Presented during a Clinical Trial Update Sessionat the AHA Scientific Sessions 2014

Background

The IMPROVE-IT trial was a multicentre, double-blind, randomised study to determine the clinical benefit and safety of an ezetimibe/simvastatin combination pill (EZ/Simva) in comparison with simvastatin monotherapy, in high-risk individuals presenting with acute coronary syndrome.
Ezetimibe inhibits the Niemann-Pick C1-like 1 (NPC1L1) protein, which is mostly localised in the epithelium of the gastrointestinal tract. Ezetimibe inhibits cholesterol absorption and gives 20% extra LDL-c lowering when given in addition to statins. It has recently been shown that polymorphisms in the NPC1L1 gene are associated with lower LDL-c levels and a lower cardiovascular (CV) risk.
In the intention-to-treat analysis a 6.4% treatment effect (HR: 0.936, 95%CI: 0.887-0.988, P=0.016) was observed for the primary composite endpoint of CV mortality, myocardial infarction, documented unstable angina requiring hospital admission, coronary revascularisation (>30 days) or stroke. Here, the on-treatment analyses are presented (total: 60.298 patient years). Patients who reported that they had not taken the drug were excluded from analysis, and data were censored at least 30 days after the last dose or the last complete endpoint ascertainment of clinical events.

Main results

• LDL-c values after 1 year were 69.5 mg/dL on Simva, and 52.5 mg/dL on EZ/Simva.
• With regard to the primary endpoint, a significant treatment effect of 7.6% was seen in EZ/Simva-treated patients (cumulative event rate: 32.4% after 7 years), as compared with Simva (29.8%) (HR: 0.924, 95%CI: 0.868-0.983, P=0.012).
  The on-treatment analysis thus shows a 19% larger treatment effect than the intention-to-treat analysis.
• Also treatment effects with regard to the secondary endpoints were better for EZ/Simva in the on-treatment analysis.
• When the cut-off point for censoring the data was increased to 6 months or 12 months, the number of events was higher in the on-treatment analysis, resulting in a progressively higher treatment effect.
• No significant differences were seen between treatment groups with regard to the occurrence of muscle- or gall bladder-related adverse effects.

Conclusion
These analyses of the on-treatment population of the IMPROVE-IT trial confirm the findings of the intention-to-treat population, namely that addition of ezetimibe to statins can further reduce the number of serious vascular events.

Also read about the results of the intention-to-treat analysis of the IMPROVE-IT trial
News • 17-11-2014

Even lower LDL-c levels obtained with addition of ezetimibe indeed lower CV risk beyond statins

AHA 2014 The IMPROVE-IT trial shows that extra LDL-c reduction obtained with ezetimibe, in high-risk patients already on statins, lowers the incidence of future CV events.