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 (Pinteraction=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.