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Use of statin therapy to treat dyslipidemia in patients with established coronary artery disease is the standard of care worldwide. Given the negative results of a number of trials that tested the use of adjuvant lipid-lowering therapies against a statin background, there has been great scepticism about whether or not non-statin drugs provide incremental benefit.1–3 Ezetimibe inhibits the absorption of both dietary and biliary cholesterol by inhibiting Niemann Pick C1 Like-1 protein.4 Ezetimibe has been the target of much criticism. Based on the ENHANCE trial,5 it appeared to lack efficacy and the SEAS trial6 suggested ezetimibe increased risk for cancer. The current trial was designed to evaluate whether or not the use of ezetimibe provides incremental reduction in risk for acute cardiovascular (CV) events in patients who had sustained an acute coronary syndrome (ACS).
This was a prospective randomised double blind trial and included 18 144 patients over 50 years of age who had sustained an ACS within 10 days of randomisation. Patients were followed for an average of 2.5 years and the trial was concluded when the target number of 5250 CV events had been observed. Median follow-up was 6 years and the trial was concluded at 7 years. All patients were treated with simvastatin 40–80 mg daily and randomised to adjuvant therapy with either placebo or ezetimibe 10 mg daily; mean attained low density-lipoprotein cholesterol (LDL-C) levels in the two groups were 1.8 mmol/L (69.5 mg/dL) and 1.4 mmol/L (53.7 mg/dL), respectively. The primary end point included cardiovascular mortality, non-fatal myocardial infarction (MI), unstable angina requiring hospitalisation, coronary revascularisation (≥30 days after randomisation) and non-fatal stroke.
The event rate for the primary end point at 7 years was 32.7% in the combination therapy group and 34.7% in the simvastatin monotherapy group (HR, 0.936; 95% CI 0.89 to 0.99; p=0.016). The combined end point of cardiovascular mortality, non-fatal MI and stroke was also reduced more with combination therapy (HR, 0.90; 95% CI 0.84 to 0.96; p=0.003). Non-fatal MI (HR, 0.90; 95% CI 0.84 to 0.96; p=0.003), ischaemic stroke (HR, 0.79; 95% CI 0.67 to 0.94; p=0.008) and need for urgent revascularisation ≥30 days after randomisation (HR, 0.81; 95% CI 0.72 to 0.91; p=0.001) were all reduced significantly better by combination therapy compared to statin monotherapy. In prespecified subgroup analysis, patients with diabetes did better than those without diabetes (interaction p=0.023), and patients >75 years of age did better than those <75 years of age (interaction p=0.005), when given combination therapy. There was no increase in risk for cancer or skeletal muscle or liver toxicity between groups. There was no heterogeneity between groups for gender, race or geographical location.
This trial demonstrates for the first time that adjuvant therapy with a non-statin drug provides incremental reduction in risk for CV events when patients are treated with statin therapy following an ACS. Importantly, incremental risk reduction was achieved for men and women, Caucasians and non-Caucasians and people older than 75 years. The trial also provides additional evidence for the conclusion that when it comes to LDL-C, lower is better. Although a cost benefit analysis is yet to be reported, the reductions in non-fatal MI, ischaemic stroke and need for urgent revascularisation were substantial in this high-risk population. Finally, the combination of ezetimibe with a statin was safe and well tolerated.
Implications for practice
Ezetimibe is safe and effective when used in combination with a statin in persons who have sustained an ACS. This trial supports the attainment of lower levels of LDL-C in order to more optimally reduce risk for CV events and need for coronary revascularisation.
Competing interests PPT is a consultant for Amgen, AstraZeneca, Kowa, Merck and Novartis. PPT is also involved in speaker's bureau activities for Amarin, AstraZeneca, Genzyme, GSK, Kowa and Merck.
Provenance and peer review Commissioned; internally peer reviewed.