IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) - ezetimibe plus statin in high risk patients with cardiovascular disease

IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial)

• study randomized 18,000 stabilized acute coronary syndrome patients (about 40% of them from North America) to either 40 mg simvastatin or 10 mg ezetimibe/40 mg simvastatin
  • patients who had LDLs higher than 79 mg/dL were up-titrated to 80 mg simvastatin
    • 27% of the simvastatin patients required higher doses as did 6% of the ezetimibe/simvastatin patients
  • patients were followed at 30 days and then every 4 months until the trial had accumulated 5,250 events, defined as MI, stroke, cardiovascular death, revascularization, or hospitalization for unstable angina

Findings:

• in high-risk patients, adding ezetimibe to statin therapy reduced LDL cholesterol by an average of 17 mg/dL (0.4 mmol/L) and reduced cardiovascular events compared with statin therapy alone
  
  
• finding from the 18,000-patient IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) trial marks the first time that adding a nonstatin lipid-lowering therapy to a statin demonstrated a clinical benefit
  
  
• niacin, fibrates, and CETP inhibitors added to statins have all failed to achieve a benefit
  • however this trial showed that ezetimibe plus simvastatin reduced the rate of cardiovascular death, myocardial infarction, or stroke by 2 percentage points (34.7% for simvastatin alone versus 32.7% for ezetimibe plus simvastatin) in IMPROVE-IT, which represented 270 fewer events over 7 years of follow-up
    
    
• no statistically significant difference in cancer, muscle, or gallbladder-related events
  
  
• treating 100 patients would prevent two events over a seven year period
  
  
• at 1 year, the average LDL-C in the simvastatin arm was 69.9 mg/dL versus 53.2 mg/dL in the ezetimibe/simvastatin group. There was no difference in HDL-C, nor was there a difference in highly-sensitive CRP, which is considered a marker for increased risk of cardiovascular events
  
  
• note that 42% of patients, regardless of treatment, stopped the study drug before the end of the trial
  
  
• average age of patients was 64 and about a fourth were women. At baseline the average LDL-C was 95 mg/dL (approx 2.4 mmol/L)
  
  
• this study is supportive of the the theory that the lower the LDL the better in terms of reduction of cardiovascular risk

Reference:

• AHA: IMPROVE-IT ((IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) - announcement of results of trial (November 17th 2014).