Clinical efficacy and safety of Ezetimibe on major cardiovascular endpoints: systematic review and meta-analysis of randomized controlled trials

Abstract

Background: Randomized 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 findings: We 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).

Conclusions: Ezetimibe±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.

Fig 1. Main analysis: net effect of Ezetimibe on Cancer stratified by comparator (E+lipid-lowering drug against the same lipid-lowering drug at the same dosage; E+simvastatin against simvastatin at the same dosage).

The medium degree of heterogeneity (I² = 60.1%) should encourage the use of the random effect method of pooling. No test for interaction was done (only two trials). The overall result, although not significant, shows a definite trend toward damage (212% increment of Cancer Risk, p = 0.167), due to an impressive trend toward damage in the UK-HARP-II trial, where simvastatin was the Not-E drug.

Fig 2. Main analysis: net effect of Ezetimibe on all-cause death stratified by comparator (E+lipid-lowering drug against the same lipid-lowering drug at the same dosage; E+simvastatin against simvastatin at the same dosage).

The low degree of heterogeneity (I² = 10.3%) should encourage use of the fixed effect method of pooling. The test for interaction does not show the formal presence of a ‘subgroup effect’ (p = 0.2696); however, the direction of the result is toward damage only in the stratum where simvastatin was the no-E drug, showing a clinically important increment of death risk. The non-significant overall result shows a small trend toward damage (3% increment of death risk, p = 0.947).

Fig 3. Main analysis: net effect of Ezetimibe on CV death stratified by comparator (E+lipid- lowering drug against the same lipid-lowering drug at the same dosage; E+simvastatin against simvastatin at the same dosage).

The low degree of heterogeneity (I² = 33.7%) should encourage the use of the fixed effect method of pooling. The test for interaction does not show the formal presence of a ‘subgroup effect’ (p = 0.2378); however, the direction of the result is toward damage only in the stratum where simvastatin was the no-E drug, showing a clinically important increment of CV death risk. The non-significant overall result shows a trend toward benefit (10% decrement of CV death risk, p = 0.844).

Fig 4. Main analysis: net effect of Ezetimibe on not-CV death stratified by comparator (E+lipid- lowering drug against the same lipid-lowering drug at the same dosage; E+simvastatin against simvastatin at the same dosage).

The low degree of heterogeneity (I² = 0.0%) should encourage the use of the fixed effect method of pooling. The test for interaction does not show the formal presence of a ‘subgroup effect’ (p = 0.422); however, the direction of the result is toward damage only in the stratum where simvastatin was the no-E drug, showing a clinically important increment of not-CV death risk. The non-significant overall result shows a small trend toward damage (4% increment of not-CV death risk, p = 0.966). We calculated the number of not-CV deaths by subtracting the number of CV deaths from the number of all-cause deaths reported by each single trial.

Fig 5. Main analysis: net effect of Ezetimibe on MI stratified by comparator (E+lipid lowering drug against the same lipid-lowering drug at the same dosage; E+simvastatin against simvastatin at the same dosage).

The low degree of heterogeneity (I² = 0.0%) should encourage the use of the fixed effect method of pooling. The test for interaction does not show the formal presence of a ‘subgroup effect’ (p = 0.4901); however, the direction of the result is toward damage only in the stratum where simvastatin was the no-E drug, showing a clinically important increment of MI risk. The non-significant overall result shows a trend toward damage (37% increment of MI risk, p = 0.636).

Fig 6. Main analysis: net effect of Ezetimibe on stroke stratified by comparator (E+lipid- lowering drug against the same lipid-lowering drug at the same dosage; E+simvastatin against simvastatin at the same dosage).

The low degree of heterogeneity (I² = 0.0%) should encourage the use of the fixed effect method of pooling. The test for interaction does not show the formal presence of a ‘subgroup effect’ (p = 0.4385); however, the direction of the result is toward damage only in the stratum where simvastatin was the no-E drug, showing a clinically important increment of stroke risk. The non-significant overall result shows a trend toward damage (45% increment of stroke risk, p = 0.546).

Fig 7. Main analysis: net effect of Ezetimibe on SAEs stratified by comparator (E+lipid- lowering drug against the same lipid-lowering drug at the same dosage; E+simvastatin against simvastatin at the same dosage).

The low degree of heterogeneity (I² = 0.0%) should encourage the use of the fixed effect method of pooling. The test for interaction does not show the formal presence of a ‘subgroup effect’ (p = 0.4803); however, the direction of the result is toward damage only in the stratum where simvastatin was the no-E drug, showing a clinically important 45% increment of SAEs risk. The non-significant overall result shows a trend toward damage (24% increment of SAEs risk, p = 0.216). The larger risk of major clinical endpoints was in fact noted in the E arms of trials where E plus simvastatin were compared with simvastatin alone (Figs 1–7).

Fig 8. Complementary analysis: net effect of the Ezetimibe/Simvastatin combination (E+Simvastatin against placebo) on cancer.

The simvastatin dosage was different in the two trials (20 mg/day in SHARP, 40 mg/day in SEAS). The high degree of heterogeneity (I² = 83.7%) should encourage use of the random effect method of pooling. The non-significant overall result shows a trend toward damage (18% increment of cancer risk, p = 0.395).

Fig 9. Complementary analysis: net effect of the Ezetimibe/Simvastatin combination (E+simvastatin against placebo) on all-cause death.

The simvastatin dosage was different in the two trials (20 mg/day in SHARP, 40 mg/day in SEAS). The low degree of heterogeneity (I² = 0.0%) should encourage the use of the fixed effect method of pooling. The nonsignificant overall result shows a small trend toward damage (2% increment of all-cause death risk, p = 0.596).

Fig 10. Complementary analysis: net effect of the Ezetimibe/Simvastatin combination (E+Simvastatin against placebo) on CV death.

The simvastatin dosage was different in the two trials (20 mg/day in SHARP, 40 mg/day in SEAS). The low degree of heterogeneity (I² = 0.0%) should encourage the use of the fixed effect method of pooling. The nonsignificant overall result shows a trend toward benefit (9% decrement of CV death risk, p = 0.162).

Fig 11. Complementary analysis: net effect of the Ezetimibe/simvastatin combination (E+simvastatin against placebo) on not-CV death.

The simvastatin dosage was different in the two trials (20 mg/day in SHARP, 40 mg/day in SEAS). The low degree of heterogeneity (I² = 0.0%) should encourage the use of the fixed effect method of pooling. The nonsignificant overall result shows a trend toward damage (8% increment of not-CV death risk, p = 0.091). We calculated the number of not-CV deaths by subtracting the number of CV deaths from the number of all-cause deaths reported by each single trial.

Fig 12. Complementary analysis: net effect of the Ezetimibe/simvastatin combination (E+simvastatin against placebo) on MI.

The simvastatin dosage was different in the two trials (20 mg/day in SHARP, 40 mg/day in SEAS). The low degree of heterogeneity (I² = 0.0%) should encourage the use of the fixed effect method of pooling. The non-significant overall result shows a trend toward benefit (19% decrement of MI risk, p = 0.051).

Fig 13. Complementary analysis: net effect of the Ezetimibe/simvastatin combination (E+simvastatin against placebo) on Stroke.

The simvastatin dosage was different in the two trials (20 mg/day in SHARP, 40 mg/day in SEAS). The low degree of heterogeneity (I² = 19.8%) should encourage the use of the fixed effect method of pooling. The non-significant overall result shows a trend toward benefit (14% decrement of Stroke risk, p = 0.115).

Fig 14. Complementary analysis: net effect of the Ezetimibe/simvastatin combination (E+simvastatin against placebo) on SAEs.

The simvastatin dosage was different in the two trials (20 mg/day in SHARP, 40 mg/day in SEAS). The low degree of heterogeneity (I² = 0.0%) should encourage the use of the fixed effect method of pooling. The non-significant overall result shows a small trend toward benefit (1% increment of SAEs risk, p = 0.837).