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Evevident
Original paper
2015NEJMCardiology

IMPROVE-IT

Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes

RCTLipid lowering after ACS

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Overview

After ACS, adding ezetimibe to simvastatin modestly reduced cardiovascular events compared with simvastatin alone.

Clinical takeaway

IMPROVE-IT provided outcomes evidence that nonstatin LDL lowering can reduce events when added to statin therapy. The absolute benefit was modest but important for the lower-is-better LDL principle.

Key result

Primary endpoint at 7 years: 32.7% with ezetimibe-simvastatin vs 34.7% with simvastatin; HR 0.936.

Practice impact

Add ezetimibe when LDL remains above goal despite maximally tolerated statin therapy, especially in secondary prevention.

Evidence

Study design

Randomized, double-blind, placebo-controlled trial.

Enrollment

18,144

Follow-up

Median 6 years; primary endpoint reported as 7-year Kaplan-Meier rate.

Geography

Multinational

Clinical question

Does ezetimibe added to statin therapy reduce cardiovascular events after acute coronary syndrome?

Population

  • Patients recently hospitalized for acute coronary syndrome with LDL cholesterol in the protocol-defined range.

Intervention

Ezetimibe plus simvastatin.

Comparator

Simvastatin alone.

Primary outcome

Composite of cardiovascular death, major coronary event, or nonfatal stroke.

Adding ezetimibe to simvastatin modestly reduced the primary composite cardiovascular endpoint.

Hazard ratio / 0.936 / CI 95% CI 0.89-0.99 / p=0.016

Key results

  • Primary endpoint at 7 years: 32.7% with ezetimibe-simvastatin vs 34.7% with simvastatin; HR 0.936; 95% CI 0.89-0.99; p=0.016.
  • Median time-weighted LDL cholesterol: 53.7 mg/dL with ezetimibe-simvastatin vs 69.5 mg/dL with simvastatin; p<0.001.
  • Prespecified muscle, gallbladder, hepatic adverse effects, and cancer were similar between groups.

Harms

  • Prespecified muscle, gallbladder, hepatic adverse effects, and cancer were similar between groups.

Clinical Use

When to cite

  • When justifying ezetimibe as an outcomes-proven add-on LDL-lowering therapy.

Practice impact

  • Supported adding ezetimibe for residual LDL risk after ACS when statin therapy alone is insufficient.
  • Strengthened the concept that LDL lowering beyond statins can improve outcomes.

Applicability

  • Most applicable to secondary-prevention patients after ACS with residual LDL above target on statin therapy.

Limitations

  • Absolute risk reduction was modest.
  • Comparator was simvastatin rather than universal modern high-intensity statin optimization.
  • Post-ACS trial; not a primary-prevention trial.

Common misinterpretations

  • Do not present ezetimibe as having a large mortality effect in IMPROVE-IT.

Related evidence

4S - Earlier TrialFOURIER - Later TrialODYSSEY OUTCOMES - Later Trial

Citation

Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015;372(25):2387-2397. doi:10.1056/NEJMoa1410489

Ezetimibe resulted in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes.