Can you summarize the IMPROVE‑IT trial—its LDL‑C management findings, the drug (ezetimibe) and dose, the patient population (adults with recent acute coronary syndrome on moderate‑intensity simvastatin), and the results?

IMPROVE-IT Trial Summary: LDL Management with Ezetimibe After Acute Coronary Syndrome

The IMPROVE-IT trial definitively established that adding ezetimibe 10 mg daily to simvastatin 40 mg in patients stabilized after acute coronary syndrome reduces major cardiovascular events by 6.4% relative risk over 6 years, with the greatest benefit in diabetic patients who achieved a 5.5% absolute risk reduction. 1

Trial Design & Patient Population

• 18,144 adults ≥50 years hospitalized for acute coronary syndrome within 10 days (median 5 days to randomization) were enrolled in this double-blind, randomized controlled trial 1, 2
• The cohort comprised 29% STEMI and 71% unstable angina/NSTEMI patients; 34% were already receiving statin therapy at the time of their ACS event 1
• Eligibility required baseline LDL-C ≥70 mg/dL (or 50-100 mg/dL if already on lipid-lowering therapy), with a mean baseline LDL-C of 93.8 mg/dL 1
• Patients were followed for a median of 6 years (up to 7 years in some analyses) 1, 3

Drug Regimen & Dosing

• Intervention arm: Ezetimibe 10 mg + simvastatin 40 mg once daily 1, 2
• Control arm: Placebo + simvastatin 40 mg once daily 1
• If consecutive LDL-C measurements exceeded 79 mg/dL at follow-up, simvastatin was uptitrated to 80 mg in a double-blind manner 2
• Ezetimibe mechanism: Blocks intestinal cholesterol absorption via the NPC1L1 protein, typically yielding a 15-25% additional LDL-C reduction when added to statin therapy 1, 4

LDL-C Lowering Achieved

• At 1 year, ezetimibe produced a 24% greater LDL-C reduction compared with placebo 1
• On-treatment LDL-C levels: 53.2 mg/dL in the ezetimibe group versus 69.9 mg/dL in the control group 5, 1
• The absolute LDL-C reduction from baseline was 16.7 mg/dL in men and 16.4 mg/dL in women at 12 months 6
• Final achieved LDL-C in the combination arm was 1.4 mmol/L (53 mg/dL) versus 1.8 mmol/L (70 mg/dL) in the simvastatin monotherapy arm 3

Primary Cardiovascular Outcomes

• 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) 1, 3
• This translates to a 6.4% relative risk reduction and an approximately 2% absolute risk reduction over 6 years 1
• When total recurrent cardiovascular events were analyzed, ezetimibe reduced events by 9% (incidence-rate ratio 0.91; 95% CI 0.85-0.97; p=0.007) 1
• The benefit manifested early after the index ACS and persisted throughout the entire 6-year follow-up period 1

High-Risk Subgroup Benefits

Diabetes Mellitus (Greatest Benefit)

• Diabetic patients achieved a 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 a significant interaction (p=0.02) 1, 7
• The LDL-C reduction was greater in diabetic patients than in those without diabetes 7
• Cardiovascular morbidity and mortality were significantly decreased in diabetic patients, whereas the reduction in non-diabetic patients did not reach statistical significance 7

Women vs. Men

• Women experienced a 12% risk reduction (HR 0.88; 95% CI 0.79-0.99) compared with a 5% reduction in men (HR 0.95; 95% CI 0.90-1.01; P=0.26 for interaction) 6
• When total events were considered, women had an 18% reduction (RR 0.81; 95% CI 0.71-0.94) and men had a 6% reduction (RR 0.94; 95% CI 0.87-1.02; P=0.08 for interaction) 6

Other High-Risk Groups

• Significant benefits were also observed in patients with prior coronary artery bypass graft, history of stroke, polyvascular disease, low baseline LDL-C, renal dysfunction, and prior heart failure 1, 8

Consistency Across Baseline LDL-C Levels

• The treatment effect was consistent regardless of baseline LDL-C: HR 0.92 (50-<70 mg/dL), HR 0.93 (70-<100 mg/dL), HR 0.94 (100-125 mg/dL); interaction p=0.95 1

Safety Profile

• Adding ezetimibe to simvastatin did not increase adverse-event rates compared with placebo 1, 8
• Safety was comparable across all high-risk subgroups, including women and men 1, 6
• 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 1
• Common adverse events (upper respiratory tract infection, diarrhea, arthralgia, sinusitis) occurred at rates similar to placebo 4
• Ezetimibe has minimal drug-drug interaction potential because it does not significantly affect cytochrome P450 enzymes 4

Current ACC/AHA Guideline Recommendations (2025)

Class I (Should Be Done)

• In ACS patients with LDL-C ≥70 mg/dL on maximally tolerated statin therapy, add a non-statin agent (including ezetimibe) to reduce major adverse cardiovascular events 5, 1

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, high TIMI score, polyvascular disease) 1

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

Clinical Implementation Algorithm

Step 1: Statin Initiation/Intensification

• If not already on a high-intensity statin, start atorvastatin 40-80 mg or rosuvastatin 20-40 mg before hospital discharge 5, 1
• Note: IMPROVE-IT used moderate-intensity simvastatin 40 mg, but current guidelines recommend high-intensity statin first 1

Step 2: Lipid Reassessment

• Check fasting lipid panel 4-8 weeks post-discharge 1

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

• Add ezetimibe 10 mg daily (Class I recommendation) 5, 1
• Anticipate an additional 15-25% LDL-C reduction 1, 4
• Goal: LDL-C <55 mg/dL 1

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

• Adding ezetimibe is reasonable (Class IIa), particularly in diabetic patients, elderly, or those with polyvascular disease 1

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 1

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 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) 1, 7
• DO NOT assume lack of benefit in patients with baseline LDL-C <70 mg/dL; IMPROVE-IT demonstrated consistent benefit even in the 50-<70 mg/dL stratum 1
• DO NOT use niacin as an add-on therapy; the AIM-HIGH trial showed that adding extended-release niacin to simvastatin plus ezetimibe improved lipid profiles but did not reduce cardiovascular events and increased adverse effects 1
• DO NOT dose ezetimibe concurrently with bile-acid sequestrants; administer ezetimibe at least 2 hours before or 4 hours after the sequestrant to avoid reduced bioavailability 4

Evidence Quality Assessment

• The IMPROVE-IT trial was double-blind, adequately powered, with appropriate randomization 1
• The only limitation was a 19% loss to follow-up, classified as a mild relevance deficiency 1
• Inclusion of total-event analyses more than doubled the number of events prevented, driven by reductions in non-fatal MI (RR 0.87; p=0.004) and non-fatal stroke (RR 0.77; p=0.005) 1