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IMPROVE-IT

IMProved Reduction of Outcomes: Vytorin Efficacy International Trial

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Year of Publication: 2015

Authors: Cannon CP, Blazing MA, Giugliano RP, et al.

Journal: New England Journal of Medicine

Citation: Cannon CP, et al. N Engl J Med. 2015;372:2387–97.

Link: https://www.nejm.org/doi/full/10.1056/NEJMoa1410489

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJMoa1410489

Clinical Question

Does ezetimibe added to simvastatin reduce cardiovascular events in patients with recent acute coronary syndrome (ACS)?

Study Overview

Objective

Evaluate whether ezetimibe added to statin therapy reduces cardiovascular events in patients after recent ACS with guideline-level LDL.

Study Summary

In patients stabilized after acute coronary syndrome, adding ezetimibe to simvastatin significantly reduced cardiovascular events compared to simvastatin alone. The benefit emerged after 1 year and was consistent across subgroups, including elderly and diabetic patients.

Intervention

Simvastatin 40 mg + ezetimibe 10 mg daily vs. simvastatin 40 mg + placebo. 18,144 patients with recent ACS (≤10 days) and LDL 50–100 mg/dL (on therapy) or 50–125 mg/dL (not on therapy). Median follow-up 6 years.

Bottom Line

Adding ezetimibe to simvastatin significantly reduced cardiovascular events in post-ACS patients with modest LDL-C lowering benefit.

        Major Points
        IMPROVE-IT was the first trial to demonstrate that adding a non-statin LDL-lowering agent (ezetimibe) to statin therapy produces incremental cardiovascular benefit — supporting the 'LDL hypothesis' that LDL lowering per se (regardless of mechanism) reduces events.
18,144 patients stabilized after acute coronary syndrome — the largest and longest lipid-lowering trial post-ACS. Median follow-up 6 years, providing robust long-term safety and efficacy data.
Between-group LDL-C difference at 1 year (mean) was 69.9 vs 53.2 mg/dL (simvastatin monotherapy vs simvastatin–ezetimibe); median time-weighted average across the trial was 69.5 vs 53.7 mg/dL — a ~24% further reduction. Established that LDL in the low 50s is safe, paving the way for PCSK9 inhibitor trials.
Primary composite endpoint (CV death, MI, unstable angina requiring rehospitalization, coronary revascularization ≥30 days, or nonfatal stroke): 7-year Kaplan-Meier rates 32.7% vs 34.7% (HR 0.936, 95% CI 0.89–0.99, p=0.016) — modest but statistically significant, with ARR 2.0 percentage points.
Ischemic stroke was significantly reduced: 3.4% vs 4.1% (HR 0.79, p=0.008) — ~21% RRR, directly relevant to stroke prevention. Any MI (HR 0.87, p=0.002) and urgent coronary revascularization (HR 0.81, p=0.001) also reached significance.
No mortality benefit: all-cause death 15.4% vs 15.3% (HR 0.99, p=0.78), CV death 6.8% vs 6.9% (HR 1.00, p=1.00) — the lack of mortality benefit despite reduced events was a key criticism.
Consistent with the Cholesterol Treatment Trialists' (CTT) meta-analysis: IMPROVE-IT's between-group LDL difference at 1 year (12.8 mg/dL with imputation) produced a proportional 7.2% lower rate of major vascular events. HR per mmol/L LDL reduction was 0.80 in IMPROVE-IT vs 0.78 in the CTT statin meta-analysis.
Ezetimibe's mechanism (NPC1L1 intestinal cholesterol absorption inhibitor) is distinct from statins — proving that the pathway of LDL lowering matters less than the magnitude, and supporting combination therapy for patients not at goal on statins alone.
Benefit was front-loaded: Kaplan-Meier curves separated after 1 year and continued to diverge through 7 years, suggesting sustained benefit with prolonged therapy.
Directly influenced 2018 AHA/ACC cholesterol guidelines, which for the first time recommended ezetimibe as a second-line agent for patients not at LDL goal on maximally tolerated statin.

      

Design

Study Type: Randomized, double-blind, placebo-controlled trial

Randomization: 1

Blinding: Double-blind

Enrollment Period: October 2005 – July 2010

Follow-up Duration: Median 6 years

Centers: 1147

Countries: 39 countries

Sample Size: 18144

Analysis: Intention-to-treat

Inclusion Criteria

Age ≥50 years.
Hospitalization for acute coronary syndrome (STEMI, NSTEMI, or high-risk unstable angina) within the preceding 10 days — patients must be stabilized post-ACS. (Detailed ACS definitions in Supplementary Appendix.)
LDL-C 50–100 mg/dL (1.3–2.6 mmol/L) if receiving long-term lipid-lowering therapy, or 50–125 mg/dL (1.3–3.2 mmol/L) if not receiving lipid-lowering therapy; measured locally within the first 24 hours after ACS onset.

Exclusion Criteria

Planned coronary artery bypass graft (CABG) surgery for the acute coronary syndrome event.
Creatinine clearance <30 mL/min.
Active liver disease.
Use of statin therapy with LDL-cholesterol-lowering potency greater than simvastatin 40 mg.

Baseline Characteristics

Characteristic	Control	Active
Age (mean, yr)	63.6	63.6
Male (%)	75.9	75.5
White race (%)	84.0	83.6
BMI (mean)	28.3	28.3
Diabetes mellitus (%)	27.3	27.1
Hypertension (%)	61.3	61.6
Current smoker (%)	33.5	32.5
Previous MI (%)	20.7	21.3
Previous PCI (%)	19.8	19.5
Previous CABG (%)	9.3	9.3
On lipid-lowering agent pre-ACS (%)	35.4	35.6
On statin pre-ACS (%)	34.3	34.6
Mean LDL-C at index event (mg/dL)	93.8	93.8
Median time from ACS to randomization (days)	5.0	5.0

Arms

Field	Control	Simvastatin 40 mg + Ezetimibe 10 mg (Vytorin)
Intervention	Simvastatin 40 mg daily + matching ezetimibe placebo. Moderate-intensity statin therapy. LDL-C achieved: mean 69.9 mg/dL at 1 year; median time-weighted average across the trial 69.5 mg/dL. Simvastatin dose could be increased to 80 mg for LDL >79 mg/dL on two consecutive measurements (later restricted after 2011 FDA safety communication).	Combination tablet: simvastatin 40 mg + ezetimibe 10 mg daily. Ezetimibe inhibits NPC1L1 in the intestinal brush border, blocking cholesterol absorption. LDL-C achieved: mean 53.2 mg/dL at 1 year; median time-weighted average across the trial 53.7 mg/dL — a ~24% further reduction beyond statin alone.
Duration	Median 6 years	Median 6 years

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Composite of death from cardiovascular causes, nonfatal MI, unstable angina requiring rehospitalization, coronary revascularization ≥30 days after randomization, or nonfatal stroke (7-year Kaplan-Meier estimates)	Primary	34.7%	32.7%	0.936	0.016
Death from any cause, major coronary event, or nonfatal stroke	Secondary	40.3%	38.7%	0.95	0.03
Death from coronary heart disease, nonfatal MI, or urgent coronary revascularization ≥30 days	Secondary	18.9%	17.5%	0.91	0.02
Death from CV causes, nonfatal MI, hospitalization for unstable angina, all revascularization ≥30 days, or nonfatal stroke	Secondary	36.2%	34.5%	0.95	0.04
ALT, AST, or both ≥3× ULN	Adverse	208/9077 (2.3%)	224/9067 (2.5%)		0.43
Cholecystectomy	Adverse	134/9077 (1.5%)	133/9067 (1.5%)		0.96
Gallbladder-related adverse events	Adverse	321/9077 (3.5%)	281/9067 (3.1%)		0.10
Rhabdomyolysis	Adverse	18/9077 (0.2%)	13/9067 (0.1%)		0.37
Myopathy	Adverse	10/9077 (0.1%)	15/9067 (0.2%)		0.32
Rhabdomyolysis or myopathy	Adverse	28/9077 (0.3%)	27/9067 (0.3%)		0.90
Rhabdomyolysis, myopathy, or myalgia with CK ≥5× ULN	Adverse	58/9077 (0.6%)	53/9067 (0.6%)		0.64
Cancer (any new, relapsing, or progressing; excluding non-melanoma skin cancer)	Adverse	732/9077 (10.2%)	748/9067 (10.2%)		0.57
Death from cancer	Adverse	272/9077 (3.6%)	280/9067 (3.8%)		0.71

Criticisms

Modest absolute risk reduction: 2.0 percentage points at 7 years (Kaplan-Meier estimates; median follow-up 6 years), NNT ~50 — translates to treating 50 post-ACS patients with ezetimibe for years to prevent one additional event. Cost-effectiveness has been debated, though generic ezetimibe availability has improved this.
No mortality benefit: all-cause death HR 0.99 (p=0.78), CV death HR 1.00 (p=1.00) — reducing nonfatal events without affecting mortality raises questions about the clinical meaningfulness of the benefit.
Used moderate-intensity statin (simvastatin 40 mg) rather than high-intensity (atorvastatin 80 mg or rosuvastatin 40 mg) — the trial design predates 2013 guidelines recommending high-intensity statins for all post-ACS patients. Adding ezetimibe to a suboptimal statin regimen may overstate its benefit compared to simply intensifying statin therapy.
Very long enrollment period (2005–2010) and follow-up (up to 7 years KM) — background therapy and practice patterns evolved substantially during the trial, with more patients on optimal medical therapy by trial's end.
Simvastatin 80 mg was restricted mid-trial (2011 FDA safety communication) — some control-arm patients may have received suboptimal LDL lowering when they could have been up-titrated to 80 mg, potentially narrowing the LDL gap between arms.
Industry-sponsored (Merck — manufacturer of both Vytorin and Zetia/ezetimibe) with industry involvement in study design and conduct. Earlier Merck controversy with ENHANCE trial (ezetimibe failed to reduce carotid intima-media thickness) cast a shadow over ezetimibe's credibility.
Primary composite endpoint was broad (5 components including hospitalization for unstable angina and coronary revascularization). While several individual endpoints reached significance (any MI HR 0.87 p=0.002; ischemic stroke HR 0.79 p=0.008; urgent coronary revascularization HR 0.81 p=0.001), there was no benefit for CV death or all-cause mortality.
No PCSK9 inhibitor comparator — by the time IMPROVE-IT reported (2015), PCSK9 inhibitors offered much larger LDL reductions (~60% vs ~24%) and were entering clinical practice. IMPROVE-IT's modest ezetimibe effect was soon overshadowed.
High discontinuation rate: ~42% of patients stopped study drug prematurely — diluting the observed treatment effect and raising generalizability concerns.

Funding

Merck & Co., Inc.

Based on: IMPROVE-IT (New England Journal of Medicine, 2015)