Clinical Efficacy and Safety of Ezetimibe on Major Cardiovascular Endpoints: Systematic Review and Meta-Analysis of Randomized Controlled Trials

Abstract

BackgroundRandomized clinical trials (RCTs) about Ezetimibe's efficacy on patient-oriented outcomes have given discordant results. The aim of this study was to determine the net effect of Ezetimibe and of the widely marketed combination, Ezetimibe+simvastatin, on mortality and morbidity outcomes.Methods and FindingsWe searched for RCT on Ezetimibe using MEDLINE, CCTR, EMBASE, ClinicalTrials.gov databases up to December 2013, Merck and Novartis online registers, and personal communications. Two authors independently selected trials fulfilling these criteria: RCTs comparing Ezetimibe±statin or another lipid-lowering drug against placebo, or against the same lipid-lowering drug at the same dosage, with a follow-up at least 24 weeks and one or more of these outcomes: all-cause mortality, cardiovascular (CV) mortality, stroke, myocardial infarction (MI), cancer, serious adverse events (SAEs); we assessed the risk of bias using the Cochrane checklist. We extracted the data for major clinical events as a dichotomous measure, with the patient the unit of analysis. Pooled analysis was done with random and fixed effect based models. Trials comparing Ezetimibe plus a lipid-lowering drug against the same lipidlowering drug representing the net effect of Ezetimibe, showed a nonsignificant tendency toward damage for cancer, MI, stroke and SAEs. Ezetimibe+simvastatin vs. simvastatin alone showed a stronger tendency towards a higher risk for all-cause death (2.52; 0.65-9.74), CV death (3.04; 0.48-19.21), non-CV death (3.03; 0.12-73.50), MI (1.91; 0.42-8.70), stroke (2.38; 0.46-12.35), cancer (RR 11.11; 0.62-198.29), and SAEs (1.45; 0.95-2.23). Limitations include small numbers of events and inadequate power of the pooling. Trials comparing Ezetimibe+simvastatin vs placebo showed non-significant effects: MI (0.81; 0.66-1.00 p = 0.051), all-cause death (1.02; 0.95-1.09), CV death (0.91; 0.80-1.04), non-CV death (108; 0.99-1.18), stroke (0.86; 0.72-1.04), cancer (1.18; 0.80-1.74), SAEs (1.01; 0.96-1.06).ConclusionsEzetimibe±simvastatin had inconsistent effects on important outcomes. No firm conclusions are possible, but findings indicative of damage suggest much more selective use of Ezetimibe±simvastatin.

Safety and efficacy of ezetimibe: A meta-analysis

“…A recent meta-analysis including 7 randomized clinical trials showed a non-significant effect of ezetimibe added to statin on allcause or CV death, MI, stroke and cancer, suggesting lack of clinical benefit associated with the use of ezetimibe [26]. However, in this analysis SHARP and SEAS trials [22], enrolling patients with chronic kidney disease and aortic stenosis respectively, were used for the evaluation of cancer risk but not for the assessment of all the other outcomes and, additionally, data from the recently published IMPROVE-IT trial [30] were not available.…”

“…Consequently, the main outcome analyses were performed on a limited sample of highly selected patients (2212 subjects) at low CV risk (mainly patients with only hypercholesterolemia) and this could explain the lack of benefit associated with ezetimibe treatment. As compared with the previous meta-analysis [26], our study included SHARP [41], SEAS [22] and IMPROVE-IT [30] trials in all outcome analyses leading to a significantly larger sample of patients with a CV risk profile more representative of the real world patient who should use ezetimibe.…”

“…The publication of a specifically designed safety analysis including data from ongoing trials was not unanimously accepted as appropriate and reassuring [23], leading to a strong controversy [24,25]. This must not have been completely solved, as suggested by the conclusions on the risk/benefit ratio of ezetimibe reached by a recent meta-analysis published [26]. Notably, this analysis did not include data from the IMPROVE-IT trial [27][28][29][30].…”

Addition of Ezetimibe to statins for patients at high cardiovascular risk: Systematic review of patient‐important outcomes

“…We aimed to assess the disease relevant patient‐important outcomes and specific side effects of statins and ezetimibe. We consulted content experts and evaluated the other published systematic review, Cochrane systematic reviews of lipid lowering therapy, and searched COMET (Core Outcome Measures in Effectiveness Trials, http://www.comet-initiative.org/) and then decided to seek a priori trial‐level data for major clinical events‐all‐cause deaths, cardiovascular deaths, non‐fatal MI, non‐fatal stroke and adverse events, including myopathy, elevated creatine kinase (CK), rhabdomyolysis and cancer, as dichotomous measures using the patient as the unit of analysis. The outcome definitions used were those reported for each trial.…”

“…We identified 4 published reviews [11][12][13]15 relevant to our review. All of the studies included in Luo's review followed patients for no more than 12 weeks and were thus ineligible for our review.…”