Midwestern University Chicago College of Pharmacy

Journal Club
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.

Commented [PJ1]: Introduction is OK. Information

provided on the disease and the drugs. A little more
information on carotid intima media thickness wouldve
been great.

Commented [PJ2]: Note that inclusion & exclusion

criteria are separated. This is the ideal way to list these.

Treatment with lipid lowering therapy with an LDL cholesterol level of

less than 210 mg per deciliter at time of screening if level was 210 mg per
deciliter or more after the placebo run-in period.
Exclusion Criteria: patient with cardiovascular events such as,
- High grade stenosis
- Occlusion of the carotid artery
- History of carotid endarterectomy or carotid stenting
- Homozygous familial hypercholesterolemia
- Congestive heart failure
- Cardiac arrhythmia
- Angina pectoris
- Recent cardiovascular events
Treatment regimen
- Study group received daily therapy with 80 mg of simvastatin with 10 mg
of ezetimibe.
- Control group received 80 mg of simvastatin with placebo.
Endpoints
- Primary: change from baseline in the mean carotid artery media thickness
- Secondary: regression in mean thickness of the carotid and femoral
arteries
Assessments
- Visits were scheduled on day 1 of months 1 and 3, and thereafter at 3month intervals.
- Ultrasonographic measurements scheduled for visits at baseline and at 6,
12, 18, and 24 months.
Statistical analysis
- Total of 325 patients were required in each study group to provide a
statistical power of 90% to detect a difference of 0.05 mm in carotid-artery
measures between the two study groups within 2 years, assuming a
standard deviation of 0.20 mm and a two-sided alpha of 0.05.
- Analysis-of-covariance models were used to calculate differences between
study groups in changes from baseline.
- Chi-square test was used to compare the two study groups with respect to
the primary and secondary outcomes.
- The last-observation-carried-forward method was used for patients who
did not complete the study.
-

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.

Commented [PJ3]: Note that primary and secondary

endpoints are separated. This is the ideal way to report this.

The same baseline variables were measured again after 24 months and the
results are summaries in table 1

Table 1: Levels of lipids, triglycerides, C-reactive protein, and artery thickness at

baseline and 24 months
Variable
Simvastatin
Simvastatin
Simvastatin
Simvastatin
Monotherapy Monotherapy
plus
plus
(N=???)
at 24 months
Ezetimibe
Ezetimibe at
24 months
LDL (mg/dl)
317.866.1
192.760.3
319.065.0
141.352.6
HDL (mg/dl)
47.413.2
50.714.7
46.711.3
50.912.8
Total
400.068.3
270.661.5
400.067.5
217.356.4
(mg/dl) +/SD
Triglycerides
160
120
157
108
C-reactive
1.70
1.20
1.70
0.90
protein
Mean
0.700.13
0.700.14
0.690.13
0.710.15
thickness of
carotid
artery (mm)
+- SD
Mean
0.800.39
0.800.37
0.770.30
0.790.33
thickness of
femoral
artery (mm)
+/- SD

P value
at 24
months
<0.01
0.05
<0.01

Commented [PJ4]: It is better to make your own table vs.

copying from the article. It is easier to read and it does not
contain excess information. If a lot of secondary variables
are assessed, you should concentrate on listing (1) the
statistically significant ones and (2) the ones that are
controversial (see discussion in article or do some
background research to help determine this)
Commented [PJ5]: Including # of people is customary at
the top of each column.

0.29

0.16

Primary and secondary outcomes

- Primary outcome measure: change from baseline in the mean (SE)
intimamedia thickness of the carotid artery and the difference from
baseline to those results at 24 months:
o 0.00580.0037 mm in the simvastatin only group and
0.01110.0038 mm in the combined therapy group. The difference
(0.0053 mm) did not reach statistical significance (P = 0.29).
- Secondary outcome measure: regression in the mean carotid artery intimamedia thickness results:
o 142 of 320 patients (44.4%) in the simvastatin-only group had
regression in the thickness while 146 of 322 patients (45.3%) in
the combined-therapy group (P=0.92) had regression in thickness
as well. The results did not reach statistical significant.
o New plaque formation (which was defined as an intimamedia
thickness of more than 1.3 mm) was seen in 9 of 320 patients
(2.8%) in the simvastatin-only group and in 15 of 322 patients
(4.7%) in the combined-therapy group (P=0.20). No significant
change was observed.

Commented [PJ6]: Again, important to clearly separate

out primary and secondary endpoints.

 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.

Commented [PJ7]: Safety MUST be included. We never

make a decision without considering the safety of the patient.

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.

Commented [PJ9]: In general, this should be about 1-2

sentences. In this case, the students included some critique
in the conclusion section, which is duplicative here.
Basically, just say if your group agrees or does not agree and
why.

Commented [PJ8]: PARAPHRASE authors conclusion.

Do not word exactly as in the text.

 The specific inclusion criteria helped increase internal validity.

The combination therapy did not prevent the thickness in the wall of arteries since
both groups had no statistical significant in the regression of the disease.
Critique
Strengths:
- The study was done in many countries, which enhances external validity.
- Pharmaceutical companies sponsored the study, however the sponsors did
not interfere with the investigation of the results.
- The sample size met the intended size for the study.
- The randomization was computer generated to avoid bias.
- The study included a run-in or a washout period, which helps both groups
start at the same level of drugs in their system.
- The specific and narrow inclusion criteria helped increase internal validity.
Weaknesses:
- The inclusion criteria did not state that the study contained people who
already have a reduced diameter due to thickness in the arteries.
- The patients who were included in the study already met the normal range
of carotid artery thickness since the baseline thickness was 0.7 mm, which
is within the range, making the interpretation of benefit difficult.
- The inclusion criteria were very specific which can reduce external
validity.
- The analyzed outcomes used a surrogate marker for atherosclerosis not a
clinical endpoint.
- The study period of 2 years may not have been enough to see changes in
thickness of arteries and may have needed to be longer to see statistically
significant differences.
References
1. Centers for Disease Control and prevention. Heart disease facts.
http://www.cdc.gov/heartdisease/facts.htm (accessed 2015 May 02)
2. Centers for Disease Control and Prevention. Heart disease facts.
http://www.cdc.gov/heartdisease/behavior.htm (accessed 2015 May 02)
3. Centers for Disease Control and Prevention. Heart disease facts.
http://www.cdc.gov/heartdisease/conditions.htm (accessed 2015 May 02)
4. Centers for Disease Control and Prevention. Cholesterol facts sheet.
http://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_cholesterol.htm (accessed
2015 May 02)
5. DrugPoint Summary. Micromedex Solutions. Simvastatin.
http://www.micromedexsolutions.com/micromedex2 (accessed 2015 May 02)
6. Groot E, Kastelein J, Duivenvoorden R. Carotid intima-media thickness.
http://www.uptodate.com/contents/carotid-intima-media-thickness (accessed 2015
May 07)
7. DrugPoint Summary. Micromedex Solutions. Ezetimibe.
http://www.micromedexsolutions.com/micromedex (accessed 2015 May 02)

Commented [PJ10]: In general, you want to aim for 2-3

STRENGTHS and 3-4 WEAKNESSES. Critique should
focus on the study DESIGN; not the results of the study.
These critiques listed here focus on the design, and are well
thought out.
Also, should include a brief elaboration on how the
strength/weakness impacted the study. For example, instead
of just saying inclusion criteria, this group put inclusion
criteria was very specific, which can reduce external
validity.

Commented [PJ11]: Be sure to use the Dept Referencing

guide when completing this section. Cite articles as
ARTICLES, not as websites (even if you got them online).