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

Abstract

Ezetimibe is widely used in combination with statins to reduce low-density lipoprotein. We sought to examine the impact of ezetimibe when added to statins on patient-important outcomes. Medline, EMBASE, CINAHL, and CENTRAL were searched through July, 2016. Randomized controlled trials (RCTs) of ezetimibe combined with statins versus statins alone that followed patients for at least 6 months and reported on at least one of all-cause mortality, cardiovascular deaths, non-fatal myocardial infarctions (MI), and non-fatal strokes were included. Pairs of reviewers extracted study data and assessed risk of bias independently and in duplicate. Quality of evidence was assessed using the GRADE approach. We conducted a narrative review with complementary subgroup and sensitivity analyses. IMPROVE-IT study enrolled 93% of all patients enrolled in the 8 included trials. Our analysis of the IMPROVE-IT study results showed that in patients at high risk of cardiovascular events, ezetimibe added to statins was associated with i) a likely reduction in non-fatal MI (17 fewer/1000 treated over 6 years, moderate certainty in evidence); ii) a possible reduction in non-fatal stroke (6 fewer/1000 treated over 6 years, low certainty); iii) no impact on myopathy (moderate certainty); iv) potentially no impact on all-cause mortality and cardiovascular death (both moderate certainty); and v) possibly no impact on cancer (low certainty). Addition of ezetimibe to moderate-dose statins is likely to result in 17 fewer MIs and possibly 6 fewer strokes/1000 treated over 6 years but is unlikely to reduce all-cause mortality or cardiovascular death. Patients who place a high value on a small absolute reduction in MI and are not adverse to use of an additional medication over a long duration may opt for ezetimibe in addition to statin therapy. Our analysis revealed no increased specific harms associated with addition of ezetimibe to statins.

A Phase III, Multicenter, Randomized, Double-blind, Active Comparator Clinical Trial to Compare the Efficacy and Safety of Combination Therapy With Ezetimibe and Rosuvastatin Versus Rosuvastatin Monotherapy in Patients With Hypercholesterolemia: I-ROSETTE (Ildong Rosuvastatin & Ezetimibe for Hypercholesterolemia) Randomized Controlled Trial

“…26 The addition of ezetimibe to a moderate-dose statin is likely to result in 17 fewer myocardial infarctions and 6 fewer strokes per 1000 treated patients over 6 years. 27 In this study, the mean percent change in LDL-C level at 8 weeks was 450% for all doses of ezetimibe/rosuvastatin combination therapy. According to the 2016 ESC/EAS guideline for management of dyslipidemia, a reduction in LDL-C level of at least 50% is recommended in patients with more than high risk.…”

Comparison of the Effects of Ezetimibe-Statin Combination Therapy on Major Adverse Cardiovascular Events in Patients with and without Diabetes: A Meta-Analysis

“…Recent reviews and meta-analyses of RCTs, including the IMPROVE-IT study, showed that ezetimibe was likely associated with a reduction of the risk of myocardial infarction and stroke, without affecting the risk of overall or cardiovascular mortality or newly-developed cancer [ 21 22 ]. However, published reviews reported marginal cardiovascular benefits of ezetimibe when ezetimibe was added to statins for reducing nonfatal myocardial infarction and stroke (17 fewer myocardial infarctions and six fewer strokes per 1,000 persons treated over 6 years) [ 21 22 23 24 ]. This uncertainty is reflected in the absence of a consensus regarding ezetimibe in international guidelines.…”

Lipid-Lowering Efficacy of Ezetimibe in Patients with Atherosclerotic Cardiovascular Disease: A Systematic Review and Meta-Analyses

“…Although previous studies have assessed the efficacy and safety of ezetimibe [15][16][17][18][19][20], this study is the first systematic literature review and meta-analysis of LDL-C lowering with ezetimibe in patients with ASCVD since the results of the IMPROVE-IT cardiovascular outcomes trial were published. In the present analysis, combination ezetimibe plus statin therapy resulted in a modest (relative to other treatment options) additional decrease in LDL-C compared with statin monotherapy (LDL-C mean difference − 21.86 mg/dL after 6 months of treatment), which was unaffected by treatment duration or a patient's prior history of statin therapy.…”