“An Examination of the ENHANCE Trial”
Jennifer G. Robinson, MD, MPH, Program Chair
President, Midwest Lipid Association
Associate Professor
Departments of Epidemiology and Medicine
Director, Lipid Research Clinic
University of Iowa
Iowa City, IA
Kastelein JJP, et al. N Engl J Med 2008;358:1431-1443
ENHANCE Study Design
Pre-randomization Phase
FH:
LDL-c ≥ 210 mg/dL
Screening and
Fibrate
Washout
Placebo LeadIn/ Drug
Washout
R
A
N
D
O
M
I
Z
A
T
I
O
N
Ezetimibe 10 mg-Simvastatin 80 mg
Simvastatin 80 mg
IMT assessment
-10 to -7
Weeks
-6
0
3
6
9
12
Months
15
18
21
24
ENHANCE Baseline Characteristics
Simvastatin Monotherapy
Simvastatin plus
Ezetimibe
All randomized patients
n=363
n=357
P-value
Age (yr)
45.710.0
46.19.0
0.69
Male sex no. (%)
179(49%)
191 (54%)
0.26
Body-mass index
26.74.4
27.44.6
0.047
5(1%)
8 (2%)
0.38
Hypertension
51 (14%)
67 (19%)
0.09
Current smoking
104 (29%)
102 (29%)
0.98
26 (7%)
14 (4%)
0.06
297 (82%)
286 (80%)
0.56
Systolic mm Hg
12415
12515
0.31
Diastolic mm Hg
7810
789
0.41
History of diabetes
History of MI
Prior use of statins
LDL-cholesterol
10
Percentage change from baseline
0
10
20
30
40
50
60
70 0
24 months
(mg/dL)
193 ± 60
Eze-Simva
319 ± 65
141 ± 53
P<0.01
-16.5 %
incremental
reduction
6
12
Months
ENHANCE
Simva
Baseline
(mg/dL)
318 ± 66
18
24
Simva
Eze-Simva
Primary outcome
• Change from baseline in mean CIMT
– Average of means of the far-wall IMT of R & L
carotid arteries, carotid bulbs, & internal carotid
arteries
ENHANCE
No significant changes in 1° or 2° endpoints
Variable
Simvastatin 80 mg
Mean
Median
Simvastatin 80 mg +
Ezetimibe 10 mg
Mean
P value
(mean)
Median
Millimeters
Baseline
n=342
n=338
Mean cIMT
0.700.13
0.69
0.690.13
0.68
0.64
Mean maximum cIMT
0.800.16
0.78
0.800.17
0.76
0.94
24 months follow-up
n=320
n=322
Mean cIMT
0.700.14
0.69
0.710.15
0.68
0.29
Mean maximum cIMT
0.81±0.17
0.79
0.82±0.18
0.78
0.27
Difference baseline to 24 months
Mean cIMT
0.00580.0037
0.0095
0.01110.0038
0.0058
0.29
Mean maximum cIMT
0.01030.0049
0.0103
0.01750.0049
0.0160
0.27
- Consistent inferential results observed for non-parametric (median) and parametric (mean) analyses
- Exclusion of patients with missing data or biologically implausible measures did not change primary or secondary
outcomes
Mean cIMT during 24 months of therapy
Longitudinal, repeated measures analysis
0.80
Mean IMT (mm)
0.75
P=0.88
0.70
0.65
0.60
ENHANCE
6
12
Months
18
24
Simva
Eze-Simva
ENHANCE Safety
• Both regimens well tolerated, with overall safety profiles generally similar
and consistent with product labels
• One case of viral hepatitis A in the simvastatin-only arm
• One case of myopathy (defined as CPK > 10 ULN, with associated muscle
symptoms) in the simvastatin-only arm and 2 cases in the EzetimibeSimvastatin arm
p
Simva 80 mg
Simva 80/Eze 10 mg
n=360
n=356
ALT and/or AST ≥ 3 X ULN
8
10
0.62
CPK ≥ 10 X ULN
8
4
0.25
Consecutive
Subjects with 2 consecutive measurements for ALT and/or AST; a single last measurement ≥ 3
ULN; a measurement ≥ 3 X ULN followed by < 2 ULN that was taken more than 2 days after the
last dose of study medication
“An Examination of the ENHANCE Trial”
Evan A. Stein, MD, PhD
Director, Metabolic and Atherosclerosis Research Center
Voluntary Professor of Pathology and Laboratory Medicine
University of Cincinnati
Cincinnati, OH
Questions after ENHANCE
Why were the results of ENHANCE different from
the earlier carotid IMT trials?
The Trial Design and Population
To have any chance using cIMT of demonstrating that one treatment
is better than another two critical factors must be present:
• The population studied must have significant and quantifiable lipid
rich intima – if minimal or no significant atherosclerosis is present
then only possible change to be assessed is progression
• The ‘control’ group must show significant progression – if not then
only significant regression in the ‘test’ group can result in a positive
trial
Critical Factors for Successful cIMT Trial
progression
regression
Critical Factors for Successful cIMT Trial
Simva progressed;
atorva regressed =
SUCCESS!!
ASAP - 1997
0.95
progression
P <0.05
0.90
Simva LDLc -40%
Atorva LDLc -52%
0.85
cIMT mm
ASAP
0.80
• In ASAP the patient population had cIMT with mean
baseline of 0.92 mm indicating presence of lipid enriched
atherosclerosis
0.75
0.70
• In ASAP the ‘control’ group of simvastatin showed
significant progression of 0.036 mm/2yrs despite 40%
reduction in LDLc
0.65
regression
0
1
years
2
Critical Factors for Successful cIMT Trial
ASAP - 1997
0.95
ASAP
progression
0.90
Simva LDLc -40%
Atorva LDLc -52%
cIMT mm
0.85
0.80
0.75
ENHANCE - 2003
P= ns
0.70
0.65
Simva No progress;
Sim/Eze No regress
FAILURE!!
regression
0
1
years
2
ENHANCE
Simva LDLc -40%
Simva/Eze LDLc -57%
Critical Factors for Successful cIMT Trial
ASAP - 1997
0.95
ASAP
progression
0.90
Simva LDLc -40%
Identical FH populations
cIMT mm
0.85
Atorva LDLc -52%
25% less cIMT
0.80
REGRESSION!!!
0.75
ENHANCE - 2003
ENHANCE
0.70
Simva LDLc -40%
Simva/Eze LDLc -57%
0.65
regression
0
1
years
2
The Patient Population
What changed from ASAP to ENHANCE?
• In ASAP, the study upon which ENHANCE was based, the progression in
cIMT over 2 years in the simvastatin 40 mg treated group (LDLc decrease
40%) was 0.036 mm over 2 years. At the end of the 2 year ENHANCE trial
the change in cIMT was substantially less than projected in both groups at
0.011 mm in the Eze/Simva group and 0.005 mm in the simvastatin 80 mg
group (p=0.29 NS).
• Thus a 40% reduction in LDLc both trials, done 5 years apart, with the
same drug, in the same patient population and similar entry LDLc levels
resulted in 6 fold less progression of cIMT in ENHANCE
• The only difference in the simvastatin monotherapy groups between the
two studies was the pre-treatment of patients and the amount of baseline
atherosclerosis in ENHANCE.
• ASAP was recruited in 1997 in Holland from a large screening program
for FH, only few statins (prava, simva, fluva) available in prior years and
not aggressive Rx
• ENHANCE recruited from global well established lipid clinics with large
and long identified and aggressively Rx patients
“An Examination of the ENHANCE Trial”
Michael H. Davidson, MD, FACC, FACP
Clinical Professor
Director, Preventive Cardiology
The University of Chicago
Executive Medical Director
Radiant Research
Chicago, IL
Questions after ENHANCE
Is there reason to suspect that ezetimibe’s
mechanism of action is less effective than that
of statins?
“An Examination of the ENHANCE Trial”
B. Greg Brown, MD, PhD
Professor of Medicine and Cardiology
University of Washington School of Medicine
Seattle, WA
Questions after ENHANCE
Can the ENHANCE results be interpreted in any
way other than:
“Ezetimibe is just an expensive placebo”?
Comparisons of Carotid Plaque Tissue Composition
Two Groups of Eight Matched Patients
Triple Therapy x 10 years
2
Total plaque area = 58 mm
Untreated
2
Total plaque area = 64 mm
2
0.7 mm
(1%)*
2
10.2 mm
(17%)*
3 mm2
(3%)
2
5 mm
(5%)
46 mm2
(84%)
6 mm2
(10%)
49 mm2
(77%)
*p=0.01
2 mm2
(3%)
2
2 of total plaque)
Fibrous tissue area, mm
(%
2 of total plaque)
Lipid plus calcium area, mm
(%
2 of total plaque)
Lipid deposits area, mm(%
2 of total plaque)
Calcium cluster area, mm
(%
Zhao, X-Q, et al. ATVB 2001;21:1623-
“An Examination of the ENHANCE Trial”
Jennifer G. Robinson, MD, MPH
Associate Professor
Departments of Epidemiology and Medicine
Director, Lipid Research Clinic
University of Iowa
Iowa City, IA
Questions after ENHANCE
Is there evidence to support the use of alternative
LDL-lowering therapies?
Selection of patients for more aggressive LDLlowering: Risk curve concept
80
CHD + Diabetes
70
Cardiovascular event rate (%)
60
50
40
CHD + MS or IFG
30
CHD- No MS or IFG
20
Diabetes - No CVD
10
No CVD No diabetes
0
0
20
40
60
80
100 120 140 160 180
LDL (mg/dl)
Robinson JG, Stone NJ. Am J Cardiol 2006: 98: 1405-1408
200
Add-on to statin therapy
Drug options to ↓LDL & ↓Non-HDL-C
Drug
LDL-C
Non-HDL-C
Trigs
HDL-C
Double statin dose
-6%
-6%
-2 to -12%
-2 to +2%
Ezetimibe 10 mg
-15%
-12%
-9%
NS
Niacin 2 gr
-14%
-31%*
-24%
+18%
Bile acid binding agent
-12%
-5-8%
0 to +23%
+1-7%
-6% to +4%
-3% to -18%*
-15 to -20%
+13%
+7%
+2%
-18%
0%
Colestipol 2 scoops (6 gr)
Cholestyramine 2 scoops (8 gr)
Coleselvalam 6 tabs (3.75 gr)
Fenofibrate 145 mg
Gemfibrozil 600 mg BID
Jones PH, et al. Am J Cardiol 2003; 92: 152-60.
Robinson JG, Davidson MH. Expert Rev Cardiovasc Ther. 2006: 4: 461-76
Kos Niaspan® prescribing information 2005
Sankyo Welchol® prescribing information 2005
Athyros VG et al. Diabetes Care 2002; 25: 1198-1202; Durrington PN et al. Diab Res Clin Pract 2004; 64: 137-51.
Wagner AM, et al. J Clin Endocrinol Metab 2003; 88: 3212-17.
*Estimated Total cholesterol-HDL
Consistent relationship between
LDL-C reduction and CHD relative risk for all LDLlowering treatments
London
Oslo
MRC
Los Angeles
Upjohn
LRC
NHLBI
POSCH
4S
100
Nonfatal MI and CHD death
relative risk reduction, %
80
60
WOSCOPS
CARE
LIPID
AF/TexCAPS
HPS
ALERT
PROSPER
ASCOT-LLA
CARDS
40
20
Cholestyramine
0
Colestipol
–20
15
20
25
30
LDL-C reduction, %
Robinson JG et al. J Am Coll Cardiol. 2005;46:1855–1862.
35
40
Niacin RCTs
Unpublished
PPAR agonists: Expected CVD risk reduction
from LDL & HDL changes
50
ADOPT-CHF*†
Rosi vs Glyb
40
Observed change in CHD ‡/CVD risk
30
ADOPT*
20 Rosi vs Glyb
RECORD-CHF§†
ADOPT-CHF*†
10
Rosi vs Met
WORSE THAN
EXPECTED
RECORD
PROactive-CHF**
-30
-25
-20
-15
-10
BIP
0
5
Rosi vs Met
-10
PROactive**
-20
VA-HIT
HHS
-30
-40
Expected change in CVD risk LDL+HDL
Robinson JG. PPAR Review 2008; in press
ADOPT*
0
-5
FIELD
§
BETTER THAN
EXPECTED
10
Gemfibrozil vs Fenofibrate Adverse Events
(excluding reports with concomitant cerivastatin use) submitted to the US
Food and Drug Administration from January 2000 to December 2004
Adverse Event
Reports
Gemfibrozil
Fenofibrate
Gemfib
vs Feno
OR
95% CI
P-value
Rates/million prescriptions
Gemfibrozil better
All
31.0
40.0
0.76
0.69 – 0.83
<0.001
Serious
20.0
27.9
0.72
0.65 – 0.81
<0.001
Liver
2.6
6.9
0.37
0.28 – 0.50
<0.001
Rhabdomyolysis
9.7
3.6
2.67
2.11 – 3.39
<0.001
Muscle-related with
no rhabdomyolysis
8.1
5.8
1.36
1.12 – 1.71
0.002
Fenofibrate better
Holoshitz N, et al. Am J Cardiol 2008; 101: 95-97
“An Examination of the ENHANCE Trial”
Jerome Cohen, MD, FACC, FAHA, FACP
Chair, NLA Consumer Affairs Committee
Professor Emeritus
St. Louis University School of Medicine
St. Louis, MO
Hosted by the Midwest Lipid Association
Questions after ENHANCE
How should ezetimibe continue to be used
in clinical practice?