Targeting Plaque Regression in

Dyslipidemia Management

(Nama Dokter)

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Doc No: ID-ATO-00044 Exp.Date: 21 Feb 2022
 Based on ESC/EAS 2019 guideline:
LDL is still the main target of lipid
management and reduction of LDL
cholesterol must be of prime concern in the
prevention of CVD

ESC Guidelines on Dyslipidemia. Eur Heart J. Epub ahead of print August 31, 2019. doi: 10.1093/eurheartj/ehz486.

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 Based on ESC 2019:
Very high risk patients should achieve >50% and <55 mg/dl

LDL-C target (mg/dl)

Risk level
ESC 2016 ESC 2019

Very high ↓50% and <70 ↓50% and <55*

High ↓50% and <100 ↓50% and <70

Moderate <100
<115
Low <116

* <40 mg/dl may be considered for patients with ASCVD who experience a
second vascular event within 2 years
ESC Guidelines on Dyslipidemia. Eur Heart J. Epub ahead of print August 31, 2019. doi: 10.1093/eurheartj/ehz486.
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 Based on ESC 2019:
Very high risk patients should achieve >50% and <55 mg/dl

Risk group LDL-C goal Class/Level

Very high risk (secondary prevention) Reduction ≥50% from baseline IA

and <1.4 mmol (<55 mg/dL)
Very high risk (primary prevention, without FH) Reduction ≥50% from baseline IC
and <1.4 mmol (<55 mg/dL)
Very high risk (primary prevention, with FH) Reduction ≥50 from baseline IIa/C
and <1.4 mmol (<55 mg/dL)
ASCVD + second event within 2 years <1.0 mmol (<40 mg/dL) IIb/B

High risk Reduction ≥50% from baseline IA

and <1.8 mmol (<70 mg/dL)
Moderate risk <2.6 mmol (<100 mg/dL) IIa/A

Low risk <3.0 mmol (<116 mg/dL) IIb/A

ESC Guidelines on Dyslipidemia. Eur Heart J. Epub ahead of print August 31, 2019. doi: 10.1093/eurheartj/ehz486.
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 CV risk stratification also determine LDL-C level goal
High to very high CV risk patients should achieve ≥50% LDL-C reduction

ESC Guidelines on Dyslipidemia. Eur Heart J. Epub ahead of print August 31, 2019. doi: 10.1093/eurheartj/ehz486.
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 Based on ESC 2019:
CV risk categories and recommendations
for management of dyslipidemia
Patients with DM and established CVD

Very or other target organ damage (proteinuria, renal impairment [eGFR≥30 mL/min/1.73 m2])

high-risk or 3 or more major risk factors (age, hypertension, dyslipidemia, smoking, obesity)
or early onset T1DM of long duration (>20 years)

Patients with DM duration ≥10 years without target organ damage plus
High-risk any other additional risk factor

Young patients (T1DM <35 years; T2DM <50 years) with DM duration <10 years,
Moderate-risk without other risk factors

Recommendations Class Level

Targets
In patients with T2DM at moderate CV risk, an LDL-C target of <2.6 mmol/L (<100 mg/dL) is recommended. I A
In patients with T2DM at high CV risk, an LDL-C target of <1.8 mmol/L (<70 mg/dL) and an LDL-C reduction of I A
at least 50% is recommended.

In patients with T2DM at very high CV risk, an LDL-C target of <1.4 mmol/L (<55 mg/dL) and an LDL-C I B
reduction of at least 50% is recommended.
In patients with T2DM, a secondary goal of a non–HDL-C target of <2.2 mmol/L (<85 mg/dL) in very high CV I B
risk patients, and <2.6 mmol/L (<100 mg/dL) in high CV risk patients, is recommended.
eGFR, estimated glomerular filtration rate
ESC Guidelines on Dyslipidemia. Eur Heart J. Epub ahead of print August 31, 2019. doi: 10.1093/eurheartj/ehz486. 6
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
 Atorvastatin+Ezetimbe
Clinical Trial
“The Powerful Combination to achieve optimal LDL level”

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 Summary of FDC ezetimibe+atorvastatin
Trial Baseline pt characteristics
EZ-PATH 579 high-risk pts with LDL-C 70-
160 mg/dl with ATO 40 mg/day
TEMPO 184 moderately-high risk pts
with LDL-C levels 100-160 mg/dl
receiving ATO 20 mg/day
Ballantyn 628 pts with primary
e et al. hypercholesterolemia and
baseline LDL-C 145-250 mg/dl
PACE 1547 high-risk pts with LDL-C
study 100 mg/dl despite treatment
with ATO 10 mg/day
PRECISE 246 pts with High risk patients
IVUS with LDL-C 100mg’/dl
ATO atorvastatin, EZE ezetimibe, LDL-C low-density lipoprotein cholesterol, pt(s) patient(s), ROS rosuvastatin
Treatment arms
EZE 10 mg/day +ATO 40 mg/day vs.
doubling ATO dose to 80 mg/day
EZE 10 mg/day +ATO 20 mg/day vs.
doubling ATO dose to 40 mg/day
Ten treatment groups: EZE 10 g/day + ATO
(10,20,40 or 80 mg), ATO (10,20,40 or 80 mg),
EZE 10 mg/day or placebo
EZE 10 mg/day + ATO 10 mg/day vs ATO 20
mg/day vs ROS 10 mg/day
Atorvastatin alone or atorvastatin plus
ezetimibe (10 mg) daily. Atorvastatin was
uptitrated with a treatment goal of low-
density lipoprotein cholesterol (LDL-C) <70
mg/dl.
Main results
Adding EZE to ATO 40 mg/day resulted in significantly greater
reductions in LDL-C and significantly more pts achieving LDL-C
<70 mg/dl
Adding EZE to ATO 20 mg/day resulted in significantly greater
reductions in LDL-C and significantly more pts achieving LDL-C
<100 mg/dl
Adding EZE to ATO (pooled doses) was significantly more
effective at reducing LDL-C than ATO monotherapy (pooled
doses)
Adding EZE to ATO 10 mg/day reduced LDL-C significantly
more than ATO 20 mg or ROS 10 mg
Atorvastatin and ezetimibe resulted in a more remarkable
reduction of LDL-C and Volumetric IVUS analysis demonstrated
superiority with regard to coronary plaque regression with
negative vascular remodeling in the analyzed target segment
than atorvastatin monotherapy
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Clinical Data for Ezetimibe/Atorvastatin:
Effect of Ezetimibe Coadministered With
Atorvastatin in 628 Patients With Primary
Hypercholesterolemia

Ballantyne CM et al.
Circulation. 2003;107:2409–2415.

Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022

 Ezetimibe in Combination
Study Result With Atorvastatin 10 mg
Reduced Mean LDL-C by 53%1
Efficacy of ezetimibe + the lowest dose of atorvastatin was similar to that of the highest dose of atorvastatin

Ezetimibe + Atorvastatin Mean Change in LDL-C

Atorvastatin 10
From Untreated Baseline
mg 10 mg 20 mg 40 mg 80 mg
0 With:
Ezetimibe + –54%a
-1 0
Change in LDL-C From

Atorva 20 mg
Untreated Baseline,%

-2 0 Ezetimibe + –56%a
Atorva 40 mg
-3 0 Ezetimibe + –61%a
Atorva 80 mg
-4 0 –37
–42
-5 0 –45
–53a –54
-6 0

-7 0
P < 0.01 P < 0.01 P < 0.01
• Ezetimibe + atorvastatin was more effective in reducing mean LDL-C than was atorvastatin alone (–56% vs –44% respectively, pooled across all doses); P<0.01.
• Mean pooled untreated baseline LDL-C was 182 mg/dL (~4.7 mmol/L) for the group receiving ezetimibe + atorvastatin (n=255) and 181 mg/dL (~4.7 mmol/L) for the
group receiving atorvastatin(n=248).
aP<0.01 for combination therapy vs corresponding dose of atorvastatin alone.
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Ballantyne CM et al. Circulation. 2003;107:2409–2415.
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
 Ezetimibe/Atorvastatin 10/10 mg
Study Result Provided Significantly Greater LDL-C Reduction
Compared With Atorvastatin 10, 20, and 40 mg1,2

Ezetimibe/atorvastatin Atorvastatin

The lowest Dosage of

Mean Percent Change in LDL-C

0
(Calculated) From Baseline

Atorvastation (10mg)
-10
in combination with
-20 Ezetimibe 10 mg
-30 provides similar LDL-C
reduction compared
-40 –37
–42
to highest dosage of
-50 –45
atorvastatin
-60
–53 –54 monotherapy (80mg)
P<0.01
-70
Mean baseline LDL-C was 182 mg/dL (~4.7 mmol/L) for ezetimibe/atorvastatin arms (n=255) and
181 mg/dL (~4.7 mmol/L) for atorvastatin arms (n=248).
Adapted with permission from Ballantyne CM et al.1

Ballantyne CM et al. Circulation. 2003;107:2409–2415.

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Ezetimibe + Atorvastatin 20 mg vs.
Doubling Atorvastatin to 40 mg
in Moderately High-Risk Patients With
Hypercholesterolemia

TEMPO STUDY

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 Ezetimibe + Atorvastatin Provided
Study Result Superior LDL-C–Lowering Efficacy vs.
Double the Dose of atorvastatin1

Ezetimibe 10 mg +
Atorvastatin 20 mg Atorvastatin 40 mg
(n=92) (n=92)
Baseline 120 mg/dL 118 mg/dL
0
Mean Change at

–10
Week 6, %

–11
–20
Reprinted from The American Journal of Cardiology, 102(11), Conard SE, Bays HE,
Leiter LA, et al, Efficacy and safety of ezetimibe added on to atorvastatin (20 mg)
–30 versus uptitration of atorvastatin (to 40 mg) in hypercholesterolemic patients at

–31a moderately high risk for coronary heart disease, 1489–1494, © 2008, with permission
from Elsevier.
aP<0.001 vs atorvastatin 40 mg.

–40

1. Conard SE et al. Am J Cardiol. 2008;102(11):1489–1494.

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 Changes Across a Range of Lipid Parameters
Study Result With Ezetimibe + Atorvastatin vs.
Double the Dose of Atorvastatin1

LDL-C HDL-C Total Triglycerides Non– Apo B Apo AI

Meana Change at Week 6, % 10 Cholesterol HDL-C
3c
1
0
–2c –1
–10 –7 –6
–8
–11 –10
–20 –18c
–20b –21b
–30
–31b –27b
–40
Ezetimibe 10 mg + atorvastatin 20 mg (n=92)
Atorvastatin 40 mg (n=92)
Apo=apolipoprotein.
aExcept for triglycerides, for which median % changes are shown; bP<0.001 vs atorvastatin 40 mg; cP=NS.

1. Conard SE et al. Am J Cardiol. 2008;102(11):1489–1494. 14

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 Ezetimibe + Atorvastatin Provided
Study Result Greater Improvements in Lipid Ratios vs.
Double the Dose of Atorvastatin1

Lipid Ratios
Total Cholesterol:HDL-C LDL-C:HDL-C Apo B:Apo AI Non–HDL-C:HDL-C
0

–10 –6
–8
Mean Change
at Week 6, %

–11 –10

–20
–19a
–21a
–30 –27a
–32a Ezetimibe 10 mg + atorvastatin 20 mg
–40 (n=92)
Atorvastatin 40 mg (n=92)
Apo=apolipoprotein.
aP<0.001 vs atorvastatin 40 mg.

1. Conard SE et al. Am J Cardiol. 2008;102(11):1489–1494.

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Efficacy and safety of ezetimibe added
to atorvastatin versus atorvastatin up-
titration or switching to rosuvastatin in
patients with primary
hypercholesterolemia.

PACE study
Bays HE et al. Am J Cardiol. 2013;112:1885–1895.

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 PACE Phase I:
Adding Ezetimibe to Atorvastatin 10 mg Provided
Study Result Greater Additional LDL-C Reduction vs Doubling
Atorvastatin to 20 mg or Switching to Rosuvastatin 10
mg1
Ezetimibe as an adjunct to diet when diet and
exercise alone are not enough
10

Treated Baseline at Week 6, %

LDL-C

IRLS Mean Change From

0

–10 –10%
–13%

–20
–22%

–30 P<0.001
IRLS = iteratively reweighted least squares.
P<0.001

Adding ezetimibe Doubling atorvastatin Switching to

to atorvastatin 10 mg to 20 mg rosuvastatin 10 mg
(n=120) (n=480) (n=939)
Mean on-statin baseline Mean on-statin baseline Mean on-statin baseline
LDL-C = 121 mg/dL (~3.1 mmol/L) LDL-C = 120 mg/dL (~3.1 mmol/L) LDL-C = 121 mg/dL (~3.1 mmol/L)
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Bays HE et al. Am J Cardiol. 2013;112:1885–1895.
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
 PACE Phase I:
Adding Ezetimibe to Atorvastatin 10 mg Resulted in
Study Result Greater Attainment of LDL-C <100 mg/dL (~2.6 mmol/L)
vs Doubling Atorvastatin to 20 mg or Switching to
Rosuvastatin 10 mg1

High-risk Patients Reaching LDL-C <100 mg/dL (~2.6 mmol/L) at 6 weeks,

as a Result of Greater LDL-C Reduction
Ezetimibe added to atorvastatin 10 mg Atorvastatin 20 mg Rosuvastatin 10 mg
(n=119) (n=471) (n=915)
Mean treated baseline LDL-C: Mean treated baseline LDL-C: Mean treated baseline LDL-C:
121 mg/dL (~3.1 mmol/L) 120 mg/dL (~3.1 mmol/L) 121 mg/dL (~3.1 mmol/L)

56% 37% 44%

IRLS = iteratively
P<0.001
reweighted least squares.
P<0.01
The IRLS mean decrease in LDL-C from statin-treated baseline was 22% with ezetimibe + atorvastatin 10 mg compared with 10% with
atorvastatin 20 mg and 13% with rosuvastatin 10 mg; P<0.001 for each comparison vs ezetimibe + atorvastatin 10 mg.. 18
Bays HE et al. Am J Cardiol. 2013;112:1885–1895. Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
 Summary
In the PACE trial of high-risk patients with hypercholesterolemia:
• In Phase I, the addition of ezetimibe 10 mg to atorvastatin 10 mg produced significantly greater
reductions in LDL-C versus doubling the dose of atorvastatin to 20 mg or switching to rosuvastatin 10
mg
• For patients on atorvastatin 20 mg at the end of Phase I who continued to Phase II, adding
ezetimibe to atorvastatin 20 mg reduced LDL-C significantly more than doubling the dose of
atorvastatin to 40 mg
• In patients on rosuvastatin 10 mg at the end of Phase I who continued to Phase II, switching to
ezetimibe plus atorvastatin 20 mg significantly reduced LDL-C compared with doubling the dose of
rosuvastatin to 20 mg
• As a result of greater LDL-C reduction, a significantly greater proportion of patients achieved LDL-C
<100 mg/dL (~2.6 mmol/L) and LDL-C <70 mg/dL (~1.8 mmol/L) among those:
• In Phase I who added ezetimibe to atorvastatin 10 mg vs those doubling the atorvastatin dose
to 20 mg or switching to rosuvastatin 10 mg
• In Phase II who added ezetimibe to atorvastatin 20 mg vs those doubling the atorvastatin dose
to 40 mg
• In Phase II who switched to ezetimibe plus atorvastatin 20 mg vs those doubling the rosuvastatin
dose from 10 to 20 mg
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Bays HE et al. Am J Cardiol. 2013;112:1885–1895. Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
 Clinical trials have been showing the powerful efficacy of
Atorvastatin+Ezetimibe in achieving optimal LDL-C level,
But how about the efficacy on coronary plaque regression?

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See beyond the number of LDL-C target,
why is it important to measure coronary
plaque regression?

The regression of atherosclerosis through lipid lowering has been a goal

since the early 1900s. Early experimental and epidemiological studies
suggested the possibility of plaque regression

the degree of plaque change was associated with the level

of LDL-C or the percentage reduction in LDL-C.

The plaque regression observations available from IVUS appear to

offer a powerful tool for predicting future clinical
events among patients with coronary artery disease.

Daida et al. 2019.J Atheroscler Thromb; 26: 592-600.

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Plaque Regression With Cholesterol
Absorption Inhibitor or Synthesis Inhibitor
Evaluated by Intravascular Ultrasound

PRECISE IVUS trial

Tsujita K, Sugiyama S, Sumida H, et al.

Trial. J Am Coll Cardiol 2015;66: 495–507.

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What is IVUS coronary imaging technique?
Rotating transducer Normal coronary anatomy

Images courtesy of Cleveland Clinic Intravascular Ultrasound Core Laboratory

Tsujita K, Sugiyama S, Sumida H, et al. Trial. J Am Coll Cardiol 2015;66: 495–507. 23
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 What is IVUS coronary imaging technique?

IVUS took its place as the principal imaging tool in atherosclerotic

progression/regression trials instead of the quantitative coronary
angiogram, because of its ability to precisely measure plaque
volume and also provide quantitative measurements of plaque
morphology and tissue characteristics

Tsujita K, Sugiyama S, Sumida H, et al. Trial. J Am Coll Cardiol 2015;66: 495–507.

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The IVUS technique can quantify atheroma

Angiogram IVUS

Little
evidence
of disease

Atheroma

IVUS=intravascular ultrasound
Nissen S, Yock P. Circulation 2001; 103: 604–616
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The IVUS technique can quantify atheroma

Arthery
Wall
Lumen

Plaque

Plaque area is in green

IVUS=intravascular ultrasound
Nissen S, Yock P. Circulation 2001; 103: 604–616
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 PRECISE-IVUS
Plaque Regression With Cholesterol Absorption Inhibitor or
Synthesis Inhibitor Evaluated by Intravascular Ultrasound

• To evaluate the effects of ezetimibe plus atorvastatin versus atorvastatin

monotherapy on the lipid profile and coronary atherosclerosis in Japanese
patients (n=246) who underwent percutaneous coronary intervention
(PCI).
• Inclusion criteria:
o Aged 30 to 85 years with CAD
o After having undergone successful coronary angiography or
percutaneous coronary intervention (PCI) under IVUS guidance to
treat ACS or stable angina pectoris (SAP).
o LDL-C level at entry of >100 mg/dl (2.6 mmol/L)
PRECISE-IVUS = Plaque Regression With Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular
Ultrasound; CAD = coronary artery disease; IVUS = intravascular ultrasound; ACS = Acute Coronary Syndrome

Tsujita K, Sugiyama S, Sumida H, et al. 2015 J Am Coll Cardiol 2015;66: 495–507.

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STUDY DESIGN

Month 0 Month 9-12

Primary endpoint: the absolute change in % coronary atheroma volume from baseline
to follow-up.
PRECISE-IVUS = Plaque Regression With Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular Ultrasound; ACS =
acute coronary syndrome; SAP = stable angina pectoris; CAG = coronary angiography; PCI = percutaneous coronary intervention; IVUS=
intravascular ultrasound.

Tsujita K, Sugiyama S, Sumida H, et al. 2015 J Am Coll Cardiol 2015;66: 495–507.

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 Study Result PRECISE-IVUS: LDL-C and Lipid Changes1

• The combination of atorvastatin/ezetimibe resulted in lower levels of LDL-C

than atorvastatin monotherapy [63.2 ± 16.3 mg/dl (1.62 ± 0.4 mmol/L) vs.
73.3 ± 20.3 mg/dl (1.89 ± 0.5 mmol/L); p < 0.001].

• The atorvastatin/ezetimibe group had a greater proportion of patients who

achieved LDL-C levels <70 mg/dl (1.8 mmol/L) (72% vs. 47%; p = 0.001)
compared to atorvastatin monotherapy group.
LZ group = atorvastatin/ezetimibe group; L group = atorvastatin monotherapy group
PRECISE-IVUS = Plaque Regression With Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular
Ultrasound
Tsujita K, Sugiyama S, Sumida H, et al. 2015 J Am Coll Cardiol 2015;66: 495–507. 29
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 Study Result IVUS IMAGE AT BASELINE AND FOLLOW UP

LZ group = atorvastatin/ezetimibe group; L

group = atorvastatin monotherapy group

PRECISE-IVUS = Plaque Regression With Cholesterol

Absorption Inhibitor or Synthesis Inhibitor
Evaluated by Intravascular Ultrasound; IVUS =
intravascular ultrasound; ACS = acute coronary
syndrome(s); SAP = stable angina pectoris; PB =
plaque burden

Tsujita K, Sugiyama S, Sumida H, et al. 2015 J Am Coll Cardiol 2015;66: 495–507.

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 a significantly greater percentage of patients who
Study Result received atorvastatin/ezetimibe showed coronary
plaque regression (78% vs. 58%; p = 0.004).

LZ group = atorvastatin/ezetimibe group; L group = atorvastatin

monotherapy group

PRECISE-IVUS = Plaque Regression With Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by
Intravascular Ultrasound; IVUS = intravascular ultrasound; PAV = percent atheroma volume

Tsujita K, Sugiyama S, Sumida H, et al. 2015 J Am Coll Cardiol 2015;66: 495–507.

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Study Result The highest plaques regression showed in the PRECISE-
IVUS Atorvastatin (ACS) with -2,3 ∆ PAV (%)

Relationship between achieved LDL-C levels and the median change

in percent atheroma volume in several intravascular ultrasound trials.

ACS = acute coronary

syndrome(s); SAP = stable angina
pectoris; PB = plaque burden

Tsujita K, Sugiyama S, Sumida H, et al. 2015 J Am Coll Cardiol 2015;66: 495–507. 32

Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
Summary
Compared with doubling the dose of atorvastatin in patients at moderate risk of CHD and
with hyperlipidemia, ezetimibe 10 mg/day + atorvastatin 20 mg/day was:

• Significantly greater reductions in LDL-C (P<0.001)

• Significantly higher rate of LDL-C goal achievement (P<0.001)
More • Greater reductions in LDL-C, total cholesterol, non–HDL-C,
Effective •
and Apo B (P<0.001)
Greater improvements in lipid ratios: total cholesterol:HDL-C,
LDL-C:HDL-C, Apo B:Apo A1, non–HDL-C:HDL-C (P<0.001)

Generally • Similar low incidence of clinical and laboratory adverse events

in each group
well
tolerated
1. Conard SE et al. Am J Cardiol. 2008;102(11):1489–1494. 33
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 Summary

Current Gaps
• Hyperlipidemia is a risk factor for CHD.1
• The need for adding non-statin treatment since many patients, including those on statins,
have elevated LDL-C or non–HDL-C levels.2,3
How do we close the gap?

• Ezetimibe/atorvastatin, as an adjunct to diet and exercise, is a therapeutic option to help

manage hyperlipidemia in statin-treated patients.5
• Ezetimibe/atorvastatin may be an effective therapeutic option to help reduce the risk of
cardiovascular events in patients with CHD.5
• Compared with standard statin monotherapy, the combination ezetimibe/atorvastatin showed
greater coronary plaque regression6
CHD = coronary heart disease.
1. NCEP ATP III Expert Panel. Circulation. 2002;106:3143–3421. 2. Gitt AK et al. Eur J Prev Cardiol. 2011;19:221–230. 3. Santos RD et al. Atherosclerosis. 2012;224:150–153.
4. Grigore L et al. Vas Health Risk Manag. 2008;4:267–278. 5. Data on file, MSD..6Tsujita K, et al. 2015 J Am Coll Cardiol 2015;66: 495–507. 34
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ATOZET Selected Safety Information
Indications: ATOZET contains ezetimibe and atorvastatin. ATOZET is indicated as adjunctive therapy to diet for use in adults with primary hypercholesterolaemia or
mixed hyperlipidaemia where use of a combination product is appropriate in patients not appropriately controlled with a statin alone or already treated with a statin
and ezetimibe.
Dosing: Patients with Hypercholesterolemia: The dosage range is 10/10 to 10/80 mg once daily. The recommended starting dose is 10/10 mg or 10/20 mg once daily.
Patient who require a larger reduction in LDL-C (more than 55%) may be started at 10/40 mg once daily. After initiation and/or up titration of ATOZET, lipid levels should
be analyzed within 2 or more weeks and dosage adjusted accordingly. Patients with Homozygous Familial Hypercholesterolemia: The dosage is 10/40 or 10/80 mg
daily. ATOZET should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.
Contraindications: Hypersensitivity to ezetimibe, atorvastatin, or any of its inactive ingredients. Active liver disease or unexplained persistent elevations of serum
transaminases exceeding three times the upper limit of normal (ULN). Pregnancy and nursing.
Precautions
Myopathy/Rhabdomyolysis: Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with atorvastatin and with other
drugs in this class. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle
effects. Atorvastatin, like other statins, occasionally causes myopathy, defined as muscle aches or muscle weakness in conjunction with increases in CPK values >10
times ULN. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be
advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persists
after discontinuing ATOZET. ATOZET therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. ATOZET therapy
should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to the
development of renal failure secondary to rhabdomyolysis (eg, severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and
electrolyte disorders, and uncontrolled seizures).
Liver Enzymes: In controlled coadministration trials in patients receiving ezetimibe with atorvastatin, consecutive transaminase elevations (≥3 X the upper limit of
normal [ULN]) have been observed. It is recommended that liver enzyme tests be obtained prior to initiating therapy with ATOZET and repeated as clinically indicated.
If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with ATOZET, promptly interrupt therapy.
Endocrine function: Statins interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production. Clinical studies have shown
that atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve. Caution should be exercised if ATOZET is administered concomitantly
with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.
Increases in hemoglobin A1c (HbA1c) and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin. Periodic
monitoring of these patients is recommended.
Hepatic impairment: Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic impairment, ATOZET is not
recommended in these patients.
Further information is available upon request. Before initiating therapy, please consult the full Prescribing Information.

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ATOZET Selected Safety Information
Drug Interactions
CYP3A4 Interactions: Concomitant administration of atorvastatin with inhibitors of cytochrome P450 3A4 can lead to increases in plasma concentrations of
atorvastatin, thus increasing the risk of myopathy.
(eg clarithromycin, combination of protease inhibitor, cyclosporine, itraconazole, grapefruit juice)
Other Interactions: Fibrates: Concomitant administration of ATOZET with gemfibrozil should be avoided due to an increased risk of myopathy/rhabdomyolysis. ATOZET
should be administered with caution when used concomitantly with fenofibrate as the risk of myopathy is increased. Coadministration of ATOZET and other fibrates is
not recommended as it has not been established. Fusidic acid: Patients on fusidic acid treated concomitantly with ATOZET may have an increased risk of myopathy/
rhabdomyolysis. Coadministration with fusidic acid is not recommended. Anticoagulants: if ATOZET is added to warfarin, another coumarin anticoagulant, or
fluindione, the International Normalized Ratio (INR) should be appropriately monitored. Inhibitors of Breast Cancer Resistant Protein (BCRP): Dose of ATOZET should not
exceed 10/20mg daily when concomitant administration of products containing elbasvir and grazoprevir. Digoxin: When multiple dose of atorvastatin and digoxin
were coadministered, steady-state plasma digoxin concentrations increased by approximately 20%. Patients taking digoxin should be monitored appropriately.
Niacin: The risk of skeletal muscle effects may be enhanced when ATOZET is used in combination with niacin; a reduction in ATOZET dosage should be considered.
Colchicine: Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin coadministered with colchicine, and caution should be exercised
when prescribing ATOZET with colchicine.
Side Effects
ATOZET (or coadministration of ezetimibe and atorvastatin equivalent to ATOZET) has been evaluated for safety in more than 2400 patients in 7 clinical trials. ATOZET
was generally well tolerated. Common side effects (≥1/100, <1/10) include: diarrhea and myalgia. In controlled clinical trials, the incidence of clinically important
elevations in serum transaminases (ALT and/or AST ≥3X ULN, consecutive) was 0.6% for patients treated with ATOZET. These elevations in transaminases were generally
asymptomatic, not associated with cholestasis, and returned to baseline spontaneously or after discontinuation of therapy.
Further information is available upon request. Before initiating therapy, please consult the full Prescribing Information.

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YOU’ E GOT THE POWER

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