Moderate-intensity statin combined with ezetimibe versus high-intensity statin monotherapy for secondary cardiovascular risk reduction: a systematic review and meta-analysis
Authors: Cani A , Ayyalu T , Klaassen J , Turch H , Loyola J , Huang E , Gewehr D , Kritya M , Martignoni F 
Published: October 2024

Abstract

Introduction
Intensive lowering of LDL cholesterol levels is recommended for patients with atherosclerotic cardiovascular disease (ASCVD) [1]. Statins are the first-line therapy for secondary prevention [1]. Recent studies such as the RACING trial suggest that the combination of moderate-intensity statins and ezetimibe (MIS+EZE) may achieve a greater LDL cholesterol reduction and a lower adverse event rate than high-intensity statins alone (HIS) [2].

Purpose
The aim of this systematic review and meta-analysis is to assess cardiovascular outcomes and clinical safety of MIS+EZE versus HIS in patients with ASCVD.

Methods
We searched PubMed, Cochrane and Embase for studies that compared MIS+EZE to HIS in patients with ASCVD and included studies reporting cardiovascular mortality, all cause mortality, non-fatal stroke, non-fatal myocardial infarction, unstable angina, coronary revascularization, heart failure, and LDL-C ≤ 70mg/dL. Studies with the same statin dose in both treatment groups and studies with overlapping populations were excluded. Treatment effects for binary endpoints were compared using pooled risk-ratios (RR) with 95% confidence intervals.

Results
Out of 6238 studies, we included 6 RCTs and 2 retrospective cohort studies with 40,236 patients of whom 10,254 were treated with MIS+EZE (25,5%). Mean follow-up ranged from 90 days to 3 years.
Cardiovascular mortality (RR 0.83; CI95% 0.73-0.94; p=0.003), all-cause mortality (RR 0.90; CI95% 0.82-0.98; p=0.02) and non-fatal stroke (RR 0.83; CI95% 0.73-0.93; p=0.002) were significantly lower in patients treated with MIS+EZE compared to those treated with HIS. A significantly higher proportion of patients in the MIS+EZE group reached an LDL-C ≤ 70mg/dL (RR 1.26; CI95% 1.19-1.34; p&lt;0.00001). No statistically significant difference was found for non-fatal myocardial infarction (RR 0.87; CI95% 0.64-1.17; p=0.36), coronary revascularization (RR 1.03; CI95% 0.78-1.35; p=0.83), heart failure (RR 0.95; CI95% 0.86-1.06; p=0.38) and unstable angina (RR 1.52; CI95% 0.62-3.75; p=0.36). A RCT sub-analysis was feasible for cardiovascular mortality and showed no statistically significant difference between the two groups (RR 1.01; CI95% 0.42-2.42; p=0.98).
Regarding safety endpoints, the risk of adverse events (RR 0.84; CI95% 0.74-0.95; p=0.004) and the risk of muscle-related adverse events (RR 0.67; CI95% 0.49-0.92; p=0.01) were significantly lower in MIS+EZE group. The significant reduction in muscle-related adverse events was maintained in the RCT sub-analysis (RR 0.61; CI95% 0.41-0.91; p=0.02). There was no difference between groups in the risk of liver-related adverse events (RR 0.63; CI95% 0.29-1.41; p=0.26) or new-onset malignancy (RR 0.99; CI95% 0.87-1.12; p=0.85).

Conclusion
The combination of moderate-intensity statins and ezetimibe may be considered as an alternative therapeutic strategy to reduce secondary cardiovascular risk with lower rates of drug intolerance.