Review of 8 trials on clinical benefit of ezetimibe on top of statins

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

Literature - Fei Y, Guyatt GH, Alexander PE, et al. - J Eval Clin Pract, 2017; published online ahead of print


Statins prevent vascular events, however many patients still suffer subsequent adverse vascular outcomes despite therapy [1]. Adjunctive lipid lowering therapies, such as ezetimibe, can further decrease cardiovascular (CV) risk. However, based on mixed results of randomised trials (RCTs) the 2013 AHA/ACC guidelines stated that there are insufficient data regarding the additional clinical benefit of ezetimibe add-on therapy [2].

Recently, the IMPROVE-IT study (2015), as well as a number of reviews, concluded that ezetimibe plus statin therapy was associated with an incremental reduction of LDL-C levels, and fewer composite CV outcomes [3-6].

To explore the robustness of the IMPROVE-IT study results in patient‐important outcomes such as mortality, CV events and adverse events, as well as to assess the consistency of various sized trials, this study systematically reviewed relevant RCTs and performed supplementary subgroup and sensitivity analyses.

Main results

  • Eight eligible trials, published between 2006 and 2016, enrolled 19,564 patients, who were followed for 6 months to 6 years, with a small to moderate sample sizes ranging from 38 to 720 participants (1414 in total) plus the IMPROVE-IT trial with 18,144 participants.
  • All‐cause mortality: 13.1% of patients receiving ezetimibe plus statin died versus 13.3% in the statin monotherapy arm. No differences between groups in both small to moderate sized trials and the IMPROVE-IT study.
  • CV death: 5.8% of patients in both arms experienced CV death. No differences between groups in both small to moderate sized trials and the IMPROVE-IT study.
  • Non‐fatal myocardial infarction (MI): 10.9% of patients receiving ezetimibe plus statin had a non‐fatal MI compared with 12.5% of patients in the statin monotherapy arm. Small to moderate sized trials found no difference between arms, but the in the IMPROVE-IT study ezetimibe plus simvastatin was favoured over simvastatin alone (RR 1.18, 95% CI 0.37-3.82, P effect=0.78, I2=0%).
  • Based on the IMPROVE-IT results, ezetimibe plus statins would result in 17 fewer non‐fatal MIs/1000 (95% CI: 27 fewer/1000 - 7 fewer/1000). Assuming rates in the ezetimibe treatment arm for patients lost to follow‐up were increased two and three‐fold compared to complete cases (and this was equal in the monotherapy arm), there was no significant difference between ezetimibe plus statin and statin monotherapy (two times event rate RR: 0.97; 95% CI: 0.90 - 1.04).
  • Non‐fatal stroke: 3.4% of patients receiving ezetimibe plus statin suffered a non-fatal stroke versus 4.0% of patients in the statin monotherapy arm. Small to moderate sized trials found no difference between arms, but the in the IMPROVE-IT study ezetimibe add-on was associated with a marginal benefit (RR 0.86, 95% CI 0.74-1.00, P effect = 0.05 with low certainty).
  • In the IMPROVE IT study, ezetimibe plus statins would result in 6 fewer non‐fatal strokes/1000 treated. However, assuming two times and three times event rates in patients lost to follow‐up in the treatment arm, the results revealed no significant difference between arms (two times event rate RR: 0.95; 95% CI: 0.83 - 1.09).
  • Adverse events: There were no significant differences between treatment groups regarding cancer (9.3% versus 9.0%; RR: 1.02; 95% CI: 0.93 - 1.13) and rhabdomyolysis (1.6‰ versus 2.2‰; RR: 0.72; 95% CI: 0.35 - 1.47) in the IMPROVE-IT study, in which 98% and 99% of events occurred, respectively.


Based on the IMPROVE-IT study, which comprised 93% of patients within the 8 eligible trials analysed, ezetimibe as add-on therapy 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 CV death. No specific increased harms were associated with the addition of ezetimibe to statins. Results of the 7 smaller trials were consistent with those of the IMPROVE-IT study. This systematic review contributes to the required evidence‐base for updating clinical practice guidelines in the face of the IMPROVE‐IT trial.


1. Parish E, Bloom T, Godlee F. Statins for people at low risk‐Independent review of the trial data is an essential next step. BMJ. 2015;351:h3908

2. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S1–45

3. Cannon CP, Blazing MA, Giugliano RP, et al. IMPROVE‐IT Investigators. Ezetimibe added to statin therapy after acute coronary syndromes. NEJM. 2015;372(25):2387–2397.

4. Savarese G, De Ferrari GM, Rosano GM, et al. Safety and efficacy of ezetimibe: A meta‐analysis. Int J Cardiol. 2015;201:247–252.

5. Luo L, Yuan X, Huang W, et al. Safety of coadministration of ezetimibe and statins in patients with hypercholesterolaemia: a meta‐analysis. Intern Med J. 2015;45(5):546–557.

6. Thomopoulos C, Skalis G, Michalopoulou H, et al. Effect of low‐density lipoprotein cholesterol lowering by ezetimibe/simvastatin on outcome incidence: Overview, meta‐analyses, and meta‐regression analyses of randomized trials. Clin Cardiol.2015;38(12):763–769.

Find this article online at J Eval Clin Pract

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