For a patient who recently had an acute coronary syndrome and is on a maximally tolerated statin but still has LDL‑C above guideline target, does adding ezetimibe improve cardiovascular outcomes as demonstrated in the IMPROVE‑IT trial?

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Last updated: February 10, 2026 • View editorial policy

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IMPROVE-IT Trial: Ezetimibe Added to Statin After Acute Coronary Syndrome

Add ezetimibe 10 mg daily to statin therapy in all post-ACS patients with LDL-C ≥70 mg/dL on maximally tolerated statin, and strongly consider it even when LDL-C is 55-69 mg/dL, as the IMPROVE-IT trial demonstrated a 6.4% relative risk reduction in major adverse cardiovascular events over 6 years. 1

Trial Design and Population

  • IMPROVE-IT randomized 18,144 adults ≥50 years who were hospitalized for ACS within 10 days (median 5 days to randomization) to ezetimibe 10 mg + simvastatin 40 mg versus placebo + simvastatin 40 mg, with median follow-up of 6 years. 1, 2

  • Eligibility required LDL-C ≥50 mg/dL and ≤125 mg/dL (≤100 mg/dL if already on lipid-lowering therapy), with median baseline LDL-C of 69.5 mg/dL at enrollment. 1

  • The trial included both STEMI (29%) and UA/NSTEMI (71%) patients, with 34% already on statin therapy at the time of their ACS event. 1, 3

LDL-C Lowering Achieved

  • Ezetimibe produced an additional 24% greater LDL-C reduction compared with placebo, achieving a median on-treatment LDL-C of 53.2 mg/dL versus 69.9 mg/dL in the simvastatin monotherapy group at 1 year. 2, 4

  • The absolute LDL-C difference between treatment arms was approximately 17-20 mg/dL across all baseline LDL-C strata. 5

Cardiovascular Outcomes: Primary Endpoint

  • The primary composite endpoint (cardiovascular death, nonfatal MI, unstable angina rehospitalization, coronary revascularization ≥30 days, or nonfatal stroke) was reduced with hazard ratio 0.936 (95% CI 0.887-0.996; p=0.016), representing a 6.4% relative risk reduction and approximately 2% absolute risk reduction over 6 years. 1, 2

  • Benefit manifested early after the index ACS and persisted throughout the entire 6-year follow-up period. 2

  • Total cardiovascular events (including recurrent events beyond the first) were reduced by 9% (incidence-rate ratio 0.91; 95% CI 0.85-0.97; p=0.007), more than doubling the number of events prevented compared with examining only first events. 4

Benefit Across Baseline LDL-C Levels

  • The treatment effect was consistent regardless of baseline LDL-C: HR 0.92 (95% CI 0.80-1.05) for LDL-C 50-<70 mg/dL, HR 0.93 (95% CI 0.87-1.01) for 70-<100 mg/dL, and HR 0.94 (95% CI 0.86-1.03) for 100-125 mg/dL (p interaction=0.95). 5

  • Normalized relative risk reductions per 1-mmol/L (~39 mg/dL) LDL-C difference were 21% in patients with baseline LDL-C 50-<70 mg/dL, 16% in those with 70-<100 mg/dL, and 13% in those with 100-125 mg/dL. 5

High-Risk Subgroups With Enhanced Benefit

  • Diabetes mellitus patients achieved the greatest absolute benefit: 7-year absolute risk reduction of 5.5% (event rates 40.0% vs 45.5%; HR 0.85,95% CI 0.78-0.94) with significant interaction (p=0.02). 2

  • Other high-risk subgroups deriving benefit included patients with:

    • Prior coronary artery bypass graft 2
    • History of stroke 2
    • Polyvascular disease 2
    • Renal dysfunction 2
    • Prior heart failure 2

Safety Profile

  • Adding ezetimibe to simvastatin did not increase adverse-event rates compared with placebo, and safety was comparable across all high-risk subgroups. 2

  • No safety concerns emerged even when median LDL-C fell to 53 mg/dL, and the regimen was well-tolerated over the full 6-year period. 2

Current ACC/AHA Guideline Recommendations

Class I (Should Be Done)

  • In patients with ACS and LDL-C ≥70 mg/dL on maximally tolerated statin therapy, add a non-statin agent (including ezetimibe) to reduce major adverse cardiovascular events. 1, 6

Class IIa (Reasonable)

  • For ACS patients on maximally tolerated statin with LDL-C 55-69 mg/dL, adding ezetimibe is reasonable to further lower MACE risk, especially in high-risk groups (diabetes, elderly, polyvascular disease). 1, 2, 6

Class IIb (May Be Considered)

  • Concurrent initiation of ezetimibe with a maximally tolerated statin at the time of ACS hospitalization may be considered to accelerate achievement of LDL-C goals. 1, 6

Clinical Implementation Algorithm

Step 1: Statin Initiation or Intensification

  • If not on a statin or on low/moderate intensity, start high-intensity statin (atorvastatin 40-80 mg or rosuvastatin 20-40 mg) before hospital discharge. 1, 2, 6

  • Note that IMPROVE-IT used moderate-intensity simvastatin 40 mg; current guidelines recommend high-intensity statin first. 2

Step 2: Lipid Reassessment

  • Check fasting lipid panel 4-8 weeks post-discharge. 2, 6

Step 3: LDL-C ≥70 mg/dL on Maximally Tolerated Statin

  • Add ezetimibe 10 mg daily (Class I recommendation). 1, 6

  • Anticipated additional LDL-C reduction of 15-25%. 1, 2

  • Goal: LDL-C <55 mg/dL. 2, 6

Step 4: LDL-C 55-69 mg/dL on Maximally Tolerated Statin

  • Adding ezetimibe is reasonable (Class IIa), especially in high-risk groups: diabetes, elderly, high TIMI score, polyvascular disease. 2, 6

Step 5: LDL-C ≥70 mg/dL Despite Statin + Ezetimibe

  • Consider a PCSK9 inhibitor (evolocumab or alirocumab) for an additional ~50-60% LDL-C reduction. 2, 6

Critical Pitfalls to Avoid

  • 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. 2, 6

  • 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). 2

  • Do not accept suboptimal LDL-C levels; only 22% of very high-risk secondary prevention patients in Europe meet LDL-C targets <55 mg/dL. 6

  • Recognize that IMPROVE-IT used moderate-intensity statin (simvastatin 40 mg); current ACC/AHA guidance recommends initiating high-intensity statin first before adding ezetimibe. 1, 2

  • Do not assume lack of benefit in patients with baseline LDL-C <70 mg/dL; IMPROVE-IT demonstrated consistent benefit even in patients with baseline LDL-C 50-<70 mg/dL. 5

Evidence Quality

  • The trial was double-blind, adequately powered, and employed appropriate randomization, with only modest limitation of 19% loss to follow-up. 2

  • Total events analysis (including recurrent events) more than doubled the number of events prevented, driven by reductions in nonfatal MI (RR 0.87; p=0.004) and nonfatal stroke (RR 0.77; p=0.005). 4

References

1
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

2
Guideline

Ezetimibe Added to Statin Therapy After Acute Coronary Syndrome: Evidence and Guideline Recommendations

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

6
Guideline

Non-Statin Lipid-Lowering Therapy in Acute Coronary Syndrome

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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