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May 8, 2015
The ENHANCE Atherosclerosis Trial
Reference
Kastelein JJ, Akdim F, Stroes ES, et al. Simvastatin with or without ezetimibe in familial
hypercholesterolemia. N Engl J Med. 2008 Apr 3; 358(14): 1431-43.
Objective
Test the hypothesis that combination therapy with ezetimibe and simvastatin in
Hypercholesterolemia enhances Atherosclerosis regression.
Introduction
One in four adults die of heart diseases in the United States every year, thats
About 610,000 people.1
Many heart diseases are associated with tobacco use, poor diet, minimal physical
activity, and obesity. These factors cause cholesterol deposition in arteries and
blocking blood flow.2
Cholesterol is a waxy substance produced by the liver or consumed in certain
foods.3
Cholesterol gets deposited in the arteries and narrows its diameter when there is
excess and can cause the heart disease Atherosclerosis.3
The desired cholesterol levels to avoid deposition in arteries are the following4:
- Total Cholesterol less than 200 mg/dl
- LDL (bad cholesterol) less than 100 mg/dl
- HDL (good cholesterol) 60 mg/dl or higher
- Triglycerides less than 150 mg/dl
The normal range for the thickness of the carotid artery for a healthy individual is
between 0.4 0.8 mm.5
Simvastatin is a lipid-lowering agent that helps remove cholesterol from the body
and reduces its production by inhibiting HMG-CoA reductase, which is the rate
limiting step in cholesterol synthesis.6
Ezetimibe reduces blood cholesterol by inhibiting absorption by the small
intestine through action on the brush border enzymes and reduces hepatic
cholesterol stores and increase in the clearance of cholesterol from the blood. 7
Methods
Randomized, double blind, prospective, multicenter 24-month trial.
Inclusion Criteria:
- Male or female between 30 and 75 years of age
- Patients diagnosed with hypercholesterolemia by genotyping or meeting
the diagnostic criteria determined by the World Health Organization
- Untreated level of LDL cholesterol of 210 mg per deciliter or more.
Results
Patient population
- 720 patients enrolled, 357 were assigned to receive simvastatin plus
ezetimibe while 363 were assigned to receive simvastatin plus placebo.
- Baseline characteristics of patients were similar with no statistical
significant within both groups as it was listed in table 2, comparing the
measured variables, cholesterol, triglycerides, apolipoprotein, c-reactive
protein.
The same baseline variables were measured again after 24 months and the
results are summaries in table 1
P value
at 24
months
<0.01
0.05
<0.01
0.29
0.16
Safety: adverse reaction were similar in both groups and the results were the
following:
- 107 of 363 patients (29.5%) in the simvastatin-only group and in 122 of
357 patients (34.2%) in the combined-therapy group (P = 0.18)
experienced adverse reactions.
- The rates of discontinuation owing to adverse events were similar: 34 of
363 patients (9.4%) in the simvastatin-only group and 29 of 357 patients
(8.1%) in the combined-therapy group (P=0.56).
- 8 of 360 patients (2.2%) in the simvastatin-only group and 10 of 356
patients (2.8%) in the combined-therapy group had to discontinue
treatment because of consecutive elevations of more than three times the
upper limit of the normal range (ULN) in alanine aminotransferase (ALT
specific for liver), aspartate aminotransferase, or both (P=0.62).
- 8 of 360 patients (2.2%) in the simvastatin-only group and 4 of 356
patients (1.1%) in the combined-therapy group had an increase in the level
of creatine kinase of more than 10 times the ULN (P = 0.25).
- Cardiovascular events were noted in 7 patients in the simvastatin group
(including 1 death from a cardiovascular cause, 2 nonfatal myocardial
infarctions, 1 nonfatal stroke, and 5 coronary revascularization
procedures) and in 10 patients in the combined-therapy group (including 2
deaths from cardiovascular causes, 3 nonfatal myocardial infarctions, 1
non- fatal stroke, and 6 coronary revascularizations).
Author Conclusions
There was a lack of vascular benefit conferred by Simvastatin with Ezetimibe
despite the observed reduction in LDL cholesterol level.
Due to the minute difference in artery thickness with active therapy, the
measurement technique did not accurately reflect changes in atherosclerotic
burden.
The patient population studied may have had too low a risk for high cholesterol,
which limited the ability to detect a differential response to the intervention.
Personal Conclusions
The study sample size met the intended size for the study and the study met
power, therefore there might be other factors that contributed to having no
statistical significance.
There was a statistically significant change in the level of LDL cholesterol as it
was decreased much more in the study group while the simvastatin only group
showed a lesser decrease in LDL.
The study showed no statistical significant in the thickness in arteries for both
groups this could be due to the fact that both groups included patients with carotid
artery thickness for 0.7 mm which is within the normal range.
The inclusion criteria did not state that it included people with a reduced diameter
in the thickness therefore decreasing external validity.
The inclusion criteria made an assumption on those patients who have familial
hypercholesterolemia and considered them at risk of developing atherosclerosis.
This assumption could be invalid if the patients were at low risk.