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Cited by 109Lipoproteins and Cardiovascular HealthCholesterol and Lipid MetabolismBlood Pressure and Hypertension Studies

The DOI matches its Crossref record; 198 of the 202 references it cites were found in a registry or an index.

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

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Zhan, Shipeng, Tang, Min, Liu, Fang, Xia, Peiyuan, Shu, Maoqin, Wu, Xiaojiao·2018·Cochrane Database of Systematic Reviews
DOI 10.1002/14651858.cd012502.pub2PMC PMC6516816
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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 o

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  1. Kastelein, 2004, The ENHANCE Trial: ezetimibe and simvastatin in hypercholesterolemia enhances atherosclerosis regression, Stroke, 35, E258
  2. Hibi, 2015, Effects of statin plus ezetimibe versus statin alone on coronary atherosclerosis in acute coronary syndrome, Circulation, 132, 14134
  3. Sekiguchi, 2017, Impact of type 2 diabetes on optimal target LDLC level for secondary prevention of cardiovascular disease in patients with acute coronary syndrome: A subanalysis of HIJPROPER, Circulation, 136, A18891
  4. Bach, 2015, Increasing age and the benefit from higher-intensity lipid lowering with ezetimibe/simvastatin vs. simvastatin alone: Results from the IMPROVE-IT trial, Circulation, 132, A16708
  5. Blazing, 2014, On-Treatment Analysis of the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), Circulation, 130, 2112
  6. Blazing, 2015, Muscle related complaints, serious adverse events vents and drug discontinuations in 17,706 subjects randomized to simvastatin or ezetimibe/simvastatin in the IMPROVE-IT study, European Heart Journal, 36, 1151
  7. Bohula May, 2015, Achievement of dual LDL-C (<70 mg/dL) and hs-CRP (<2 mg/L) goals more frequent with addition of ezetimibe and associated with better outcomes in IMPROVE-IT, European Heart Journal, 36, 1060
  8. Cannon, 2014, IMPROVE-IT Trial: A comparison of ezetimibe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes after acute coronary syndromes, Circulation, 130, 2109
  9. Fanaroff, 2016, Association of type of presentation, STEMI vs NSTEMI/UA, with the relative long-term incidence of cardiovascular and non-cardiovascular mortality, Circulation, 134, A18895
  10. Giugliano, 2015, Prospectivev evaluation of cancer in 18,144 patients randomized to ezetimibe vs placebo: A prespecified analysis from the IMPROVE IT trial, European Heart Journal, 36, 181
  11. Kato, 2015, Benefit and safety of adding ezetimibe to statin therapy on cardiovascular outcomes in 4416 women in the IMPROVE-IT trial, Circulation, 132, A17862
  12. Magnuson, 2015, Impact of ezetimibe on hospitalization-related costs among patients with a recent acute coronary syndrome: Results from the improve-it trial, Circulation, 132, A13035
  13. Stanifer, 2016, Comparative efficacy of ezetimibe plus simvastatin combined therapy vs. simvastatin monotherapy for individuals with reduced estimated glomerular filtration rate, European Heart Journal, 37, 1205
  14. Wiviott, 2015, Reduction in non-hemorrhagic stroke with ezetimibe/simvastatin compared with simvastatin alone in the IMPROVE-IT trial, Circulation, 132, A19694
  15. Kouvelos, 2011, The effect of intensified lipid lowering therapy on one-year prognosis in patients undergoing vascular surgery, Interactive Cardiovascular and Thoracic Surgery, 12, S61
  16. Okada, 2012, Long-term effects of ezetimibe plus statin combination vs double-dose statin therapy on low-density lipoprotein cholesterol lowering in coronary artery disease patients pre-treated with statins; focus on proprotein convertase subtilisin/kexin type 9, Circulation, 126, A10846
  17. Okada, 2011, Long-term effect of ezetimibe-plus-statin vs double-dose statin on low-density lipoprotein cholesterol lowering in coronary artery disease patients pre-treated with a statin focus on cholesterol absorption and synthesis, Circulation, 124, A12204
  18. Tsujita, 2015, Impact of statin-ezetimibe combination on coronary atheroma progression/regression in patients with and without prior statin therapy-subanalysis of precise-IVUS trial, Circulation, 132, A13849
  19. Kawamura, 2015, RESEARCH: Superior effect of ezetimibe was sustained on LDL-C level and the rate of achievement of target value in a 52-week analysis, Diabetologia, 58, S82
  20. Pisanu, 2012, Lipid lowering therapy decreases LDL-S-homocysteinilation levels in chronic kidney desease patients, FEBS Journal, 279, 104
  21. Sanna, 2012, Effect of combined simvastatin/ezetimibe administration on taurine levels and oxidative status in patients CDK, FEBS Journal, 279, 218
  22. Zou, 2016, Effect of ezetimibe combined with low-dose atorvastain calcium on carotid atherosclerosis in elderly patients with coronary heart disease, Journal of the American Geriatrics Society, 64, S328
  23. Kovarnik, 2013, 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, 9 EuroPCR Abstr, no pagination
  24. Kovarnik, 2009, Virtual histology evaluation of atherosclerosis regression during atorvastatin and ezetimibe administration - HEAVEN study (ongoing), American Journal of Cardiology, 104, 60D
  25. Okada, 2010, 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, 122, 2
  26. Palacio, 2016, 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, 62, 203
  27. Pandey, 2008, 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, 28, E132
  28. Pesaro, 2010, A randomized trial comparing the pleotropic effects of ezetimibe plus moderate dose statin versus high dose statin monotherapy, Circulation, 122, 2
  29. Pop-Purceleanu, 2009, Cholesterol lowering treatment in atrial fibrillation (AF) reduces MTL atrophy, Biological Psychiatry, 65, 152S
  30. Steg, 2007, Does patient counseling enhance the lipid-lowering efficacy of ezetimibe in hypercholesterolemic patients uncontrolled with a statin? The TWICE randomized trial, European Heart Journal, 28, 589
  31. Stein, 2007, 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, 28, 209
  32. Stein, 2006, 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, 114, 905
  33. 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 119 20
  34. Hiro, 2014, 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, 64, 501, 10.1016/j.jjcc.2014.02.026 · DOI
  35. Baigent, 2011, 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, 377(9784), 2181, 10.1016/S0140-6736(11)60739-3 · DOI · Paper page
  36. Cannon, 2015, Ezetimibe added to statin therapy after acute coronary syndromes, New England Journal of Medicine, 372, 2387, 10.1056/NEJMoa1410489 · DOI · Paper page
  37. Kastelein, 2008, Simvastatin with or without ezetimibe in familial hypercholesterolemia, New England Journal of Medicine, 358, 1431, 10.1056/NEJMoa0800742 · DOI · Paper page
  38. Lefebvre C Manheimer E Glanville J Chapter 6: Searching for studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011 Available from handbook.cochrane.org
  39. Nusßaumer, 2016, Ezetimibe-statin combination therapy, Deutsches Arzteblatt International, 113, 445
  40. Nordic Cochrane Centre; The Cochrane Collaboration Review Manager 5 (RevMan 5) 2014
  41. Rossebo, 2008, Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis, New England Journal of Medicine, 359, 1343, 10.1056/NEJMoa0804602 · DOI · Paper page
  42. Schünemann HJ Oxman AD Vist GE Higgins JP Deeks JJ Glasziou P Chapter 12: Interpreting results and drawing conclusions. In: Higgins JPT, Green S (editors), Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011 Available from handbook.cochrane.org

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Metadata

Authors
Zhan, S., Tang, M., Liu, F., Xia, P., Shu, M., & Wu, X.
Affiliations
Army Medical University (CN)
ORCID
Venue
Cochrane Database of Systematic Reviews
Publisher
Wiley
Published
2018-11-19
Volume
2018
Issue
11
Pages
CD012502-CD012502
ISSN
  • 1361-6137 (ISSN-L)
  • 1465-1858
DOI
10.1002/14651858.cd012502.pub2
PMC
PMC6516816
OpenAlex
W2778116940
Semantic Scholar
24392a10a2db231bd0830e952fca00b38d0309f5
Cited by
109
References
202
Citations by year
2026: 8 · 2025: 6 · 2024: 14 · 2023: 26 · 2022: 23 · 2021: 11 · 2020: 15 · 2019: 4 · 2018: 1
FWCI
1.72
Type
journal article
Language
en
Open access
Locations
  • Cochrane Database of Systematic Reviews (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
Keywords
ezetimibe, cardiovascular disease prevention, all-cause mortality, major adverse cardiovascular events, cholesterol absorption inhibition, statin intolerance, lipid-modifying drugs, LDL cholesterol, IMPROVE-IT trial, statin-sparing therapy, drug safety, adverse events, hypercholesterolemia, cardiovascular risk reduction, cardiovascular risk stratification
MeSH terms
Ezetimibe, Aged, Aged, 80 and over, Anticholesteremic Agents, Cardiovascular Diseases, Cause of Death, Cholesterol, Drug Therapy, Combination, Humans, Cholesterol, LDL, Middle Aged, Myocardial Infarction, Fenofibrate, Triglycerides, Randomized Controlled Trials as Topic, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Simvastatin, Stroke

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