Efficacy and safety of ezetimibe coadministered hypercholesterolemia: a prospective,

European Heart Journal (2003) 24, 717–728
Efficacy and safety of ezetimibe coadministered
with pravastatin in patients with primary
hypercholesterolemia: a prospective,
randomized, double-blind trial
Lorenzo Melani a*, Richard Mills b, David Hassman c, Robert Lipetz d,
Leslie Lipka a, Alexandre LeBeaut a, Ramachandran Suresh a,
Pabak Mukhopadhyay a, Enrico Veltri a, for the Ezetimibe Study Group 1
a
Schering-Plough Research Institute, Kenilworth, NJ, USA
Coastal Carolina Research Center, Mount Pleasant, SC, USA
c
Comprehensive Clinical Research, Berlin, NJ, USA
d
Encompass Clinical Research, Spring Valley, CA, USA
b
KEYWORDS
Ezetimibe;
Pravastatin;
Hypercholesterolemia;
Cholesterol absorption
inhibitor;
Coadministration;
LDL-cholesterol
Aims To evaluate the efficacy and safety of ezetimibe 10 mg administered with
pravastatin in patients with primary hypercholesterolemia.
Methods and results After dietary stabilization, 2–12 week screening/washout
period, and 4-week, single-blind, placebo lead-in period, 538 patients with baseline
LDL-C ≥3.8 to ≤6.5 mmol/l and TG ≤4.0 mmol/l were randomized to one of eight
possible treatments administered daily for 12 weeks: ezetimibe 10 mg; pravastatin
10, 20, or 40 mg; ezetimibe 10 mg plus pravastatin 10, 20, or 40 mg; or placebo. The
primary efficacy endpoint was percent reduction in LDL-C from baseline to study
endpoint for ezetimibe 10 mg plus pravastatin (pooled doses) compared to pravastatin
alone (pooled doses) and ezetimibe alone. The combined use of ezetimibe and
pravastatin resulted in significant incremental reductions in LDL-C and TG compared
to pooled pravastatin alone (p<0.01). Coadministration therapy reduced LDL-C by
34–41%, TG by 21–23%, and increased HDL-C by 7.8–8.4%, depending on the dose of
pravastatin. The combined regimen was well tolerated, with a safety profile similar to
pravastatin alone and placebo.
Conclusions When coadministered with pravastatin, ezetimibe provided significant
incremental reductions in LDL-C and TG and was well tolerated with a safety profile
similar to pravastatin alone.
© 2003 The European Society of Cardiology. Published by Elsevier Science Ltd. All
rights reserved.
Introduction
* Corresponding author. Tel.: +1-908-740-7405; fax:
+1-908-740-4070
1
Members of the Ezetimibe Study Group are listed in the
acknowledgments.
E-mail address: [email protected]orp.com (L. Melani).
The 3-hydroxy-3-methylglutaryl coenzyme A
(HMG-CoA) reductase inhibitors (statins) are the
most potent and commonly prescribed drugs for
the treatment of hypercholesterolemia. However,
despite widespread use of statins in clinical
0195-668X/03/$ - see front matter © 2003 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0195-668X(02)00803-5
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Received 8 October 2002; accepted 16 October 2002
718
Methods
Patients
This study was conducted in 52 clinical centers
across the United States. Institutional review board
approval was obtained at each study center and all
patients provided written informed consent. A total
of 538 patients (238 men and 300 women) participated in the study. Adult men or women with
primary hypercholesterolemia were eligible for
inclusion. Lipid entry criteria included plasma
LDL-C concentration ≥3.8 to ≤6.5 mmol/l, as calculated by the Friedewald equation,12 and TG levels
≤4.0 mmol/l.
Prohibited concomitant illnesses and procedures included congestive heart failure (defined
as New York Heart Association Class III or IV heart
failure),13 uncontrolled cardiac arrhythmias,
history of unstable or severe peripheral artery
disease (within 3 months of study entry), unstable
angina pectoris, myocardial infarction, coronary
bypass surgery, or angioplasty (within 6 months of
study entry), uncontrolled or newly diagnosed
(within 1 month of study entry) diabetes mellitus,
active or chronic hepatic hepatobiliary disease,
known impairment of renal function, known
coagulopathy, and unstable endocrine disease.
Individuals receiving immunosuppressant drugs or
corticosteroids were not eligible to participate in
this study.
Study design
This multicenter, double-blind, randomized,
placebo-controlled, balanced-parallel-group, 2×4
factorial study consisted of three phases (Fig. 1).
During the initial 2- to 12-week screening/washout
period, all lipid-altering drugs were discontinued,
and patients were instructed to follow an NCEP
Step I diet throughout the trial.14 The subsequent
4 weeks constituted the single-blind, placebo
lead-in period. Blood samples were collected to
assay for qualifying lipid values at Visit 2 (Q1; Week
−4) and Visit 3 (Q2; Week −2). Patients with mean
plasma LDL-C values at Q1 and Q2 of at least
3.8 mmol/l and not more than 6.5 mmol/l, with no
single value less than 3.8 mmol/l or greater than
6.5 mmol/l were eligible to continue in the study.
At Visit 4 (Week 0), qualifying patients were randomized to receive one of eight possible treatments administered orally at bedtime once daily for
12 consecutive weeks: ezetimibe 10 mg (Merck/
Schering-Plough Pharmaceuticals, Inc., Kenilworth,
NJ); pravastatin 10, 20, or 40 mg (Bristol-Myers
Squibb Company, Inc., Princeton, NJ); ezetimibe
10 mg plus pravastatin 10, 20, or 40 mg; or placebo.
Balanced randomization across treatment groups
was accomplished using a single computergenerated randomization schedule with treatment
codes in blocks of eight.
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practice, a large proportion of at-risk patients do
not achieve low-density lipoprotein cholesterol
(LDL-C) goals as recommended by the European
Second Joint Task Force1 and the US National Cholesterol Education Program Adult Treatment Panel
III (NCEP ATP III) guidelines.2 The combined use of
statins with other lipid-lowering therapies is an
attractive treatment option for patients who require reductions in LDL-C that cannot be achieved
with statin monotherapy. Yet, the coadministration
of statins with other lipid-lowering agents (e.g.
fibric acid derivatives, bile acid sequestrants, and
niacin) is often limited by an increased risk of side
effects, intolerance, patient noncompliance, and
drug interactions.3–7
Ezetimibe is a novel cholesterol-lowering drug
that inhibits the absorption of dietary and biliary
cholesterol across the intestinal wall without affecting the absorption of triglycerides (TG) and
fat-soluble vitamins.8–10 By comparison, statins
block the endogenous synthesis of cholesterol in
the liver via inhibition of HMG-CoA reductase.11
Because ezetimibe and statins have distinct and
potentially complementary mechanisms of action,
it was hypothesized that the combined use of these
agents may produce incremental antihypercholesterolemic effects. A study in hypercholesterolemic
men demonstrated that coadministration of
ezetimibe with pravastatin produced no alteration
in pharmacokinetic profiles of either drug (data on
file).
The purpose of the present study was to evaluate
the efficacy and safety profile of ezetimibe 10 mg
coadministered with pravastatin (10, 20, or 40 mg)
for 12 consecutive weeks in patients with primary
hypercholesterolemia. The primary hypothesis was
that coadministration therapy (ezetimibe 10 mg
plus pravastatin pooled across all doses) would
provide additional LDL-C-lowering effects compared to pravastatin alone (pooled across all
doses). Secondary objectives were to evaluate the
change from baseline for additional lipid-related
variables. Additionally, the proportion of patients
reaching NCEP ATP II (guidelines in clinical use
during study conduct) and ATP III (guidelines
issued before study closed) LDL-C goals with various
treatments was examined.
L. Melani et al.
Efficacy and safety of ezetimibe
719
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Fig. 1
Schematic of study design.
Blood samples for routine lipid measurements
(direct LDL-C, calculated LDL-C, total cholesterol
(TC), high-density lipoprotein cholesterol (HDL-C)
and TG) were collected at Weeks −4, −2, 0, 2, 4, 8,
and 12. Baseline for these lipid parameters was
defined as the mean of the last three available
measurements prior to and including Week 0.
Samples for HDL-C subfractions, apolipoproteins,
and lipoprotein(a) (Lp(a)) were measured at Weeks
0 and 12. Baseline was defined as the last available
value through Week 0. Evaluation of safety was
accomplished through reports of patients and investigators and results from specific tests and
measurements (laboratory tests, electrocardiograms, physical examinations, and vital signs).
Patients completed 3-day diet diaries between
prespecified visits. Diary entries were analyzed by
Professional Nutrition Systems, Inc. (Overland Park,
KS), the central diet analysis center.
Laboratory methods
Medical Research Laboratories (Highland Heights,
KY) performed all clinical laboratory assays.
Laboratory assays included fasting blood chemistry,
hematology, coagulation tests, and urinalysis. All
qualifying lipid determinations, as well as lipid
profiles after Visit 1 were blinded to the investigators and study sponsor beginning with the first
qualifying lipid value.
LDL-C concentration was measured directly by
ultracentrifugation (beta-quantification) and also
calculated by the Friedewald equation:12 LDL-C⫽
TCK(TG/5)KHDL-C. Concentrations of TC and TG
720
were quantified enzymatically with the Hitachi
747 analyzer (Roche Diagnostics Corporation,
Indianapolis, IN). HDL-C was determined enzymatically after selective removal of LDL-C and
very low-density lipoprotein cholesterol (VLDL-C)
by heparin and manganese chloride precipitation. The HDL3-C subfraction was quantified
enzymatically following separation by ultracentrifugation, and the HDL2-C subfraction was
calculated as follows: HDL2-C⫽HDL-CKHDL3-C.
Non-HDL-C was calculated using the following
equation: non-HDL-C⫽TCKHDL-C. Apolipoprotein
A-I (apo A-I) and apolipoprotein B (apo B) were
determined by fixed-rate nephelometry. Lp(a)
was quantified by competitive enzyme-linked
immunosorbent assay.
Statistical analysis
The incremental effect of ezetimibe across
all pravastatin dose groups was evaluated with
an ANOVA model using a test of interaction via
contrast statement. If the interaction was not
statistically significant at p≤0.05, then the average
effect across all doses of pravastatin was considered the best estimate of the incremental
ezetimibe effect. Additional secondary efficacy
analyses with respect to LDL-C reduction were performed using an ANOVA model. These analyses
included the comparison of ezetimibe monotherapy
versus placebo, ezetimibe plus individual doses of
pravastatin versus the corresponding pravastatin
dose, and ezetimibe plus individual doses of pravastatin versus the next higher and the second
higher pravastatin dose. Additional key secondary
efficacy endpoints were evaluated using the same
model. These endpoints included mean change and
percent change from baseline in LDL-C as calculated by the Friedewald equation, TC, TG, HDL-C,
the ratios of direct LDL-C:HDL-C and TC:HDL-C at
study end and various time points, as well as nonHDL-C, Apo A-I, Apo B, HDL2-C, HDL3-C, and Lp(a) at
study end. Finally, the percent of patients achieving NCEP ATP II and ATP III target levels for direct
LDL-C at study end was assessed using logistic
regression with baseline percent LDL-C difference
from target as a covariate. All patients were
included in the goal attainment analysis irrespective of baseline LDL-C levels.
Results
Patient characteristics
Of the 1722 patients enrolled in this study, 538
(31%) met the eligibility criteria and were randomized to treatment. A total of 492 (91%) patients
completed the double-blind treatment phase,
while 46 (9%) discontinued study treatment early
because of an adverse event (19 patients), noncompliance with protocol (6 patients), patient request
(17 patients), or lost to follow-up (4 patients) (Fig.
2). The reasons for withdrawal and study discontinuation rates were similar across treatment
groups.
The treatment groups were comparable with
regard to baseline lipid parameters and demographics (Table 1). The intention-to-treat population consisted of 300 women and 238 men, 20–86
years of age, with hypercholesterolemia characterized by plasma concentrations of direct LDL-C from
3.4 to 6.3 mmol/l. Mean baseline plasma concentrations of direct LDL-C ranged from 4.4 to
4.7 mmol/l across treatment groups. Of the 538
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The primary endpoint was the percent change in
direct LDL-C (measured by beta-quantification)
from baseline to study end (last available postbaseline LDL-C measurement) for the intention-to-treat
population. The primary hypothesis was that the
coadministration of ezetimibe with pravastatin
(pooled across all doses: 10, 20, 40 mg) would
result in a significantly greater reduction in direct
LDL-C compared to pravastatin monotherapy
(pooled across all doses: 10, 20, 40 mg) and
ezetimibe monotherapy. The primary efficacy
analysis was performed using a two-way analysisof-variance (ANOVA) model that extracted effects
due to dose (pravastatin 0, 10, 20 and 40 mg),
treatment (ezetimibe, placebo), and treatmentby-dose interaction. The comparisons (pooled
ezetimibe 10 mg plus pravastatin [10, 20, 40 mg]
versus pooled pravastatin [10, 20, 40 mg], and
pooled ezetimibe 10 mg plus pravastatin [10, 20,
40 mg] versus ezetimibe 10 mg) were performed
using contrast statements under the model to
evaluate the primary hypothesis. Consistency of the
treatment effect across subgroups (sex, age [<65,
≥65 years], and race [Caucasian, non-Caucasian]),
treatment-by-factor (defining such subgroups) interactions were evaluated for the primary variable
in the intention-to-treat population using an ANOVA
model including factors for treatment, dose,
treatment-by-dose, subgroup, and treatment-bysubgroup interaction. With the planned sample size
of approximately 520 patients (65 patients per
treatment group), a difference of ≥5 percentage
points in direct LDL-C reduction could be detected
between any two individual treatment groups
with 80% power and a significance level of p<0.05
(two-tailed), assuming a standard deviation of 10.
L. Melani et al.
Efficacy and safety of ezetimibe
721
patients who were randomized to treatment, 37
(7%) had known coronary heart disease (CHD), and
309 (57%) had risk factors or a history of cardiovascular disease. Overall, approximately 40% (216/
538) of patients had a known family history of CHD,
31% (165/538) had a history of hypertension, 5%
(28/538) had a history of diabetes mellitus, and 1%
(8/538) had peripheral vascular disease.
Efficacy data
The coadministration of ezetimibe plus pravastatin
(pooled across all doses) was significantly more
effective than pravastatin alone (pooled across all
doses) at reducing plasma levels of direct LDL-C
from baseline to endpoint, as evidenced by a mean
percentage change of −38% for coadministration
versus −24% for pravastatin alone (p<0.01)
(Table 2). Similarly, coadministration of ezetimibe
plus pravastatin (pooled) was more effective
than ezetimibe alone at reducing direct LDL-C
(−38% versus −19%; p<0.01). Mean percentage
changes in direct LDL-C from baseline to endpoint
ranged from approximately −20% to −29% for individual doses of pravastatin monotherapy (pravastatin 10, 20, or 40 mg) versus −34% to −41% for
coadministration therapy (Fig. 3A). The incremental mean percentage reductions in direct LDL-C
resulting from the coadministration of ezetimibe
with each dose of pravastatin (ezetimibe plus
pravastatin 10 mg, ezetimibe plus pravastatin
20 mg, and ezetimibe plus pravastatin 40 mg) were
statistically significant (p≤0.01) when compared
with each corresponding dose of pravastatin monotherapy (pravastatin 10, 20, or 40 mg alone). Coadministration of ezetimibe plus pravastatin 10 mg
produced a larger mean percentage reduction in
direct LDL-C compared to the highest dose of
pravastatin monotherapy (−34% for ezetimibe plus
pravastatin 10 mg versus −29% for pravastatin
40 mg; p≤0.05). The incremental reduction in LDL-C
concentrations resulting from coadministration
of ezetimibe with pravastatin occurred as early
as Week 2 and was maintained throughout the
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Fig. 2 Trial profile. Number of patients who were randomized, who completed the studies, and who discontinued prematurely, are
shown for the placebo, ezetimibe monotherapy, pooled pravastatin monotherapy, and pooled coadministration treatment
groups.
722
Table 1
Baseline summary of patient demographics and lipid parameters
Characteristic
Placebo (n=65)
Ezetimibe (n=64)
Pooled pravastatina (n=205)
Ezetimibe+pooled pravastatina (n=204)
Mean age (year) (range)
Number of patients (%) ≥65 years
53.4 (32–76)
11 (17%)
52.0 (26–75)
10 (16%)
55.1 (23–84)
53 (26%)
56.9 (20–86)
50 (25%)
Race
Caucasian
Black
Hispanic
Asian
Pacific Islander
Other
52 (80%)
6 (9%)
1 (2%)
6 (9%)
0
0
60 (94%)
3 (5%)
1 (2%)
0
0
0
174 (85%)
12 (6%)
15 (7%)
3 (1%)
1 (<1%)
0
176 (86%)
11 (5%)
10 (5%)
5 (2%)
0
2 (<1%)
Gender
Male
Female
31 (48%)
34 (52%)
23 (36%)
41 (64%)
101 (49%)
104 (51%)
83 (41%)
121 (59%)
Baseline lipid values (mean, SD) mmol/l
Direct LDL-C
Calculated LDL-C
HDL-C
TG
4.6
4.6
1.3
1.8
4.6
4.7
1.3
2.0
4.6
4.6
1.3
2.0
4.6
4.6
1.3
2.0
Family history of CHD
Patient history of CHD
History of hypertension
History of diabetes mellitus
History of peripheral vascular disease
Current smoker
Currently physically active
27 (42%)
2 (3%)
15 (23%)
2 (3%)
0
10 (15%)
38 (58%)
24 (38%)
2 (3%)
20 (31%)
1 (2%)
1 (2%)
15 (23%)
33 (52%)
87 (42%)
16 (8%)
64 (31%)
14 (7%)
2 (<1%)
31 (15%)
107 (52%)
78 (38%)
17 (8%)
66 (32%)
11 (5%)
5 (2%)
22 (11%)
126 (62%)
Washout information
HMG-CoA reductase inhibitor
Fibrate
Nicotinic acid
Other
15 (23%)
1 (2%)
0
1 (2%)
14 (22%)
0
2 (3%)
2 (3%)
62 (30%)
1 (<1%)
4 (2%)
17 (8%)
63 (31%)
1 (<1%)
6 (3%)
15 (7%)
(0.5)
(0.5)
(0.3)
(0.7)
(0.6)
(0.6)
(0.3)
(0.7)
(0.6)
(0.6)
(0.3)
(0.7)
(0.5)
(0.5)
(0.3)
(0.7)
CHD=coronary heart disease; Direct LDL-C=low-density lipoprotein cholesterol measured by ultracentrifugation; calculated LDL-C=low density lipoprotein cholesterol calculated by
the Friedewald equation; HDL-C=high-density lipoprotein cholesterol; TG=triglycerides.
Pooled pravastatin=pravastatin pooled across all doses (10, 20, and 40 mg).
L. Melani et al.
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a
Efficacy and safety of ezetimibe
Table 2
Least-square mean percentage change from baseline to endpoint (Week 12) in plasma concentrations of various lipid-related variables
Variable (mmol/l)
Direct LDL-C
Calculated LDL-C
TC
TG
HDL-C
Apo Bc
Non-HDL-C
HDL2-C
HDL3-C
Apo A-Ic
Lipoprotein(a)d
Direct LDL-C:HDL-C
TC:HDL-C
Placebo (n=65)
Ezetimibe (n=64)
Pooled pravastatin (n=205)
Ezetimibe+pooled pravastatin (n=204)
Difference
B/E
% Change (SE)
B/E
% Change (SE)
B/E
% Change (SE)
B/E
% Change (SE)
P valuea
P valueb
4.6/4.6
4.6/4.6
6.8/6.8
1.8/1.8
1.3/1.3
1.7/1.6
5.5/5.5
0.5/0.5
0.9/0.8
1.6/1.5
1.2/1.2
3.6/3.6
5.3/5.3
1.3 (1.6)
−0.6 (1.5)
0.2 (1.2)
2.0 (3.8)
2.0 (1.5)
−2.2 (1.8)
−0.1 (1.4)
10.4 (4.7)
−1.6 (2.8)
−1.1 (1.5)
10.9 (7.0)
0.1 (1.7)
−1.2 (1.4)
4.6/3.7
4.7/3.7
6.9/6.0
2.0/1.9
1.3/1.4
1.7/1.4
5.6/4.6
0.5/0.5
0.9/0.9
1.6/1.6
1.1/1.1
3.7/2.9
5.5/4.6
−18.7 (1.6)
−19.6 (1.5)
−13.2 (1.2)
−2.1 (3.8)
4.1 (1.5)
−14.8 (1.8)
−17.2 (1.4)
13.8 (4.6)
0.5 (2.7)
2.5 (1.5)
15.0 (6.9)
−21.8 (1.7)
−16.0 (1.4)
4.6/3.5
4.6/3.4
6.8/5.6
2.0/1.8
1.3/1.4
1.7/1.3
5.5/4.3
0.5/0.5
0.8/0.9
1.6/1.6
1.1/1.1
3.7/2.6
5.5/4.3
−24.3 (0.9)
−25.2 (0.9)
−17.2 (0.6)
−7.6 (2.1)
6.7 (0.8)
−20.0 (1.0)
−22.7 (0.8)
17.0 (2.6)
5.4 (1.6)
3.6 (0.9)
−2.7 (3.9)
−28.6 (0.9)
−21.7 (0.8)
4.6/2.8
4.6/2.8
6.8/5.0
2.0/1.6
1.3/1.4
1.7/1.2
5.5/3.5
0.5/0.6
0.9/0.9
1.6/1.7
1.1/1.2
3.6/2.1
5.4/3.6
−37.7 (0.9)
−38.6 (0.9)
−27.1 (0.6)
−17.6 (2.1)
8.1 (0.8)
−30.2 (1.0)
−35.6 (0.8)
17.0 (2.6)
4.0 (1.6)
3.8 (0.9)
2.2 (3.9)
−41.7 (0.9)
−32.0 (0.8)
<0.01
<0.01
<0.01
<0.01
NS
<0.01
<0.01
NS
NS
NS
NS
<0.01
<0.01
<0.01
<0.01
<0.01
<0.01
0.02
<0.01
<0.01
NS
NS
NS
NS
<0.01
<0.01
B=baseline; E=endpoint; TC=total cholesterol; TG=triglyceride; Apo=apolipoprotein; NS=not significant (p>0.05).
Not every patient had an endpoint measurement for every variable; n ranged from 53 to 65 for the placebo group, 56 to 64 for the ezetimibe group, 174 to 205 for the pooled
pravastatin group, and from 173 to 204 for the coadministration group.
a
Ezetimibe+pooled pravastatin versus pooled pravastatin.
Ezetimibe+pooled pravastatin versus ezetimibe.
c
g/l.
d
µmol/l.
b
723
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724
L. Melani et al.
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Fig. 3 Percentage change in direct LDL-C (A), calculated LDL-C (B), HDL-C (C), and TG (D) concentrations from baseline to
endpoint. EZE5ezetimbe 10 mg; Prava5pravastatin.
duration of the study (Fig. 4). The overall increase
in LDL-C-lowering effect resulting from the coadministration of ezetimibe and pravastatin was
generally consistent across all subgroups, irrespective of risk-factor status, gender, age, race, and
baseline lipid profile (data not shown).
Ezetimibe plus pravastatin (pooled) also significantly improved the following secondary efficacy
variables compared to pravastatin alone (pooled)
(Table 2): calculated LDL-C, TG, TC, apo B, nonHDL-C, direct LDL-C:HDL-C, and TC:HDL-C (p<
0.01). Fig. 3 summarizes the changes in LDL-C (direct and calculated), HDL-C, and TG concentrations
across the individual treatment groups. Coadministration of ezetimibe with pravastatin significantly
reduced direct (Fig. 3A) and calculated (Fig. 3B)
LDL-C at all pravastatin doses (p<0.01) and TG (Fig.
3D) at pravastatin doses of 10 and 20 mg (p<0.05).
The combined regimen also produced greater but
not significant increases in HDL-C at the 10 and
40 mg doses (Fig. 3C).
Overall, 47% (96/204) of patients receiving
coadministration therapy achieved a ≥40% reduction in direct LDL-C concentrations at endpoint
compared with 8% (17/203) of patients receiving
pravastatin monotherapy. Of those patients with
baseline LDL-C levels above established NCEP ATP
III goals, 71% (144/204) receiving coadministration
therapy and 48% (97/203) receiving pravastatin
monotherapy attained target LDL-C levels by study
end (Table 3). The differences in the proportion
of patients achieving either NCEP ATP II or III
goals between the pooled treatment groups
(ezetimibe plus pooled pravastatin and pooled
Efficacy and safety of ezetimibe
Fig. 4 Mean percent change from baseline in plasma concentrations of direct LDL-C over time and at endpoint.
pravastatin alone) were statistically significant
(p<0.01).
Adverse events resulting in treatment discontinuation (19/538, or 4% of the total population) or
interruption (38/538, or 7% of the total population)
were generally no more common or severe in any of
the eight treatment groups. Treatment-related
adverse events were reported for 15% (31/205) of
patients receiving pravastatin monotherapy and
17% (35/204) of patients receiving coadministration
therapy. The type and incidence of non-laboratoryrelated adverse events were generally comparable
between the pooled treatment groups. Adverse
events causing discontinuation were reported for
4% (9/204) of patients on coadministration therapy
versus 1% (3/205) of patients in the pravastatin
monotherapy group. None of the types of adverse
events resulting in treatment discontinuation were
more common in any of the treatment groups.
Serious adverse events were rare and occurred with
similar frequency in both treatment groups. No
patient died during the study.
Overall, three patients demonstrated asymptomatic consecutive or presumed consecutive elevations in alanine aminotransferase (ALT) and/or
aspartate aminotransferase (AST) activity greater
than or equal to three times the upper limit of
normal (ULN) (Table 4). Two of these patients were
in the coadministration treatment arm (ezetimibe
plus pravastatin 20 mg, ezetimibe plus pravastatin
40 mg) and one was in the pravastatin monotherapy
arm (pravastatin 40 mg). The patient receiving
ezetimibe plus pravastatin 40 mg had elevated ALT
levels at baseline (patients with elevations up to 2×
ULN at baseline were eligible for randomization)
and discontinued from the study because of elevations in hepatic enzyme activity. The other
patient on coadministration therapy (ezetimibe
plus pravastatin 20 mg) with AST and/or ALT elevations ≥3× ULN completed the study. No cases of
hepatitis, jaundice, or other signs of liver dysfunction were reported in this study.
Clinically important elevations in creatine phosphokinase (CPK) values ≥10× ULN or >5× ULN and
<10× ULN with muscle symptoms were observed in
three patients, none of whom were in the coadministration group. Two patients (one in the pravastatin 10 mg group and one in the pravastatin 40 mg
group) experienced CPK elevations >10× ULN without associated muscle symptoms. A third patient
(ezetimibe monotherapy) reported symptoms of
myalgia and had CPK elevations between 5 and less
than 10× ULN. All three of these patients completed
the study. In all cases, physical exercise was
considered by the investigator to be a possible
contributing factor to the increased CPK activity.
Results of other laboratory tests, vital signs,
electrocardiograms, and cardiopulmonary examinations did not suggest any clinically important
differences between the coadministration and
pravastatin monotherapy groups.
Discussion
Efficacy of coadministration of ezetimibe
and pravastatin
The results of this study demonstrate that coadministration of ezetimibe plus pravastatin (pooled
across 10, 20, and 40 mg doses) produced greater
reductions in LDL-C than either pravastatin (p<
0.01) or ezetimibe (p<0.01) monotherapy. The
combined regimen (ezetimibe 10 mg plus pravastatin 10, 20, or 40 mg) also produced significant
LDL-C reductions compared with each corresponding and higher dose of pravastatin alone (p<0.01).
Moreover, the coadministration of ezetimibe with
pravastatin 10 mg provided greater LDL-C reductions compared to pravastatin 40 mg (−34%
versus −29%, respectively; p<0.05). A further enhancement of the LDL-C-lowering effect was
obtained when ezetimibe was combined with pravastatin 40 mg, resulting in a mean percentage
change from baseline of approximately −41%
compared to only −29% with pravastatin 40 mg
monotherapy.
Overall 47% of patients receiving coadministration therapy experienced a ≥40% reduction in
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Safety data
725
726
Table 3
L. Melani et al.
Achievement of NCEP ATP II and ATP III LDL-C goals at endpoint
Placebo (n=62)
Ezetimibe (n=63)
Pooled pravastatina
(n=203)
Ezetimibe+pooled
pravastatina (n=204)
NCEP ATP II14
Below goal at
Below goal at
Below goal at
Below goal at
baseline
endpoint
endpoint only
baseline only
9 (15%)
13 (21%)
7 (11%)
3 (5%)
11 (17%)
41 (65%)
30 (48%)
0
28 (14%)
131 (65%)
104 (51%)
1 (<1%)
26 (13%)
174 (85%)
148 (73%)
0
NCEP ATP III2
Below goal at
Below goal at
Below goal at
Below goal at
baseline
endpoint
endpoint only
baseline only
9 (15%)
14 (23%)
8 (13%)
3 (5%)
10 (16%)
38 (60%)
28 (44%)
0
25 (12%)
121 (60%)
97 (48%)
1 (<1%)
23 (11%)
167 (82%)
144 (71%)
0
a
Pooled pravastatin=pravastatin pooled across all doses (10, 20, and 40 mg).
Table 4
Number (%) of patients with adverse events
CPK
≥5×ULN
At least 10×ULN
Ezetimibe (n=64) Pooled
(n=205)
37 (57%)
7 (11%)
5 (8%)
45 (70%)
6 (9%)
2 (3%)
129 (63%)
31 (15%)
3 (1%)
134 (66%)
35 (17%)
9 (4%)
0
0
0
0
1 (<1%)c
1 (<1%)c
1 (<1%)
1 (<1%)
0
0
1 (2%)
0
1 (<1%)
2 (<1%)
1 (<1%)
0
ULN=upper limit of normal; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CPK=creatine phosphokinase.
a
Pooled pravastatin=pravastatin pooled across all doses (10, 20, and 40 mg).
Patients were considered to have two consecutive postbaseline elevations if their last record was ≥3× ULN, or if a measurement
of ≥3× ULN during treatment or ≤2 days after the end of treatment was followed by a measurement of <3× ULN that was taken >2
days following the last dose of study medication.
c
One patient receiving pravastatin 40 mg monotherapy experienced coincident elevations in ALT and AST.
b
LDL-C, compared to 8% of patients on pravastatin monotherapy. Coadministration of the two
lipid-lowering therapies produced maximal or nearmaximal incremental reductions in LDL-C relative
to statin monotherapy within the first 2 weeks of
treatment and this effect was maintained throughout the 12-week treatment period.
The efficacy results of this trial in conjunction
with the results of three similarly designed studies
with simvastatin, atorvastatin, and lovastatin demonstrate that ezetimibe is effective in enhancing
the lipid-modifying effects of statins.15–17 In addition to the LDL-C-lowering effects, coadministration therapy also produced favorable effects
on other lipid-related variables, including significant reductions in TC, TG, and apo B compared to
pravastatin (p<0.01) or ezetimibe alone (p<0.01).
Indicators of risk for CHD, such as LDL:HDL-C and
TC:HDL-C and non-HDL-C, also showed significant improvement with the coadministration of
ezetimibe plus pravastatin compared with pravastatin and ezetimibe monotherapy (p<0.01).
Finally, the combined use of ezetimibe and pravastatin produced greater, but not statistically
significant increases in HDL-C levels.
Analyses were performed to evaluate the proportion of patients achieving NCEP ATP II or ATP
III-defined LDL-C goals with combination therapy.
The results of these analyses showed that a significantly greater proportion of patients receiving
ezetimibe plus pravastatin coadministration
therapy were able to reach their treatment goals
compared to those who received pravastatin
therapy alone. This study was conducted while the
NCEP ATP II guidelines were still in clinical use. The
current NCEP-ATP III guidelines were issued before
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All adverse events
Treatment-related adverse events
Discontinuation due to adverse
event
Liver function tests
ALT≥3× ULN (consecutive)b
AST≥3× ULN (consecutive)b
pravastatina Ezetimibe+pooled
pravastatina (n=204)
Placebo (n=65)
Efficacy and safety of ezetimibe
the study was completed. These results suggest
that coadministration therapy may have the potential to increase the number of patients achieving
recommended lipid levels, and thus further studies
are warranted.
Safety of coadministration of ezetimibe and
pravastatin
In summary, the coadministration of ezetimibe
and pravastatin offers a promising new lipid
management strategy for patients with hypercholesterolemia. The combined use of these agents
provides complementary lipid-lowering effects to
statins with no apparent increased risk of adverse
events. In clinical practice, the combination regimen may prove a useful treatment for patients who
are either unable to reach LDL-C target concentrations with statins alone, or are at increased
risk for side effects with more potent doses of
statin monotherapy. In addition, the need for less
frequent dose titration with combination therapy
may lead to improved patient compliance and help
more patients achieve their LDL-C goals.
Acknowledgements
The authors wish to thank Dr Amy O. JohnsonLevonas from Merck Research Laboratories for
assistance in preparing this manuscript for
publication. This study was conducted by ScheringPlough Research Institute, Kenilworth, New Jersey,
USA, on behalf of Merck/Schering-Plough Pharmaceuticals, North Wales, Pennsylvania, USA.
The Ezetimibe Study Group consisted of the following investigators. Nicola Abate, MD, Dallas, TX;
Robert Ambruster, MD, Tucson, AZ; Robert E.
Broker, MD, Simpsonville, SC; Robert Benjamin
Chadband, MD, Birmingham, AL; Mukul S. Chandra,
MD, Louisville, KY; Linda Crouse, MD, Kansas City,
MO; Adnan Dahdul, MD, Springfield, MA; Z. A. Dalu,
MD, St. Louis, MO; Eugene DuBoff, MD, Denver, CO;
Steven L. Duckor, MD, Orange, CA; William T.
Ellison, MD, Greer, SC; Walter Gaman, MD, Irving,
TX; Richard Gilmore, MD, Lake Charles, LA; Raul E.
Goana, Sr., MD, San Antonio, TX; Salah El Hafi, MD,
Houston, TX; Regina C. Hamlin, MD, Fresno, CA;
David R. Hassman, DO, Berlin, NJ; Srini Hejeebu,
DO, Toledo, OH; Richard Heuser, MD, Phoenix, AZ;
Walter E. Hood, MD, Atlanta, GA; Harvey L. Katzeff,
MD, New Hyde Park, NY; Robert H. Knopp, MD,
Seattle, WA; Wayne Larson, MD, Lakewood, WA;
James R. LaSalle, DO, FAAFP, Excelsior Springs, MO;
Judy D. Laviolette, MD, Shreveport, LA; Robert S.
Lipetz, DO, Spring Valley, CA; Dennis C. McCluskey,
MD, Mogadore, CA; Jeffrey R. Medoff, MD,
Greensboro, NC; Avishai Mendelson, MD, West Palm
Beach, FL; Dennis Mikolich, MD, Cranston, RI;
Michael Miller, MD, Baltimore, MD; Richard Mills,
MD, Mount Pleasant, SC; Jane E. Mossberg, MD,
Eugene, OR; Michael J. Noss, MD, Cincinnati, OH;
Barry Packman, MD, Philadelphia, PA; Hitesh D.
Patel, MD, Tustin, CA; Robert W. Reindollar, MD,
Charlotte, NC; Deborah L. Richmond, DO, Lansing,
MI; Dennis S. Riff, MD, Anaheim, CA; Sid Rosenblatt,
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The safety results showed that coadministration of
ezetimibe plus pravastatin was well tolerated, with
an overall safety profile similar to pravastatin alone
and placebo. Generally, the adverse event profiles
were similar across treatment groups. There was no
evidence to suggest that the addition of ezetimibe to
any dose of pravastatin increased the risk of developing a non-laboratory adverse event. Furthermore,
there was no evidence to suggest a dose–response
relationship in adverse events across the pravastatin
treatment groups (10, 20, or 40 mg), either administered alone or in combination with ezetimibe.
Asymptomatic, dose-dependent increases in
transaminases are a well-recognized possible side
effect of statin therapy, and most other lipidlowering therapies.18,19 Overall, very few patients
in this study experienced clinically important
elevations in liver function tests. All transaminase
elevations were asymptomatic, and no cases of
hepatitis, jaundice, or signs of liver dysfunction
were reported. Of note was the finding that
coadministration of ezetimibe with low doses of
pravastatin (10, 20 mg) produced larger LDL-C
reductions compared to the highest dose of pravastatin monotherapy (40 mg). Thus, the combination
of ezetimibe with low-dose pravastatin therapy
provided greater LDL-C-lowering efficacy than
the highest recommended dose of pravastatin
monotherapy with no increased risk of clinically
important elevations in liver function tests.
Statin therapy also is known to cause increases in
CPK activity, mostly during the initial stages of
treatment and upward dose titration. While CPK
activity has been shown to fluctuate within a given
individual over time (often related to physical
exertion or muscular trauma), elevations of greater
than or equal to 10× ULN are generally considered
clinically relevant, requiring close monitoring for
signs and symptoms of muscle damage and possible discontinuation of treatment. No cases of
rhabdomyolysis were reported in this study. Overall, the lack of clinically relevant elevations in CPK
activity in this study suggested no increased risk
of myopathy with the coadministration of
ezetimibe and any dose of pravastatin compared to
pravastatin alone.
727
728
MD, FACP, Irvine, CA; Paul G. Sandall, MD,
Albuquerque, NM; Shobha Sekhon, MD, Fresno, CA;
Philip G. Smaldone, MD, Denver, CO; William
Spisak, MD, Portland, OR; Daniel VanHamersveld,
MD, Sacramento, CA; Robert Vogel, MD, Baltimore,
MD; Robert J. Weiss, MD, FACC, FAC, Auburn, ME;
Douglas G. Young, MD, Fair Oaks, CA; James H.
Zavoral, MD, Edina, MN; Edward T. Zawada, Jr.,
MD, Sioux Falls, SD; Franklin J. Zieve, Richmond,
VA.
References
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
through the identification of the active metabolites of
SCH48461. J Pharmacol Exp Ther 1997;283:157–63.
van Heek M, Farley C, Compton DS et al. Comparison of the
activity and disposition of the novel cholesterol absorption
inhibitor, SCH58235, and its glucuronide, SCH60663. Br J
Pharmacol 2000;129:1748–54.
Knopp RH, Bays H, Manion CV et al. Effect of ezetimibe
on serum concentrations of lipid-soluble vitamins.
Atherosclerosis 2001;2(Suppl):90.
Miettinen TA. Cholesterol absorption inhibition: a strategy
for cholesterol-lowering therapy. Drug Focus 2001;
55:710–6.
Friedewald WT, Levy RI, Fredrickson DS. Estimation of the
concentration of low-density lipoprotein cholesterol in
plasma, without use of the preparative ultracentrifuge. Clin
Chem 1972;18:499–502.
New York Heart Association. Disease of the heart and blood
vessels. Nomenclature and criteria for diagnosis. 6th ed.
Boston, MA: Little Brown, 1964. p. 114.
Summary of the Second Report of the National Cholesterol
Education Program (NCEP) Expert Panel on Detection,
Evaluation, and Treatment of High Blood Cholesterol in
Adults (Adult Treatment Panel II). JAMA 1993;269:3015–23.
Davidson MH, McGarry T, Bettis R et al. Ezetimibe coadministered with simvastatin in patients with primary
hypercholesterolemia. J Am Coll Cardiol 2002;40:2125–34.
Ballantyne C, Houri J, Notarbartolo A et al. Ezetimibe
coadministered with atorvastatin in 628 patients with
primary hypercholesterolemia. J Am Coll Cardiol 2002;
39:227A.
Kerzner B, Corbelli J, Sharp S et al. Efficacy and safety of
ezetimibe coadministered with lovastatin in primary
hypercholesterolemia. Am J Cardiol 2003;91:418–24.
Bradford RH, Shear CL, Chremos AN et al. Expanded Clinical
Evaluation of Lovastatin (EXCEL) study results. I. Efficacy in
modifying plasma lipoproteins and adverse event profile in
8245 patients with moderate hypercholesterolemia. Arch
Intern Med 1991;151:43–9.
Tolman KG. Defining patient risks from expanded preventive
therapies. Am J Cardiol 2000;85:9E–15E.
Downloaded from by guest on October 15, 2014
1. Wood D, De Backer G, Faergeman O et al. Prevention of
coronary heart disease in clinical practice: recommendations of the Second Joint Task Force of European and
other Societies on Coronary Prevention. Eur Heart J 1998;
19:1434–503.
2. Executive Summary of the Third Report of the National
Cholesterol Education Program (NCEP) Expert Panel on
Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;
285:2486–97.
3. Knopp RH. Drug treatment of lipid disorders. N Engl J Med
1999;341:498–511.
4. Fruchart J-C, Brewer HB Jr, Leitersdorf E. Consensus for the
use of fibrates in the treatment of dyslipoproteinemia and
coronary heart disease. Am J Cardiol 1998;81:912–7.
5. Backman JT, Kyrklund C, Kivisto
¨ KT et al. Plasma concentrations of active simvastatin acid are increased by
gemfibrozil. Clin Pharmacol Ther 2000;68:122–9.
6. Federman DG, Hussain F, Walters AB. Fatal rhabdomyolysis
caused by lipid-lowering therapy. South Med J 2001;
94:1023–6.
7. Bays HE, Dujovne CA. Drug interactions of lipid-altering
drugs. Drug Safety 1998;19:355–71.
8. van Heek M, France CF, Compton DS et al. In vivo
metabolism-based discovery of a potent cholesterol absorption inhibitor, SCH58235, in the rat and rhesus monkey
L. Melani et al.
`