High-intensity statin monotherapy vs. moderate-intensity statin plus ezetimibe in ASCVD
Long-term efficacy and safety of moderate-intensity statin with ezetimibe combination therapy versus high-intensity statin monotherapy in patients with atherosclerotic cardiovascular disease (RACING): a randomised, open-label, non-inferiority trial
Introduction and methods
Combinations of drugs may be more effective and may be associated with lower risks than increasing doses of one drug . As an alternative to high-intensity statin monotherapy, ezetimibe may be added to lower-intensity statin. This treatment strategy could lead to a reduction in the potential intolerances and adverse events related to high-intensity statin therapy [2-7]. Two meta-analyses of RCTs showed that lower-intensity statin with ezetimibe combination therapy results in significantly lower LDL-c concentrations, compared with high-intensity statin monotherapy [8,9]. However, no randomized study has examined the long-term effects of these 2 treatment strategies in patients with ASCVD.
Aim of the study
This randomized study compared the 3-year efficacy and safety of moderate-intensity statin plus ezetimibe versus high-intensity statin monotherapy in patients with ASCVD.
The researchers conducted the RACING study, a multicenter, open-label, non-inferiority trial in 26 hospitals in South Korea. Patients aged 19-80 years with ASCVD (n = 3780) were randomized to moderate-intensity statin (rosuvastatin 10 mg once daily) with ezetimibe (10 mg once daily) combination therapy or high-intensity statin (rosuvastatin 20 mg once daily) monotherapy. Randomization was stratified by LDL-c concentration (< 100 mg/dL) and presence of diabetes at baseline. ASCVD was defined as the presence or occurrence of myocardial infarction, acute coronary syndrome, coronary revascularization or other arterial revascularization, ischemic stroke, or PAD. Patients with active liver disease or a life expectancy <3 years, donor organ recipients, and pregnant or lactating women were excluded from participation. Patients were followed up for 3 years.
The primary outcome was a composite of cardiovascular death, major cardiovascular events, or non-fatal stroke within 3 years, for which the noninferiority margin was set at 2%. A major cardiovascular event was defined as coronary or peripheral revascularization or hospitalization for a cardiovascular event, being cardiac ischemia, heart failure or PAD. Secondary efficacy outcomes were (a) an LDL-c concentration < 70 mg/dL at 1, 2, and 3 years; (b) a composite of all-cause death, major cardiovascular events, or non-fatal stroke; and (c) the individual components of the primary and secondary composite outcomes. Secondary safety outcomes were: (a) discontinuation or dose reduction of study medication caused by intolerance; and (b) adverse events, including new-onset diabetes, muscle-, liver-, or gallbladder-related adverse events, and cancer.
- Within 3 years, the primary outcome occurred in 172 of 1894 patients (9.1%) in the combination therapy group and in 186 of 1886 patients (9.9%) in the monotherapy group (absolute difference: -0.78; 90%CI: -2.39 to 0.83: HR: 0.92; 95%CI: 0.75-1.13; p =0.43); this result met the non-inferiority margin of 2.0%, meaning that moderate-intensity statin with ezetimibe combination therapy was non-inferior to high-intensity statin monotherapy.
- At 1, 2 and 3 years, an LDL-c concentration < 70 mg/dL was observed in 74%, 75% and 72% of patients in the combination therapy group, respectively, compared with 55%, 60% and 58% of patients in the monotherapy group, respectively (all p <0.0001).
- Within 3 years, the secondary composite outcome occurred in 176 patients (9.8%) in the combination therapy group and 197 patients (10.4%) in the monotherapy group (absolute difference: -0.62; 90%CI: -2.28 to 1.03: HR: 0.94; 95%CI: 0.77-1.15; p =0.94).
- No significant differences in the occurrence of the individual components of the primary and secondary composite outcomes between the two groups were observed.
- Discontinuation or dose reduction of study medication caused by intolerance was observed in 88 patients (4.8%) in the combination therapy group and in 150 patients (8.2%) in the monotherapy group (p <0.0001).
- There were no significant differences in adverse events between groups.
This multicenter, open-label trial shows that moderate-intensity statin with ezetimibe combination therapy is non-inferior to high-intensity statin monotherapy in patients with ASCVD in the long term. Within 3 years, the primary outcome, which was a composite of cardiovascular death, major cardiovascular events, and non-fatal stroke, occurred equally often in both groups. In the combination therapy group, the percentage of patients with an LDL-c concentration < 70 mg/dL was higher and the percentage of patients in whom treatment had to be discontinued or the dose reduced was lower than in the monotherapy group.