Ezetimibe in high-risk, previously treated statin patients: a systematic review and network meta-analysis of lipid efficacy

Abstract

Purpose

While statins are used as first-line treatments for high-risk patients with hypercholesterolemia, statin monotherapy is often insufficient to achieve target low-density lipoprotein cholesterol (LDL-C) levels. Second-line treatment options include up-titration of statin dose, switching to a more potent statin, or combination therapy, e.g., with ezetimibe. The aim of this study was to evaluate the efficacy of adding ezetimibe to simvastatin, atorvastatin, or rosuvastatin monotherapy versus doubling the dosage or switching to a higher-potency statin in a population of patients with hypocholesterolemia at high risk of cardiovascular disease (CVD) and who had been previously treated with a statin.

Methods

A systematic literature search was performed and evidence bases were established for populations of atorvastatin-, simvastatin-, and rosuvastatin-experienced patients using eligible randomized controlled trials (RCTs). Based on the available data, we constructed networks of evidence and conducted a Bayesian network meta-analysis (NMA) within each statin population. The primary outcome of interest was percent change from baseline in LDL-C. Changes in total cholesterol were explored as a secondary outcome.

Findings

Across all patient populations, 35 RCTs were identified and included in the evidence base. Among patients on simvastatin therapy, the addition of ezetimibe resulted in a mean difference (MD) in LDL-C of − 13.62% (95% CrI − 19.99, − 6.91; see table below) compared to doubling the starting dose of simvastatin. In the population of patients on atorvastatin therapy, the addition of ezetimibe resulted in an MD in LDL-C of − 14.71% (95% CrI − 16.46, − 12.95) compared to doubling the starting dose of atorvastatin. The addition of ezetimibe to rosuvastatin resulted in an MD in LDL-C of − 14.96% (95% CrI − 17.79, − 12.11), compared to doubling the starting rosuvastatin dose. Similar trends were observed for changes in total cholesterol.

Implications

Given the available data, the addition of ezetimibe to ongoing simvastatin, atorvastatin, or rosuvastatin monotherapy offers greater reduction in LDL-C among patients at high risk of CVD compared to doubling the initial statin dose.

Appendices

Appendix 1: Search strategies.

A comprehensive systematic search of the literature was conducted of Medline, EMBASE, and Cochrane Central Register of Controlled Trials databases with a pre-specified search strategy.

The combined search strategy for Medline and EMBASE using OVID is presented as follows:

• 1. randomized controlled trial.pt.;

• 2. (random$ or placebo$ or single blind$ or double blind$ or triple blind$).ti,ab.;

• 3. (retraction of publication or retracted publication).pt.;

• 4. 1 or 2 or 3;

• 5. (animals not humans).sh.;

• 6. ((comment or editorial or meta-analysis or practice-guideline or review or letter or journal correspondence) not “randomized controlled trial”).pt.;

• 7. (random sampl$ or random digit$ or random effect$ or random survey or random regression).ti,ab. not “randomized controlled trial”.pt.;

• 8. 5 or 6 or 7;

• 9. 4 not 8;

• 10. (random$ or placebo$ or single blind$ or double blind$ or triple blind$).ti,ab.;

• 11. RETRACTED ARTICLE/;

• 12. 10 or 11;

• 13. (animal$ not human$).sh,hw.;

• 14. (book or conference paper or editorial or letter or review).pt. not exp randomized controlled trial/;

• 15. (random sampl$ or random digit$ or random effect$ or random survey or random regression).ti,ab. not exp randomized controlled trial/;

• 16. 13 or 14 or 15;

• 17. 12 not 16;

• 18. 9 or 17;

• 19. (cholesterol OR lipid OR hypercholesterolaemia OR hypercholesterolemia OR hyperlipidaemia OR hyperlipidemia OR dyslipidaemia OR dyslipidemia).ti.ab

• 20. (statin or simvastatin or atorvastatin or rosuvastatin or ezetimibe).ti,ab.;

• 21. 18 and 19 and 20;

• 22. limit 21 to human;

• 23. remove duplicates from 22;

• 24. limit 23 to yr="1990-Current”.

.pt. denotes a publication type term;

.ab. denotes a word in the abstract;

.sh. denotes a medical subject heading (MeSH) term;

.ti. denotes a word in the title.

The following search strategy was be used for the Cochrane Central Register of Controlled Trials (clinical trials):

“hyperlipidemia” OR “hypercholesterolemia” OR “hypercholesterolaemia” OR “dyslipidemia” OR “dyslipidaemia” in all fields.

Appendix 2: Statin potency relationships according to the National Institute for Clinical Excellence (NICE)

Atorvastatin	Rosuvastatin	Simvastatin
–	–	10 mg
–	–	20 mg
10 mg	5 mg	40 mg
20 mg	10 mg	80 mg
40 mg	20 mg	–
80 mg	40 mg	–

This table was reproduced from the National Clinical Guideline Centre [15].

Appendix 3: Baseline characteristics

See Tables 4 and 5.

Table 4 Baseline patient characteristics of included studies, arranged by prior statin

Table 5 Laboratory measures at baseline, arranged by prior statin

Appendix 4: Evidence base and results of NMA for total cholesterol

Presented here are the evidence bases and respective NMA results for the change from baseline in total cholesterol outcome, arranged by patient treatment experience.

See Figs. 4, 5 and Tables 6, 7 and 8.

Fig. 4

Network diagrams of evidence for change from baseline in total cholesterol. a Simvastatin experienced, b atorvastatin experienced, c rosuvastatin experienced. HP higher potency, LP lower potency, EP equal potency, SIM simvastatin, RO rosuvastatin, AT atorvastatin, EZ ezetimibe. Doses in brackets indicate the baseline or run-in statin dose

Fig. 5

Modeled outcomes for change from baseline in total cholesterol. HP higher potency, LP lower potency, EP equal potency, SIM simvastatin, RO rosuvastatin, AT atorvastatin, EZ ezetimibe

Table 6 Mean differences in mean percent change from baseline in total cholesterol among simvastatin-experienced patients from random-effects network meta-analysis

Table 7 Mean differences in mean percent change from baseline in total cholesterol among atorvastatin-experienced patients from random-effects network meta-analysis

Table 8 Mean differences in mean percent change from baseline in total cholesterol among rosuvastatin-experienced patients from fixed-effects network meta-analysis