IMPROVE-IT

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Cannon CP, et al. "Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes". The New England Journal of Medicine. 2015. 375(25):2387-2397.
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Clinical Question

Among individuals with ACS, does ezetimibe+simvastatin reduce CV mortality, major CV event, or nonfatal stroke when compared to simvastatin alone?

Bottom Line

Among individuals with recent ACS, the addition of ezetimibe to moderate-intensity statin therapy is associated with a reduction in CV mortality, major CV event, or nonfatal stroke when compared to statin therapy alone.

Major Points

Ample evidence supports the use of statins for the primary and secondary prevention of CVD and its complications, including death. On the other hand, evidence supporting the use of ezetimibe, a non-statin agent inhibiting small intestinal cholesterol absorption,[1] is conflicting. In fact, the FDA approved ezetimibe for the treatment of hyperlipidemia in 2002 based upon its effect on LDL-cholesterol (LDL-C) and not on its impact on cardiovascular outcomes.[2] Subsequent studies demonstrated that the addition of ezetimibe to statin therapy reduces LDL-C by an additional ~23%.[3] The industry-sponsored 2008 ENHANCE trial[4] failed to demonstrate slowing of progression of atherosclerotic disease when added to statin therapy. Based upon these and other studies, the 2013 ACC/AHA cholesterol guidelines[5] did not include ezetimibe in the treatment algorithm given insufficient evidence for prevention CVD outcomes. A trial demonstrating effectiveness of ezetimibe was needed in order for the medication to remain relevant.

Published in 2015, the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) randomized 18,144 patients with ACS to simvastatin 40 mg/d plus ezetimibe 10 mg/d or simvastatin alone. With median follow-up of 6 years, simvastatin+ezetimibe was found to reduce the primary outcome of CV mortality, major CV event, or nonfatal stroke (34.7% vs. 32.7%; P=0.016; NNT 50). There was no reduction in all-cause or CV mortality with simvastatin+ezetimibe, though there was a reduction in MI and stroke.

There are currently two leading hypotheses to explain the effects of statins and other lipid-modifying agents on CV outcomes: 1) the LDL hypothesis posits that any reduction in LDL-C should lead to improved outcomes; 2) the statin hypothesis suggests it is the pleiotropic effects of statins and not specifically the lipid lowering itself that accounts for improvements in CV outcomes.[6] IMPROVE-IT is the first trial to show that adding a non-statin lipid-modifying agent in concert with a statin improves CV outcomes in addition to enhancing lipid lowering effects. The reduction in LDL-C was associated with a decreased CV event rate. While this trial does not prove that this effect was a result of lowering LDL-C alone, it does support the LDL hypothesis that lipid lowering improves CV outcomes.

At the time of enrollment in this trial, guidelines suggested the lowering of LDL to less than 70 mg/dL in patients with ACS on the basis of the PROVE IT-TIMI 22 and MIRACL trials.[7] Modern guidelines[5] recommend high-intensity statin therapy (eg, atorvastatin 40-80 mg/d or rosuvastatin 20-40 mg/d). Simvastatin 40 mg/d is considered a moderate-intensity statin and is not standard-of-care for this high-risk group.

Guidelines

As of June 2015, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, double-blind, randomized controlled trial
  • N=18,144 patients
    • Simvastatin (n=9,077)
    • Simvastatin+ezetimibe (n=9,067)
  • Setting: 1,147 sites in 39 countries
  • Enrollment: 2005-2010
  • Median follow-up: 6 years
  • Analysis: Intention-to-treat
  • Primary outcome: CV mortality, major CV event, or nonfatal stroke

Population

Inclusion Criteria

  • Either sex, age ≥50 years
  • Hospitalized in prior 10 days for ACS (acute MI with or without ST-segment elevation) or high-risk unstable angina
  • LDL-C ≥50mg/dL
  • Maximum LDL-C:
    • Patients who were not receiving long-term lipid-lowering therapy, the maximum LDL-C for enrollment was 125 mg/dL
    • Patients on chronic lipid-lowering therapy, the maximum LDL-C was 100 mg/dL
  • Fasting TG ≤350 mg/dL

Exclusion Criteria

  • Clinically-unstable (eg, cardiogenic shock)
  • Recurrent ischemia symptoms
  • Stroke or TIA
  • Arrhythmia (eg, VF, SVT >30 sec, high-grade second-degree heart block)
  • Planned CABG for ACS event
  • CrCl <30 mL/min
  • Active liver disease
  • Use of statin therapy that had LDL-C lowering potency greater than 40mg of simvastatin (including any simvastatin+ezetimibe combinations)
  • Need to continue medications with CYP3A4 activity
  • Alcohol or drug abuse
  • Lactating women or women of childbearing potential without effective contraception
  • Investigator discretion
  • Investigational drug in prior 30 days or prior enrollment in the study

Baseline Characteristics

From the simvastatin group.

  • Demographics: Age 64 years, male 76%, White race 84%
  • Vital measurements: BMI 28 mg/kg2
  • PMH: DM 27%, HTN 61%, HF 4%, PAD 6%, smoker 34%, MI 21%
  • PSH: PCI 20%, CABG 9%
  • Medications: Lipid-lowering 35%, statin 34%, ASA 42%
  • Laboratory: CrCl 85 mL/min, LDL-C 94 mg/dL
  • Post-ACS medications: ASA 97%, thienopyridine 86%, beta blocker 87%, ACE-inhibitor or ARB 76%

Interventions

  • Randomization to simvastatin 40mg daily plus placebo or simvastatin 40mg daily plus ezetimibe 10mg daily
    • For patients with LDL-C >79 mg/dL on two consecutive measurements, the simvastatin dose was increased to 80mg daily
      • This was subsequently modified to reflect FDA recommendations against use of simvastatin 80 mg[8]
  • Both groups received standard medical and interventional treatment for ACS

Outcomes

Comparisons are simvastatin vs. simvastatin+ezetimibe.

Primary Outcome

CV mortality, major CV event, or nonfatal stroke
34.7% vs. 32.7% (HR 0.94; 95% CI 0.89-0.99; P=0.016; NNT 50)

Secondary Outcomes

All-cause mortality, major CV event, or nonfatal stroke
40.3% vs. 38.7% (HR 0.95; 95% CI 0.90-1.00; P=0.03)
CV mortality, nonfatal MI, urgent coronary revascularization ≥30 days
18.9% vs. 17.5% (HR 0.91; 95% CI 0.85-0.98; P=0.02)
CV mortality, nonfatal MI, unstable angina hospitalization, any revascularization ≥30 days, nonfatal stroke
36.2% vs. 34.5% (HR 0.95; 95% CI 0.90-1.00; P=0.04)

Tertiary Outcomes

A full list of outcomes is presented in Table 2 on page 2393.

Mortality type
All-cause: 15.3% vs. 15.4% (HR 0.99; 95% CI 0.91-1.07; P=0.78)
CV: 6.8% vs. 6.9% (HR 1.00; 95% CI 0.89-1.13; P=1.00)
CHD: 5.8% vs. 5.7% (HR 0.96; 95% CI 0.84-1.09; P=0.50)
MI
14.8% vs. 13.1% (HR 0.87; 95% CI 0.80-0.95; P=0.002)
Non-fatal: 14.4% vs. 12.8% (HR 0.87; 95% CI 0.80-0.95; P=0.002)
Fatal: 0.7% vs. 0.5% (HR 0.84; 95% CI 0.55-1.27; P=0.41)
Stroke
4.8% vs. 4.2% (HR 0.86; 95% CI 0.73-1.00; P=0.05)
Ischemic: 4.1% vs. 3.4% (HR 0.79; 95% CI 0.67-0.94; P=0.008)
Hemorrhagic: 0.6% vs. 0.8% (HR 1.38; 95% CI 0.93-2.04; P=0.11)
LDL at 1 year
Both groups had baseline LDL of 94 mg/dL
69.9 vs. 53.2 mg/dL (P<0.001)
Mortality from CV causes, MI, or stroke
22.2% vs. 20.4% (HR 0.90; 95% CI 0.84-0.96; P=0.003)

Adverse Events

There was no difference in the prespecified safety endpoint between the groups. This includes liver and gallbladder abnormalities, rhabdomyolysis, myopathy, cancer, and cancer mortality.

Discontinuation of study medication because of an adverse event
10.1% vs. 10.6%

Criticisms

  • 42% of the patients discontinued the study medication for any reason prematurely, with an equal proportion in both groups
  • Overall treatment effect on the composite primary end point was modest considering the large sample size and relatively long follow-up period (NNT of 50 with ARR of 2%)
  • As the trial was designed prior to contemporary guidelines, these patients were treated with a moderate-intensity statin rather than with a standard-of-care high-intensity statin

Funding

  • Merck, the manufacturers of Vytorin (the brand name of simvastatin+ezetimibe) and Zetia (the brand name of ezetimebe)
  • Authors with multiple financial disclosures

Further Reading

  1. Garcia-Calvo M, et al. “The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1).” Proc Natl Acad Sci U S A. 2005 Jun 7;102(23):8132-7.
  2. Mitka M. "Ezetimibe prescribing fails to keep up with evidence." JAMA. 2014;311(13):1279-1280.
  3. Morrone D, et al. “Lipid-altering efficacy of ezetimibe plus statin and statin monotherapy and identification of factors associated with treatment response: a pooled analysis of over 21,000 subjects from 27 clinical trials”. Atherosclerosis 2012;223:251-261.
  4. Kastelein JJ, et al. "Simvastatin with or without ezetimibe in familial hypercholesterolemia." The New England Journal of Medicine. 2008;358(14):1431-1443.
  5. 5.0 5.1 Stone NJ, et al. "2013 ACC/AHA guideline on the treatment of blood cholesterol o reduce atherosclerotic cadiovascular risk in adults." Journal of the Amercan College of Cardiology. 2014;63(25 Pt B):2889-2934.
  6. Jarcho JA and Keaney JF. "Editorial: Proof that lower is better -- LDL cholesterol and IMPROVE-IT." The New England Journal of Medicine. 2015;372:2448-2450.
  7. Perk J, et al. “European Guidelines on cardiovascular disease prevention in clinical practice (version 2012): the Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts)”. Eur Heart J 2012;33:1635-1701
  8. FDA writers. "FDA News release: FDA announces new safety recommendations for high-dose simvastatin: Increased risk of muscle injury cited." FDA.gov. Published 2011-06-08. Accessed 2015-06-18.