IMPROVE-IT Trial Summary: LDL-Cholesterol Management After Acute Coronary Syndrome
Trial Design and Dosing
The IMPROVE-IT trial randomized 18,144 adults ≥50 years hospitalized for acute coronary syndrome to ezetimibe 10 mg plus simvastatin 40 mg versus placebo plus simvastatin 40 mg, with a median follow-up of 6 years. 1
- Patients were enrolled within 10 days of ACS (median 5 days to randomization) 1
- Eligibility required baseline LDL-C ≥70 mg/dL (or 50-100 mg/dL if already on lipid-lowering therapy) 1
- Mean baseline LDL-C was 93.8 mg/dL in both treatment arms 1
- The cohort comprised 29% STEMI and 71% UA/NSTEMI patients 1
LDL-Cholesterol Reduction Achieved
- At 1 year, ezetimibe produced a 24% greater LDL-C reduction compared with placebo 1
- On-treatment LDL-C levels achieved: 53.2 mg/dL in the ezetimibe group versus 69.9 mg/dL in the placebo group 1
- This represents an absolute additional reduction of approximately 16.7 mg/dL from adding ezetimibe 1, 2
Primary Cardiovascular Outcomes and Statistical Significance
The primary composite endpoint (cardiovascular death, non-fatal MI, unstable angina rehospitalization, coronary revascularization ≥30 days, or non-fatal stroke) was reduced with a hazard ratio of 0.936 (95% CI 0.887-0.996; p=0.016), corresponding to a 6.4% relative risk reduction and approximately 2% absolute risk reduction over 6 years. 1, 3
- The benefit manifested early after the index ACS and persisted throughout the 6-year follow-up 1
- When total recurrent events were analyzed, cardiovascular events were reduced by 9% (incidence-rate ratio 0.91; 95% CI 0.85-0.97; p=0.007) 1
- Non-fatal MI was reduced by 13% (RR 0.87; p=0.004) 1
- Non-fatal stroke was reduced by 20% (RR 0.77; p=0.005) 1, 2
Significance of High-Risk Subgroups
Patients with diabetes mellitus derived the greatest absolute benefit: 5.5% absolute risk reduction over 7 years (event rates 40.0% vs 45.5%; HR 0.85,95% CI 0.78-0.94) with significant interaction (p=0.02). 1
- The treatment effect was consistent regardless of baseline LDL-C level: HR 0.92 for 50-<70 mg/dL, HR 0.93 for 70-<100 mg/dL, HR 0.94 for 100-125 mg/dL (interaction p=0.95) 1
- Other high-risk subgroups showing benefit included patients with prior CABG, history of stroke, polyvascular disease, renal dysfunction, and prior heart failure 1
- Women experienced a 12% risk reduction (HR 0.88; 95% CI 0.79-0.99) compared with 5% in men (HR 0.95; 95% CI 0.90-1.01), though the interaction was not statistically significant (p=0.26) 2
Safety Profile
- Adding ezetimibe to simvastatin did not increase adverse-event rates compared with placebo 1
- No safety concerns emerged even when median LDL-C fell to 53 mg/dL, with the regimen well-tolerated throughout the 6-year period 1, 3
- Safety was comparable across all high-risk subgroups 1
Current Guideline Integration (ACC/AHA 2025)
For ACS patients with LDL-C ≥70 mg/dL on maximally tolerated statin therapy, adding a non-statin agent (including ezetimibe) is a Class I recommendation to reduce major adverse cardiovascular events. 4, 1
- For ACS patients on maximally tolerated statin with LDL-C 55-69 mg/dL, adding ezetimibe is reasonable (Class IIa), especially in high-risk groups 1
- Concurrent initiation of ezetimibe with a maximally tolerated statin at the time of ACS hospitalization may be considered (Class IIb) 1
Critical Context for Clinical Application
- IMPROVE-IT used moderate-intensity simvastatin 40 mg, whereas current ACC/AHA guidelines recommend initiating high-intensity statin first (atorvastatin 40-80 mg or rosuvastatin 20-40 mg) before adding ezetimibe 4, 1
- The trial's target LDL-C goal of <70 mg/dL has been superseded by current recommendations of <55 mg/dL for very high-risk ACS patients 1
- Do not delay ezetimibe in diabetic ACS patients with LDL-C ≥70 mg/dL, as they achieve the greatest absolute benefit (5.5% reduction over 7 years, NNT=18) 1
- Do not de-escalate high-intensity statin therapy even when LDL-C falls to ~53 mg/dL; safety data show no adverse signal at very low LDL-C levels 1