor Usage on Target Vessel Dysfunction After Coronary Stenting), a multicenter randomized controlled trial. Arteriosclerosis, Thrombosis and Vascular Biology 2017;37(2):350‐8. - PubMed
Tendolkar 2012 {published data only}
    1. Tendolkar I, Enajat M, Zwiers MP, Wingen G, Leeuw FE, Kuilenburg J, et al. One‐year cholesterol lowering treatment reduces medial temporal lobe atrophy and memory decline in stroke‐free elderly with atrial fibrillation: evidence from a parallel group randomized trial. International Journal of Geriatric Psychiatry 2012;27(1):49‐58. - PubMed
Teramoto 2013 {published data only}
    1. Teramoto T, Abe K, Taneyama T. Safety and efficacy of long‐term combination therapy with bezafibrate and ezetimibe in patients with dyslipidemia in the prospective, observational J‐COMPATIBLE study. Cardiovascular Diabetology 2013;12:163. - PMC - PubMed
Thongtang 2012 {published data only}
    1. Thongtang N, Lin J, Schaefer EJ, Lowe RS, Tomassini JE, Shah AK, et al. Effects of ezetimibe added to statin therapy on markers of cholesterol absorption and synthesis and LDL‐C lowering in hyperlipidemic patients. Atherosclerosis 2012;225(2):388‐96. - PMC - PubMed
Troxel 2016 {published data only}
    1. Troxel AB, Asch DA, Mehta SJ, Norton L, Taylor D, Calderon TA, et al. Rationale and design of a randomized trial of automated hovering for post‐myocardial infarction patients: The HeartStrong program. American Heart Journal 2016;179:166‐74. - PubMed
Turk 2008 {published data only}
    1. Turk TR, Voropaeva E, Kohnle M, Nurnberger J, Philipp T, Kribben A, et al. Ezetimibe treatment in hypercholesterolemic kidney transplant patients is safe and effective and reduces the decline of renal allograft function: a pilot study. Nephrology Dialysis Transplantation 2008;23(1):369‐73. - PubMed
UK‐HARP‐Ⅱ 2006 {published data only}
    1. Landray M, Baigent C, Leaper C. Biochemical safety and efficacy of co‐administration of Ezetimibe and Simvastatin among patients with chronic kidney disease: the second UK‐heart and renal protection (UK‐HARP‐II) study. Oxford University Research Archive 2003; Vol. 18, issue Suppl 4:119‐20.
    1. Landray M, Baigent C, Leaper C, Adu D, Altmann P, Armitage J, et al. The second United Kingdom Heart and Renal Protection (UK‐HARP‐II) Study: a randomized controlled study of the biochemical safety and efficacy of adding ezetimibe to simvastatin as initial therapy among patients with CKD. American Journal of Kidney Diseases 2006;47(3):385‐95. - PubMed
van der Graaf 2008 {published data only}
    1. Graaf A, Cuffie‐Jackson C, Vissers MN, Trip MD, Gagne C, Shi G, et al. Efficacy and safety of coadministration of ezetimibe and simvastatin in adolescents with heterozygous familial hypercholesterolemia. Journal of the American College of Cardiology 2008;52(17):1421‐9. - PubMed
van Kuilenburg 2011 {published data only}
    1. Kuilenburg J, Lappegard KT, Sexton J, Plesiewicz I, Lap P, Bouwels L, et al. Persisting thrombin activity in elderly patients with atrial fibrillation on oral anticoagulation is decreased by anti‐inflammatory therapy with intensive cholesterol‐lowering treatment. Journal of Clinical Lipidology 2011;5(4):273‐80. - PubMed
Vera‐Lastra 2016 {published data only}
    1. Vera‐Lastra O, Mendez‐Flores S, Cruz‐Dominguez MP, Medina G, Calderon‐Aranda E, Jara LJ. Effect of ezetimibe plus pravastatin on endothelial dysfunction in patients with systemic lupus erythematosus. Lupus 2016;25(7):741‐8. - PubMed
Wierzbicki 2005 {published data only}
    1. Wierzbicki AS, Doherty E, Lumb PJ, Chik G, Crook MA. Efficacy of ezetimibe in patients with statin‐resistant and statin‐intolerant familial hyperlipidaemias. Current Medical Research and Opinion 2005;21(3):333‐8. - PubMed
Zhao 2014 {published data only}
    1. Zhao XQ, Davis J, Isquith D, Dowdy A, Boltz S, Neradilek M, et al. Mortality reduction in patients treated with long‐term intensive lipid therapy: 20‐year follow‐up of the familiar atherosclerosis treatment study‐observational study. Journal of the American College of Cardiology 2014;63(12 SUPPL 1):A1287. - PMC - PubMed
ZIPANGU 2017 {published data only}
    1. Hiro T, Hirayama A, Ueda Y, Komatsu S, Matsuoka H, Takayama T, et al. Rationale and design of a randomized clinical study to investigate the effect of ezetimibe, a cholesterol absorption inhibitor, on the regression of intracoronary plaque evaluated by non‐obstructive angioscopy and ultrasound: The ZIPANGU study. Journal of Cardiology 2014;64(6):501‐7. - PubMed
    1. Ueda Y, Hiro T, Hirayama A, Komatsu S, Matsuoka H, Takayama T, et al. Effect of ezetimibe on stabilization and regression of intracoronary plaque: the ZIPANGU study. Circulation Journal 2017; Vol. 81, issue 11:1611‐9. - PubMed

References to studies awaiting assessment

JPRN‐UMIN000002964 {published data only}
    1. JPRN‐UMIN000002964. Prospective, randomized, open‐label, clinical trial comparing fibrate monotherapy and fibrate‐ezetimibe combination therapy on progression of atherosclerotic plaques, endothelial function, and markers for anti‐inflammatory properties/obesity/antioxidative properties. apps.who.int/trialsearch/Trial2.aspx?TrialID=JPRN‐UMIN000002964 (date of registration 3 January 2010).
JPRN‐UMIN000011745 {published data only}
    1. JPRN‐UMIN000011745. Prospective, randomized, open‐label, clinical trial comparing rosuvastatin monotherapy and combination therapy with ezetimibe on progression of atherosclerotic plaques and endothelial function. apps.who.int/trialsearch/Trial2.aspx?TrialID=JPRN‐UMIN000011745 (date of registration 14 September 2013).
NCT01086020 {published data only}
    1. NCT01086020. Atorvastatin plus Ezetimibe on coronary Plaque Progression (AEPP). clinicaltrials.gov/ct2/show/NCT01086020 (first posted 12 March 2010).
NCT02588235 {published data only}
    1. NCT02588235. Ezetimibe and atorvastatin Therapy on TCFA. clinicaltrials.gov/ct2/show/NCT02588235 (first posted 27 October 2015).

References to ongoing studies

NCT03044665 {published data only}
    1. NCT03044665. RAndomized Comparison of efficacy and safety of lipid‐lowerING with statin monotherapy versus statin/ezetimibe combination for high‐risk cardiovascular diseases (RACING Trial). https://clinicaltrials.gov/ct2/show/NCT03044665.
NCT03169985 {published data only}
    1. NCT03169985. Usual dose Rosuvastatin plus EZetimibe versus high‐dose rosuvastatin on coronary atherosclerotic plaque (Rosuzet‐IVUS). clinicaltrials.gov/ct2/show/nct03169985 (first posted 30 May 2017).
NCT03543774 {published data only}
    1. NCT03543774. Lipid‐lowering therapies in Vietnamese Chronic Kidney Disease population (VietCKD). clinicaltrials.gov/ct2/show/NCT03543774 (first posted 1 June 2018).

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Battaggia 2015
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Cannon 2015
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CTT 2010
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References to other published versions of this review

Zhan 2017
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