DR. Dr. J. NUGROHO E. P, Sp.

JP(K) , FIHA, FAsCC

J. Nugroho E.P was born in Yogyakarta-Indonesia in 1968 and is the staff
of the Cardiovascular Department Dr. Soetomo General Hospital.
Education :
1992 : Medical degree, Gajah Mada University, Jogjakarta-Indonesia
2003 : Cardiovascular Specialist, Airlangga University, Surabaya- Indonesia Cardiologist certification
by National Board of Examination, The Indonesian Heart Association
2013 : Consultant Cardiologist (Vascular Cardiology) by National Board of Certification/ Collegiums of
Cardiology & Vascular Medicine)
2014 : Doctoral degree, Airlangga University, Surabaya - Indonesia
Training in board :
2005 : ECHO Singapore
2007 : Singapore, Cardiac CT Course
2007 : Peripheral Computed Tomography, UCLA, los Angeles
2010 : Cardiac MRI Siriraj Hospital Bangkok, Thailand
2011 : Vascular Training, Harapan Kita National Heart Centre, Jakarta
2012 : Echocardiography and Vascular Training in Philipine Health Centre, Quezon City
2013 : Fellowship on Intermediate Interventional Cardiology, Dr. Soetomo Teaching Hospital Faculty of
Medicine Airlangga
Memberships:
Member Indonesian Medical Association
Member Indonesian Heart Association
Fellow of ASEAN Federation of Cardiology (FAsCC)

Heart and
Vascular

Challenging LDLCholesterol Treatment :

IMPROVE-IT and Beyond

J. Nugroho, MD, Ph.D., SpJP (K),FIHA, FAsCC

Department of Cardiology and Vascular Medicine
Faculty of Medicine, Airlangga University Dr.Soetomo General Hospital
Surabaya-Indonesia

Dyslipidemia is a major risk factor for coronary heart disease

(CHD)1
Clinical trials conclusively have demonstrated that treatment
of lipid disorders can reduce CHD morbidity and mortality.
In meta-analysis of 38 statin trials :
10% reduction in Total Cholesterol
15% reduction in CHD mortality risk &11% reduction in
total mortality risk 2
LDL-C is the primary target to prevent CHD3
Intensity of intervention depends on total CV risk3
1. Goode et al.Lancet.1995;345(8946):362-64
2. Gould AL, et al. Circulation. 1998;97:946-952.
3. NCEP, Adult Treatment Panel III. JAMA. 2001;285:2486-2497.

30

4S - Placebo

25

Rx - Statin therapy
PRA pravastatin
ATV - atorvastatin
4S - Rx

20

LIPID - Placebo

15

CARE - Placebo

LIPID - Rx
CARE - Rx
HPS - Rx

10

TNT ATV80

HPS - Placebo

TNT ATV10
PROVE-IT - PRA

WOSCOPS Placebo
AFCAPS - Placebo

PROVE-IT ATV

AFCAPS - Rx

WOSCOPS - Rx
ASCOT - Placebo

ASCOT - Rx

0
40
(1.0)

60
(1.6)

80
(2.1)

100
(2.6)

120
(3.1)

140
(3.6)

160
(4.1)

180
(4.7)

200
(5.2)

LDL-C achieved mg/dL (mmol/L)

Secondary Prevention
Primary Prevention

1.Rosenson RS. Exp Opin Emerg Drugs.2004;9(2):269-279

2.LaRosa JC et al.N Engl J Med.2005;352:1425-1435

58,8
49,1

51,2

48,7

43,3

Overall
1
2
With
Without
(n=7279) prevention prevention Metabolic Metabolic
(n=3384) (n=3614) syndrome syndrome
(n=4409) (n=2775)

% of patients attaining LDL-C goals

% of patients attaining
LDL-C goals

100
90
80
70
60
50
40
30
20
10
0

100
90
80
70
60
50
40
30
20
10
0

75,4

76

55,4
34,9

Very high-risk :
<70mg/dl
(n=3557)

High-risk:
<100mg/dl
(n=2323)

Moderate risk:
<130 mg/dl
(n=1343)

Lower-risk: <160
mg/dl (n=25)

LDL-C goal according to risk category

Only 49.1% of patients overall attained LDL-C goal treatment

The proportion of patients attaining their respective LDL-C goal decreased
with increasing cardiovascular risk level1

Park, Jeung Euy et al. European Journal of Cardiovascular Prevention & Rehabilitation.2011. 0(00) 114
Hermans MP et al. Curr Med Res Opin 2010; 26: 445454

Based on 2004 updated National Cholesterol Educational Program Adult Treatment Panel III

40,1

Vietnam (n=847)

52,7

Thailand (n=847)

49,5

Taiwan (n=999)

48,6

Philipines (n=834)
45,1

Malaysia (n=767)

51,4

Korea (n=1591)
31,3

Indonesia (n=833)

82,9

Hongkong (n=561)
0

10

20

30

40

50

60

70

80

90

100

% of patients attainingnLDL-C goals

Indonesia were found to have the lowest success rate, with 31.3% attaining
their LDL-C goals, compared with other countries
Park, Jeung Euy et al. European Journal of Cardiovascular Prevention & Rehabilitation.2011. 0(00) 114

44%
56%

Titraned and Attained Goal

Titraned and Failed to Attain Goal

Most patients (56%) whose statin doses were up-titrated failed

to achieve their LDL-C targets.
Kim HS et al.Curr Med Res Opin.2007;24(7):1951-63

Aggressive goals recommended by NCEP ATP III 2004 Update and

AHA/ACC Guidelines for Secondary Prevention 2006 Update.1,2

Many patients are never treated or do not follow their treatment

program.3
Most LDL-C reduction with statins occurs with the starting dose.4

Each doubling of the statin dose lowered LDL-C about 6%3

Therefore, an additional 18% reduction would require doubling the
dose 3 times.
Most patients taking statins do not have their dose increased.4

1. Grundy SM et al. Circulation. 2004;110:227239. 2. Smith SC Jr et al. Circulation. 2006;113:23632372 3. Leitersdorf E. Int J Clin
Pract. 2002;56:116-119. 4. Foley KA et al. Am J Cardiol. 2003;92:79-81.

Incremental Reduction: One Step or Three Steps?

% Reduction in LDL Cholesterol

6%
THREE-STEP TITRATION

60

6%

50

6%
Titrasi Statin

40
ONE-STEP COADMINISTRATION
30

20

Add Ezetrol

21 %

10

2.

1.
Leitersdorf E. Int J Clin Pract. 2001; 56:116 119.
2. Bays H. Ezetimibe. Expert Opin Investing Drugs. 2002; 11:1587-1604.

Whole Body Cholesterol Homeostatis is

Maintained through 3 Major Pathway
Intestinal
Absorption

LDL-C

De novo
Synthesis

Billiary
Excretion
Bays H. Expert Opin. Investing Drugs 2002; 11: 1587-1604

Bridging the Gap Through Complementary

Mechanisms of Action
VLDL

IDL

LDL

Statins
synthesis

BILIARY SECRETION

Absorption

Cholesterol
Absorption
Inhibition

INTESTINE

DIETARY
CHOLESTEROL

Ezetimibe

Excretion

Ezetimibe + Low Dose Statin = High Dose

Statin Efficacy
EZETROL+Ator 10mg

10
20

Sim

10
mg

30

Sim
80
mg

Eze+
Sim
10

-32.7%

40
50

-48.5%

60
70

Bays,et.al, Clin Ther, 2004 Vol 26 No 11

- 44.8%

0
10
20

Ator
10
mg

30
40

Ator
80
mg

Eze+
Ator
10

-35%

50
-51%

60

70
Ballantyne, et.al, Circulation May 2003

- 50%

EZETROL+Rosu 10mg

Mean LDL-C Change From Baseline %

Mean LDL-C Change From Baseline %

Mean LDL-C Change From Baseline %

EZETROL+Simva 10mg

0
10
20
30

Ros
10
mg

Ros
40
mg

Eze+
Ros
10

40
50

-44.9%
-55%

60

- 61.4%

70
Kosoglu, et.al, Curr Med Res & Opin 2004, Vol 20 No.8

Pooled-analysis of 27 clinical trials comparing

the efficacy of Eze/Statin vs Statin therapies
in patients with and without diabetes
LDL-C

% change from baseline

Non-HDL-C

ApoB/ApoA1

with
diabetes

without
diabetes

with
diabetes

without
diabetes

with
diabetes

without
diabetes

n 3043 3394

7012 7831

3044 3397

7013 7832

2342 2467

4461 5238

-16,3

-15,9

-15

-23,7

-20,3

-21,7

-22,3

-30
-33,9
-37,2

-45

-27,8

-29,4

-41,1

-17.4%

-13.6%
-14.9%

p < 0.0001

= difference vs statin alone

-36,7

-15.0%

-13.0%

-11.9%
p = 0.0297

p = 0.0015

Statin alone

Eze/Statin

Leiter et al. Diab Obes Metab 2011; 13: 615-28

IMProved Reduction of
Outcomes: Vytorin Efficacy
International Trial
A Multicenter, Double-Blind, Randomized Study to
Establish the Clinical Benefit and Safety of Vytorin
(Ezetimibe/Simvastatin Tablet) vs Simvastatin
Monotherapy in High-Risk Subjects Presenting
With Acute Coronary Syndrome

National Lead Investigators and Steering

Committee (1158 sites, 39 Countries)
Enrique Gurfinkel
Argentina (331)

Jindrich Spinar
Czech Rep (371)

Basil Lewis
Israel (589)

Tibor Duris
Slovakia (121)

Philip Aylward
Andrew Tonkin*
Australia (116)

Peer Grande
Denmark (576)

Gaetano DeFerrari
Italy (593)

Anthony Dalby
S. Africa (186)

Juri Voitk
Estonia (10)

Ton Oude Ophuis

J. Wouter Jukema*
Netherlands (1191)

Jose Lopez-Sendon
Spain (551)

Gerald Maurer
Germany (935)
Frans Van de Werf
Belgium (249)
Jose C. Nicolau
Brazil (423)

Pierre Theroux
Paul Armstrong*
Jacques Genest*
Canada (1106)
Ramon Cobalan
Chile (152)
Daniel Isaza
Colombia (568)

Antero Kesaniemi
Finland (341)
Jean-Pierre Bassand
Michel Franier*
France (268)

Harvey White
New Zealand (164)
Terje Pedersen
Norway (295)

Harald Darius
Germany (935)

Frank Britto
Peru (66)

Matayas Keltai
Hungary (116)

Witold Ruzyllo
Poland (589)

Atul Mathur
Sanjay Mittal
Krishna Reddy
India (259)

Manuel Carrageta
Portugal (102)

Ki-Bae Seung
S. Korea (118)

Singapore (75), Malaysia (59), Hong Kong (58) Ecuador (45), Taiwan (46)
*Steering Comm Member, Deceased, 20052013

Mikael Dellborg
Sweden (480)
Francois Mach
Switzerland (263)
Sema Guneri
Turkey (50)
Alexander Parkhomenko
Ukraine (159)
Adrian Brady
United Kingdom (318)
Michael Blazing
Christopher Cannon
Christie Ballantyne*
James de Lemos*
Neal Kleiman*
Darren McGuire*
United States (5869)

Study Design
Patients stabilized post ACS 10 days:
LDL-C 50125*mg/dL (or 50100**mg/dL if prior lipid-lowering Rx)
N=18,144

*3.2mM
**2.6mM

Standard Medical & Interventional Therapy

Simvastatin
40 mg

Uptitrated to
Simva 80 mg
if LDL-C > 79
(adapted per
FDA label 2011)

Ezetimibe / Simvastatin
10 / 40 mg

Follow-up Visit Day 30, every 4 months

90% power to detect

~9% difference

Duration: Minimum 2 -year follow-up (at least 5250 events)

Primary Endpoint: CV death, MI, hospital admission for UA,
coronary revascularization ( 30 days after randomization), or stroke
Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12

Baseline Characteristics
Simvastatin
(N=9077)
%

EZ/Simva
(N=9067)
%

Age (years)

64

64

Female

24

25

Diabetes

27

27

MI prior to index ACS

21

21

STEMI / NSTEMI / UA

29 / 47 / 24

29 / 47 / 24

Days post ACS to rand (IQR)

5 (3, 8)

5 (3, 8)

Cath / PCI for ACS event

88 / 70

88 / 70

35

36

95 (79, 110)

95 (79,110)

Prior lipid Rx
LDL-C at ACS event (mg/dL, IQR)

LDL-C and Lipid Changes

1 Yr Mean

LDL-C

TC

TG

HDL

hsCRP

Simva

69.9

145.1

137.1

48.1

3.8

EZ/Simva

53.2

125.8

120.4

48.7

3.3

in mg/dL

-16.7

-19.3

-16.7

+0.6

-0.5

Median Time avg

69.5 vs. 53.7 mg/dL

Primary Endpoint ITT

Cardiovascular death, MI, documented unstable angina requiring
rehospitalization, coronary revascularization (30 days), or stroke
HR 0.936 CI (0.887, 0.988)
p=0.016

Simva 34.7%
2742 events

NNT= 50

EZ/Simva 32.7%
2572 events

7-year event rates

Primary and 3 Prespecified

Secondary Endpoints ITT
Simva* EZ/Simva* p-value

0.936

Primary
CVD/MI/UA/Cor Revasc/CVA

0.948

Secondary #1
All D/MI/UA/Cor Revasc/CVA

0.912

Secondary #2
CHD/MI/Urgent Cor Revasc

0.945

Secondary #3
CVD/MI/UA/All Revasc/CVA
0.8

1.0
Ezetimibe/Simva
Better

1.1
Simva
Better

34.7

32.7

0.016

40.3

38.7

0.034

18.9

17.5

0.016

36.2

34.5

0.035

*7-year
event rates (%)

UA, documented unstable angina requiring rehospitalization; Cor Revasc, coronary revascularization
(30 days after randomization); All D, all-cause death; CHD, coronary heart disease death;
All Revasc, coronary and non-coronary revascularization (30 days)

CV Death, Non-fatal MI,

or Non-fatal Stroke
HR 0.90 CI (0.84, 0.97)
p=0.003
NNT= 56

Simva 22.2%
1704 events

EZ/Simva 20.4%
1544 events

7-year event rates

IMPROVE-IT vs. CTT:

Ezetimibe vs. Statin Benefit

IMPROVE-IT

CTT Collaboration.
Lancet 2005; 366:1267-78;
Lancet 2010;376:1670-81.

Safety ITT
No statistically significant differences in cancer or
muscle- or gallbladder-related events
Simva
n=9077
%

EZ/Simva
n=9067
%

ALT and/or AST3x ULN

2.3

2.5

0.43

Cholecystectomy

1.5

1.5

0.96

Gallbladder-related AEs

3.5

3.1

0.10

Rhabdomyolysis*

0.2

0.1

0.37

Myopathy*

0.1

0.2

0.32

Rhabdo, myopathy, myalgia with CK elevation*

0.6

0.6

0.64

Cancer* (7-yr KM %)

10.2

10.2

0.57

* Adjudicated by Clinical Events Committee

% = n/N for the trial duration

Conclusions
IMPROVE-IT: First trial demonstrating incremental
clinical benefit when adding a non-statin agent
(ezetimibe) to statin therapy:
YES: Non-statin lowering LDL-C with ezetimibe
reduces cardiovascular events
YES: Even Lower is Even Better
(achieved mean LDL-C 53 vs. 70 mg/dL at 1 year)

YES: Confirms ezetimibe safety profile

Reaffirms the LDL hypothesis, that reducing
LDL-C prevents cardiovascular events

Results could be considered for future guidelines