ENHANCE

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Kastelein JJ, et al. "Simvastatin with or without ezetimibe in familial hypercholesterolemia". The New England Journal of Medicine. 2008. 358(14):1431-1443.
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Clinical Question

In patients with familial hypercholesterolemia, does ezetimibe in combination with simvastatin reduce the progression of atherosclerosis, as compared to simvastatin only?

Bottom Line

In patients with familial hypercholesterolemia, ezetimibe in combination with simvastatin did not change the mean carotid-artery intima-media thickness significantly. However, a significant decrease in LDL and CRP level was observed.

Major Points

Ezetimibe binds to the Niemann–Pick C1-like 1 (NPC1L1) protein and selectively inhibits cholesterol absorption. In combination with statins, ezetimibe has been shown to provide additional reduction in LDL-cholesterol (LDL-C) by ~23%.[1] However, the trial sought to determine if ezetimibe therapy leads to improvement in progression of atherosclerosis.

The Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial randomized 720 patients with familial hypercholestrolemia to receive simvastatin in combination with either ezetimibe or placebo to assess the effects of ezetimibe on carotid-artery intima-media thickness. The results showed that ezetimibe in combination with simvastatin did not change the mean carotid-artery intima-media thickness significantly. However, a significant decrease in LDL, triglyceride and CRP levels were seen. Ezetimibe treatment was not associated with significant increase in adverse events compared to placebo.

The ACC statement related to the ENHANCE trial suggests that ezetimibe is a reasonable option for patients not reaching their lipid goals despite high-dose statin therapy. Ezetimibe can also be considered for patients who are partially or completely intolerant of statins.[2]

The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) published in 2015 showed that among patients with recent acute coronary syndrome, ezetimibe added to statin therapy is associated with a reduction in cardiovascular (CV) mortality, major CV event, or nonfatal stroke as compared to statin therapy alone.

Guidelines

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

Design

  • Double-blind, randomized, active-comparator, multicenter study
  • N=720
    • Experimental: simvastatin+ezetimibe (n=357)
    • Control: simvastatin+placebo (n=363)
  • Setting: 18 ambulatory care centers in the United States, Canada, South Africa, Spain, Denmark, Norway, Sweden, and the Netherlands 
  • Enrollment: 2002-2004
  • Mean follow-up: 2 years
  • Analysis: intention-to-treat
  • Primary outcome: mean change in carotid-artery intima-media thickness from baseline

Population

Inclusion Criteria

  • Age: 30-75 years
  • Familial hypercholesterolemia diagnosed either by genotyping or by the WHO diagnostic criteria
  • Untreated LDL cholesterol ≥210 mg/dl(5.43 mmol/l)

Exclusion Criteria

  • high-grade carotid artery stenosis
  • previous carotid endarterectomy or carotid stenting
  • homozygous familial hypercholesterolemia
  • heart failure of NYHA class III or IV, cardiac arrhythmia, angina pectoris, or recent cardiovascular events

Baseline Characteristics

From the ezetimibe+simvastatin group (n=357):

  • Demographics: age 46.1±9 years; 53.5% males
  • BMI: 27.4±4.6 kg/m2
  • PMH: Diabetes 2.2%; Hypertension 18.8%; Active smoker: 28.6%; previous MI 3.9%
  • BP: systolic 125±15 mm Hg; diastolic 78±9 mm Hg

Interventions

  • The study consisted of three periods: a screening phase, a single-blind placebo run-in period of 6 weeks, and a double-blind study period with a scheduled duration of 24 months.
  • Patients were randomized in a 1:1 ratio to receive daily therapy with simvastatin 80 mg either with placebo or with ezetimibe 10 mg
  • Carotid intima-media thickness was measured at 6 sites: right and left common carotid arteries, carotid bifurcations, and internal carotid arteries
  • femoral artery intima-media thickness was also measured

Outcomes

comparisons are simvastatin+ezetimibe vs. control

Primary Outcome

mean change in carotid-artery intima-media thickness
0.0111±0.0038 mm vs. 0.0058±0.0037 mm (P=0.29)

Secondary Outcomes

patients with regression in the mean carotid-artery intima–media thickness
45.3% vs. 44.4% (P=0.92)
patients with new carotid-artery plaques of more than 1.3 mm
4.7% vs. 2.8% (P=0.20)
change in mean maximal carotid-artery intima-media thickness
0.0175±0.0049 mm vs. 0.0103±0.0049 mm (P=0.27)
change in mean common carotid-artery intima-media thickness
0.0019±0.0014 mm vs. 0.0024±0.0043 mm (P=0.93)
change in mean carotid bulb intima-media thickness
0.0144±0.0070 mm vs. 0.0062±0.0069 mm (P=0.37)
change in mean internal carotid-artery intima-media thickness
0.0099±0.0065 mm vs. -0.0007±0.0064 mm (P=0.21)
change in mean femoral-artery intima-media thickness
0.0182±0.0135 mm vs. -0.0067±0.0132 mm (P=0.16)
change in average of mean carotid- and femoral-artery intima-media thickness
0.0182±0.008 mm vs. 0.0033±0.0079 mm (P=0.15)

Additional Outcomes

mean LDL at 2 years
141.3±52.6 mg/dl (3.65±1.36 mmol/l) vs. 192.7±60.3 mg/dl (4.98±1.56 mmol/l); (between-group difference: 16.5%; P<0.01)
change in LDL from baseline to 2 years
-55.6% vs. -39.1% (between-group difference: 16.5%; P<0.01)
change in HDL from baseline to 2 years
10.2% vs. 7.8% (between-group difference: 2.4%; P=0.05)
change in triglyceride from baseline to 2 years
-29.8% vs. -23.2% (between-group difference: 6.6%; P<0.01)
change in CRP from baseline to 2 years
-49.2% vs. -23.5% (between-group difference: 25.7%; P<0.01)
change in Apolipoprotein B from baseline to 2 years
-46.7% vs. -33.1% (between-group difference: 13.6%; P<0.01)

Adverse Events

treatment-related
34.2% vs. 29.5% (P=0.18)
discontinuation due to treatment-related adverse effects
8.1% vs. 9.4% (P=0.56)
  • Elevation in ALT, AST or both of >3x the upper limit of the normal range
    • 2.8% vs. 2.2% (P=0.62)
  • Elevation in CK of ≥10x the upper limit of the normal range
    • 1.1% vs. 2.2% (P=0.25)
    • 2 patients in the experimental arm and 1 in the control group developed clinically significant myopathy
cardiovascular events
10 vs. 7 patients (P not given)

Criticisms

  • Changes in atherosclerotic arteries occur very slowly. It is thus possible that the study period was not long enough to observe any benefit.[3]
  • The patients in the study had been on statin therapy for years therefore improvement in atherosclerotic plaques may have occurred before the trial.[4]
  • The ultrasonographic methodology used was reported to be highly precise. However, the precision results in magnified relative errors when small differences in intima-media thickness were measured.[3]
  • There is a lack of consensus on technique of measuring carotid-intima thickening which results in a lack of reproducibility.[3]
  • The primary outcome was measured by ultrasonography therefore effects observed may not reflect improvement in clinical outcomes.

Funding

  • Supported by Merck and Schering-Plough

Further Reading

  1. 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
  2. Statement from the American College of Cardiology Related to the ENHANCE Trial [Internet]. American College of Cardiology. [cited 2015 Dec 21]. Available from: http://www.acc.org/about-acc/press-releases/2010/02/19/15/01/15-2
  3. 3.0 3.1 3.2 Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia. N Engl J Med 2008; 359:529-533
  4. Brown BG, Taylor AJ. Does ENHANCE Diminish Confidence in Lowering LDL or in Ezetimibe? N Engl J Med 2008; 358:1504-1507