Ezetimibe in Combination With Statins Ameliorates Endothelial Dysfunction in Coronary Arteries After Stenting: The CuVIC Trial (Effect of Cholesterol Absorption Inhibitor Usage on Target Vessel Dysfunction After Coronary Stenting), a Multicenter Randomized Controlled Trial

Takase S, Matoba T, Nakashiro S, et al.
Arterioscler Thromb Vasc Biol 2017;37: published online ahead of print

Background

High rates of cholesterol absorption have been associated with more recurrent coronary events under statin therapy, even with equivalent levels of LDL-c, and there are data showing that the statin-related decrease in coronary events is blunted in coronary artery disease (CAD) patients with high rates of cholesterol absorption [1,2]. In these patients, ezetimibe may be of clinical benefit when given on top of statins, by acting via different mechanisms. However, the effects of ezetimibe on coronary endothelial function in association with coronary events is unclear.

Coronary endothelial dysfunction (CED) precedes atherogenesis and plays an important role in the progression of atherosclerosis and CAD. In this study, the CuVIC trail (Effect of Cholesterol Absorption Inhibitor Usage on Target Vessel Dysfunction after Coronary), it was evaluated whether the combined treatment with ezetimibe and statins, improves coronary endothelial function, compared with statin monotherapy that results in equivalent target LDL-c levels (≤100 mg/dL). This effect was studied in patients after coronary stenting, who were allocated either to statin monotherapy (S arm, N = 131), or to the combination of ezetimibe and statins (E+S arm, N = 129).

Main results

• The incidence of target vessel dysfunction (TVD, including target vessel-related death, nonfatal myocardial infraction, ischemia-drive repeat revascularisation and CED) after 6 to 8 months of follow-up was significantly lower in the E+S arm compared with the S arm (43% vs. 62%; P=0.0059; χ² test).
• The incidence of target vessel failure (TVF) at follow-up was 21% in the S arm versus 12% in the E+S arm (P=0.0831, χ² test), with no target vessel–related deaths in either arm, and 1 target vessel–related myocardial infarction in the S arm.
• The cumulative ischemia-driven target vessel revascularisation rates were 20% in the S arm and 12% in the E+S arm (P=0.1162, χ² test), and in all cases, revascularisation was performed at the previously stented site.
• The rate of target lesion revascularisation in ACS cases was not greater than the rate in non–ACS cases (16.0% vs. 15.8%; P=0.97).
• Intracoronary acetylcholine testing in patients without TVF showed that the incidence of coronary endothelial dysfunction (CED) was 52% in the S arm versus 35% in the E+S arm (P=0.0256).
• Incremental doses of acetylcholine induced significant vasoconstriction (P<0.0001, 2-way ANOVA), and ezetimibe treatment significantly inhibited vasoconstriction in response to acetylcholine (P=0.0014, 2-way ANOVA).
• The maximum vasoconstriction induced with low, middle, or high doses of acetylcholine in each subject was 49±19% in the S arm and 43±23% in the E+S arm (P=0.0295, t test), suggesting that lipid-lowering therapy with ezetimibe and statins ameliorates endothelial dysfunction in target coronary arteries.
• The incidence of CED tended to be higher in the high oxysterol tertile (P=0.23, Cochran–Armitage test) and in the high LDL-c category (P=0.30, Cochran–Armitage test), although the statistical analyses were underpowered.
• Prespecified subgroup analyses demonstrated that the benefit of the addition of ezetimibe remained significant among men, patients ≥65 years, with metabolic syndrome, with hypertension, without diabetes, with dyslipidaemia, with a bare metal stent, and with C-reactive protein levels <0.2 mg/dL.  

Conclusion

In the CuVIC trial, ezetimibe, administered with statins, benefited the endothelial function in the stented coronary arteries, compared with statin monotherapy. This may lead to a decrease in future cardiovascular events.

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References

1. Miettinen TA, Gylling H, Strandberg T, et al. Baseline serum cholestenol as predictor of recurrent coronary events in subgroup of Scandinavian simvastatin survival study. Finnish 4S Investigators. BMJ.1998;316:1127–1130.
2. Strandberg TE, Tilvis RS, Pitkala KH, et al. Cholesterol and glucose metabolism and recurrent cardiovascular events among the elderly: a prospective study. J Am Coll Cardiol. 2006;48:708–714.