Statin–Ezetimibe Combination Therapy versus Statin Monotherapy in Atherosclerotic Cardiovascular Disease: A Prespecified Secondary Analysis of the Randomized Ez-PAVE Trial

BACKGROUND: In a target-directed low-density lipoprotein cholesterol (LDL-C)–lowering strategy, the impact of the initial treatment regimen has not been investigated in patients with atherosclerotic cardiovascular disease. We compared the efficacy and safety of initial statin–ezetimibe combination therapy versus statin monotherapy within intensive or conventional LDL-C–targeting strategies. METHODS: In this prespecified second randomization of the randomized Ez-PAVE trial (Effects of Ezetimibe Combination Therapy for Patients With Atherosclerotic Cardiovascular Disease: Randomized Comparison of LDL Cholesterol Targeting <70 versus <55 mg/dL) conducted at 17 centers in South Korea, a total of 3048 patients with atherosclerotic cardiovascular disease were enrolled between January 2021 and July 2022. Following the first randomization to either an intensive (<55 mg/dL) or conventional (<70 mg/dL) LDL-C–targeting strategy, patients underwent subsequent randomization (initial statin–ezetimibe combination therapy [n=1525] versus statin monotherapy [n=1523]) and were followed up for 3 years. Lipid-lowering therapy was adjusted according to a predefined protocol to achieve LDL-C targets. The primary end point was a 3-year composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, any revascularization, or hospitalization for unstable angina. RESULTS: The mean±SD age was 64.4±9.0 years, and 638 patients (20.9%) were female. The incidence of the primary end point did not differ between statin–ezetimibe combination therapy (128 patients [8.5%]) and statin monotherapy (119 patients [7.9%]; hazard ratio, 1.07 [95% CI, 0.83–1.37]; P =0.596). Patients who received statin–ezetimibe combination therapy achieved lower median LDL-C levels during follow-up than those who received statin monotherapy in both the intensive-targeting (53 mg/dL [interquartile range, 45–62 mg/dL] versus 62 mg/dL [interquartile range, 53–74 mg/dL]) and conventional-targeting (63 mg/dL [interquartile range, 55–73 mg/dL] versus 70 mg/dL [interquartile range, 62–81 mg/dL]) strategies. During follow-up, ezetimibe was added to the treatment regimen of 241 patients (34.3%) and 177 patients (24.8%) who initially received statin monotherapy in the intensive- and conventional-targeting strategies, respectively. The treatment effect of intensive-targeting versus conventional-targeting strategies was consistent regardless of therapy regimens without significant heterogeneity ( P interaction =0.583). The safety end points were similar between the groups. CONCLUSIONS: Within a target-directed LDL-C–lowering strategy, cardiovascular efficacy and safety did not differ significantly, whether initiated as statin–ezetimibe combination therapy or as statin monotherapy, but combination therapy facilitated achievement of a lower LDL-C target. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04626973.