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IMPROVE-IT Trial Summary

Adding ezetimibe to a statin therapy (simvastatin) shows superior results in the reduction of CV events compared to statin therapy alone….

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Low-density lipoprotein (LDL) lowering has been the mainstay of therapy for primary and secondary cardiovascular (CV) prevention, and the data has been supported with statin use. Other non-statin agents such as fibrates, niacin, and high-density lipoprotein (HDL)-raising agents have all failed to show clinical benefit when added to statins.

The IMPROVE-IT trial (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) by Dharam Kumbhani MD, and colleagues studied the safety and efficacy of ezetimibe/simvastatin compared to simvastatin alone in reducing CV events in patients at high risk. They hypothesized that the combination of ezetimibe (a cholesterol absorption inhibitor) with simvastatin would be superior to simvastatin alone in reducing CV events for patients with acute coronary syndrome (ACS).

A total of 18,144 patients were randomized in a 1:1 fashion to receive either ezetimibe 10mg/simvastatin 40mg or simvastatin 40mg. Baseline characteristics were fairly similar between the two arms, and a baseline LDL level were 95mg/dl in both arms.

Results showed a median follow-up average was 53.7 mg/dl versus 69.5 mg/dl in the ezetimibe/simvastatin and simvastatin arms respectively. LDL lowering was seen as early as 1 month, and sustained over the duration of the follow-up. After 1 year, triglycerides were also lowered by 16.7mg/dl in the combination group, while HDL was increased by 0.6mg/dl.

The primary endpoint of CV death/MI/UA/coronary revascularization beyond 30 days/stroke was significantly lower in the combination arm compared to simvastatin alone over the duration of follow-up (32.7% vs. 34.7%, HR 0.94, 95% CI 0.89-0.99; p=0.016). These numbers corresponded to the number needed to treat of 50 patients to prevent one event.

Other endpoints compared cardiovascular events between the two arms including; MI (13.1% vs 14.8%, p= 0.002), stroke (4.2% vs 4.8%, p=0.03) were all significantly lower in the ezetimibe/simvastatin arm. No differences were noted for all-cause mortality, CV mortality, and need for coronary revascularization. On subgroup analysis, diabetic patients seemed to show a greater benefit with ezetimibe/simvastatin (HR=0.86, p for interaction =0.023). No difference was observed for cancer incidence, myopathy, and transaminitis.

These results indicated that in patients post high-risk ACS, combination treatment with ezetimibe 10mg/simvastatin 40mg is superior to simvastatin 40mg alone in reducing CV events. This is the first trial powered for clinical outcomes to show benefit with non-statin agent when added to a statin. This trial reaffirms the hypothesis that lower LDL levels (<60 mg/dl in the combination arm) appears to benefit patients. Future guidelines need to factor in the findings from this landmark trial for patients requiring lipid therapy for secondary prevention.

Practice Pearls:

  • Combination treatment with ezetimibe 10mg/simvastatin 40mg is superior to simvastatin 40mg alone in reducing CV events in patient post high-risk ACS
  • Diabetic patients seemed to show a greater benefit with ezetimibe/simvastatin
  • Trial reaffirms that lower LDL levels appear to benefit patients with CV disease

American College of Cardiology. “Trial Summary of IMPROVE-IT.” Cardiosource, Intl., 17 Nov. 2014. Web. 18 Nov. 2014