CURRICULUM VITAE

Name

Dr. Anwar Santoso, PhD, FIHA, FAsCC, FICA, FACC

Place & Date of Surabaya, 20 July

birth
Official
Lecturer in Dept. of Cardiology Faculty of Medicine ~ University of Indonesia,
designation
Jakarta - Indonesia
Clinical Researcher in Division of Cardiovascular Research of National
Cardiovascular Centre Harapan Kita Hospital, Jakarta - Indonesia
Consultant Cardiologist in Harapan Kita Hospital, Jakarta - Indonesia
Academic rank Lektor Kepala (gol IV-D) Associate Professor
Office Address Jl. Letjen S Parman kav 87, Jakarta Barat 11420, Indonesia,
Phone: +62 21 568 1149; Fax: +62 21 568 4220
Educational
1. Medical Doctor, Airlangga University, School of Medicine, Indonesia.
background
2. Cardiologist, Airlangga University, School of Medicine, Indonesia, 1992
3. PhD, Udayana University, Post Graduate Program, Bali - Indonesia, 2005
4. Cardiology Consultant, Indonesian Heart Association, 2004
5. Advanced Cardiology Training Epworth Hospital & Victoria Heart Centre in
Melbourne, 1996
Professional
1. The Indonesian Medical Association, member, 1993 - now
Society
2. Indonesian Heart Association, member, 1993 now
Memberships
3. President of Indonesian Heart Association, 2014 2016
4. Indonesian Internal Medicine Society, member, 1993 - now
5. Indonesian Atherosclerosis and Vascular Disease Association, member, 1996 - now
6. Asean College of Cardiology, fellow, 2009 now
7. International College of Angiology, fellow, 2012 now
8. American College of Cardiology, fellow, 2014 - now

Acute Coronary Syndromes:

Risk stratification and how to deal with?
Anwar Santoso
Dept. of Cardiology Faculty of Medicine; University of Indonesia
National Cardiovascular Centre Harapan Kita Hospital
President of Indonesian Heart Association
Jakarta - Indonesia

Disclosure
Speaker has received honorarium from the following
industry as an independent advisory board

Astra Zeneca
Merck Sharpe & Dome
Pfizer
Takeda

Outlines
Challenges of ACS management in Asia Pacific
Risk stratifications and the issues in ACS
What the recent guidelines teach us?
Summary

AsPac ACS Medical Management Working Group, Int J Cardiol 2015; (183): 63 - 75

Overview of main international and AsPac ACS Guidelines

AsPac ACS Medical Management Working Group, Int J Cardiol 2015; (183): 63 - 75

Accessibility/systems of care
Barriers

Unmet needs

Geographical barriers

Significant delays between symptom

onset and FMC

Limited ambulance services, equipment

and staff

Low rates of pre-hospital triage and

fibrinolysis

Limited PCI-capable facilities and

manpower and lack of access to
guideline-approved drugs

Disparity in quality of care

Recommendations

Shorten the delay between patient first experiencing symptoms and FMC

Encourage regional co-ordination of ambulance services

Encourage ambulance services to liaise with hospitals and perform

pre-hospital triage and pre-hospital fibrinolysis where appropriate

Establish rapid assessment protocols in the ER

Utilize existing infrastructure more efficiently through cardiac networks

AsPac ACS Medical Management Working Group, Int J Cardiol 2015; (183): 63 - 75

Risk stratification
Barriers

Unmet needs

Risk factors and ethnic profiles vary

within the Asia-Pacific region

Subjective estimation of patient

risk and under-estimation of
treatment benefit

Variability in use of structured models for

risk stratification

Disparity in formal risk assessment

Recommendations

Recommend risk assessment at first medical contact

Identify high-risk groups (ethnicity, obesity, diabetes, renal dysfunction)

Recommend use of formal risk scores (primarily GRACE)

Validate TIMI and GRACE risk scores using Asia-Pacific registry data

Develop decision support tools to complement risk tools

Consider bleeding risk

AsPac ACS Medical Management Working Group, Int J Cardiol 2015; (183): 63 - 75

Education
Barriers

Unmet needs

Low public awareness of ACS signs and

symptoms and risk factors

Significant delays between symptom

onset and FMC

Poor patient compliance with lifestyle

modification and pharmacotherapy

Sub-optimal long-term
secondary prevention

Low rates of guideline adherence

DAPT use varies greatly between AsiaPacific countries

Lack of familiarity with new drugs

amongst non-cardiac physicians

Adoption of newer, more potent P2Y12

receptor antagonists is slow

Recommendations

Improve public awareness and plan of action to avoid late presentation

Enlist cardiac society/industry support to disseminate guidelines and

educate patients

Promote national and individual smoking cessation initiatives

Educate non-cardiac physicians

AsPac ACS Medical Management Working Group, Int J Cardiol 2015; (183): 63 - 75

Cost/affordability
Barriers

Unmet needs

User-funded healthcare systems in some

countries

Inequity in standards of care

Reimbursement systems

Limited real-world access to

optimal pharmacotherapy

Recommendations

Prioritize treatment to achieve the greatest benefit with available funding:

Aspirin immediately and continued indefinitely

Statin therapy in hospital, continued indefinitely irrespective of LDL-C
DAPT for 12 months with a newer potent antiplatelet if feasible
Oral BBs in the medium term
Long-term ACEi/ARBs in presence of LV dysfunction
Aldosterone antagonists in presence of LV dysfunction
AsPac ACS Medical Management Working Group, Int J Cardiol 2015; (183): 63 - 75

Risk Stratification is important in NSTE-ACS

Management
1

CLINICAL CONDITION

TIMI SCORE

Less accurate in predicting events but its

simplicity makes it useful and widely
accepted

GRACE SCORE

recommended as the preferred

classification to apply on admission and at
discharge in daily clinical routine practice

Hamm W et al. European Heart Journal 2007; 28:15981660; Hamm CW et al. Eur Heart J 2011;32:2999 3054

HIGH RISK
PRIMARY
Relevant rise or fall in troponin
Dynamic ST- or T-wave changes
(symptomatic or silent)
SECONDARY
Diabetes mellitus
Renal insufficiency
(eGFR <60 mL/min/1.73 m)
Reduced LV function (EF <40%)
Early post infarction angina
Recent PCI
Prior CABG
Intermediate to high GRACE risk score

Hamm CW et al. Eur Heart J 2011;32:2999 3054

VERY HIGH RISK

Refractory angina
Severe heart failure
Life-threatening ventricular arrhythmias, or
hemodynamic instability

TIMI SCORE
Risk
Score

TIMI risk score for developing at least

1 component of the primary end point
through 14 days after randomization.1

0-1

4.7%

8.3%

ST-segment deviation on ECG 0.5mm?

13.2%

Use of aspirin in prior 7 days

19.9%

At least 2 anginal events in prior 24 hours?

26.2%

6- 7

40.9%

Age 65 years or older?

At least 3 risk factors for CAD?
Prior coronary stenosis of 50% or more?

Elevated serum cardiac markers?

Hamm W et al. European Heart Journal 2007;28:15981660

GRACE SCORE
Predictor

Score

Age, years

Predictor

Score

Predictor

Score

Killip class

Systolic Blood Pressure (mmHg)

< 40

< 80

63

40 - 49

18

80 99

58

II

21

50 - 59

36

100 - 119

47

III

43

60 - 69

55

120 - 139

37

IV

64

70 - 79

73

140 - 159

26

80

91

160 - 199

11

Predictor

Score

> 200

Cardiac
arrest at
admission

43

Elevated
cardiac
markers

15

ST Segment
deviation

30

Predictor

Score

Heart Rate , beats/min

Predictor

Score

Creatinine (mol/L)

< 70

0 - 34

70-89

35 70

90-109

13

71 105

110 - 149

23

106 140

11

150 - 199

36

141 176

14

> 200

46

177 353

23

354

31

Khalill R et al. Exp Clin Cardiol.2009; 14(2): e25 e30

Risk category
(tertile)

GRACE
Risk Score

In-hospital
death
(%)

Low

108

<1

Intermediate

109 - 140

1-3

High

> 140

>3

Das Sein und Das Sollen

Predictive value of the HFA/CSANZ, TIMI and GRACE risk

score for major adverse cardiac events within 30 days

Cullen L, et. al. Heart, Lung and Circulation 2013: 22: 844 - 51

Accuracy of GRACE in predicting MACE

in 3 ethnics in Singapore

GRACE risk score is underpredicted in Asian

ACS management should be more agressive

Chan MY, et. al. Am Heart J 2011: 0: 1 - 9

Cath lab or later ?

Benefit of early intervention in high risk patients

Primary endpoint : death, myocardial infarction, or stroke.

Mehta, SR et al. N Engl J Med 2009;360:2165-75.

Evidence-based medication in ACS in China and India

Bi Y, et. al. Am Heart J 2009: 157: 509 516. e1

Xavier D, et. al. The Lancet 2008: 371: 1435 - 42

Use of evidence based-treatment in low-, moderate- and

high-risk ACS in Korea and Singapore

Lee JH, et. al. Am Heart J 2010: 159: 1012 - 19

Chan MY, et. al. Am Heart J 2011: 0: 1 - 9

Proportions and reasons for non-adherence in

Chinese ACS patients

Bi Y, et. al. Am Heart J 2009: 157: 509 516. e1

Das Sein und Das Sollen

Timing of angiography for NSTE-ACS

Refractory angina
Severe heart
Failure
Life-threatening ventricular
arrhythmias, or Hemodynamic
instability

At least one

< 2 hour

Urgent coronary angiography

none
Relevant rise or fall in troponin
Dynamic ST- or T-wave changes
(symptomatic or silent)
Grace risk score > 140

At least one

< 24 hour
Early invasive strategy

none
Diabetes mellitus
Renal insufficiency
(eGFR <60 mL/min/1.73 m)
Reduced LV function (EF <40%)
Early post infarction angina
Recent PCI
Prior CABG
GRACE risk score 109-140

At least one

< 72 hour

none
Non- invasive investigation
Hamm CW et al. Eur Heart J 2011;32:2999 3054

Elective if indicated

Initial Treatment
Initial Therapeutic Measures

Hamm CW et al. Eur Heart J 2011;32:2999 3054

Checklist of treatments when an ACS

diagnosis appears likely

Oral Antiplatelet Plays Important Role in ACS

1. Bode C and Huber K. European Heart Journal Supplements. 2008: 10 (Supplement A), A13A20
2. Bassand JP et al. European Heart Journal 2007;28:15981660

Benefit CV Mortality P2Y12 Inhibitor

CURE1

TRITON TIMI 382

P = N/A

P = NS

P = 0.001

5,50

5,10

5,10

Rate of CV death (%)

PLATO3

4,00

2,40

Plasebo

Clopidogrel

n = 12.562
NNT = 250

Clopidogrel

2,10

Prasugrel *

n = 13.608
NNT = 333

Clopidogrel

Ticagrelor

n = 18.624
NNT = 91

1.Yusuf S et al. N Engl J Med 2001;345; 2.Wiviott SD e tal. N Engl J Med 2007;357:2001-15; 3.Wallentin L, et al. N Engl J Med. 2009;361:10451057.
* Prasugrel is not yet approved and available in Indonesia

ESC 2012 STEMI guidelines:

periprocedural antiplatelet therapy in PPCI
Recommendations

Class

Level

ASA oral or iv (if unable to swallow) is recommended

An ADP receptor blocker is recommended in addition to ASA.

Options are:

Prasugrel* in clopidogrel-nave patients, if no history of prior

stroke/TIA, age <75 years

Ticagrelor

Clopidogrel, preferably when prasugrel or ticagrelor are either not

available or contraindicated

* Prasugrel is not yet approved and available in Indonesia

Steg PG et al. Eur Heart J 2012;33:25692619

ESC/EACTS 2014 Guidelines on

myocardial revascularization1
Recommendation in STEMI
A P2Y12 inhibitor is recommended in
addition to ASA and maintained over 12
months unless there are
contraindications such as excessive
bleeding

It is recommended to give P2Y12

inhibitors at the time of first medical
contact

Class

Level

A/B

1. Kolh P et al. Eur Heart J August 29 2014; DOI:10.1093/eurheart/ehu278 [Epub ahead of print]
2. Bellemain-Appaix A et al. JAMA 2012;308:25072516
3. Zeymer U et al. Clin Res Cardiol 2012;101:305312
4. Koul S et al. Eur Heart J 2011;32:29892997
5. Dorler J et al. Eur Heart J 2011;32:29542961

Evidence
PLATO
TRITON
CURRENT-OASIS 7

2,3,4,5

2014 AHA/ACC NSTEACS Guidelines

Recommendations

Dosing and
special consideration

Class / Level

P2Y12 inhibitors
Clopidogrel loading dose followed by daily
maintenance dose in patients unable to take aspirin

75 mg

IB

P2Y12 inhibitor, in addition to aspirin, for up to 12

months for patients treated initial with either an early
invasive or initial ischemia-guided therapy :

a. Clopidogrel

300 mg or 600 mg loading

dose, then 75 mg/d

b. Ticagrelor*

180 mg loading dose, then 90

mg BID

P2Y12 inhibitor therapy (clopidogrel, prasugrel, or

ticagrelor) continued for at least 12 months in postPCI patients treated with coronary stents

N/A

Ticagrelor in preferable to clopidogrel for patients

treated with an early invasive or ischemia-guided
therapy

N/A

IB

IB

*The recommended maintenance dose of aspirin to be used with ticagrelor is 81 mg daily

Amsterdam EA et al. J Am Coll Cardiol Sept 23, 2014 Epub ahead of print. DOI:10.1016/j.jack.2014.09.017

IIaB

Evolving issues?

Short-term (< 6 months) versus long-term

(1 year) DAPT in post stent CAD?

How to deal with stable CAD after 1 year?

Palmerini T, et al. J Am Coll Cardiol 2015; 65: 1092 102.

Dual anti-platelet therapy duration after DES

Palmerini T, et al. J Am Coll Cardiol 2015; 65: 1092 102.

Patient subgroups and DAPT duration

Palmerini T, et al. J Am Coll Cardiol 2015; 65: 1092 102.

PEGASUS-TIMI 54
A randomised, double-blind, placebo-controlled,
parallel-group, multinational trial to assess the prevention
of thrombotic events with ticagrelor compared with placebo
on a background of acetylsalicylic acid therapy in patients
with a history of myocardial infarction

The PEGASUS-TIMI 54 study investigates the efficacy and safety of ticagrelor in

an unlicensed patient population. Therefore this slide deck is restricted solely for
Medical Affairs use in Scientific Exchange activities and is for reactive use only
Please ensure local review prior to external use

PEGASUS-TIMI 54: Rationale (1)

Patients who have suffered a MI are at heightened risk of recurrent
ischaemic events13
The recent APOLLO-HELICON registry highlighted that 1 in 5 patients who remain
event free 1 year post-MI will go on to suffer another MI, a stroke, or die from CV
causes in the subsequent 3 years3
These data suggest that patients with a history of MI may derive particular benefit
from intensive secondary prevention strategies

However, the role of P2Y12 receptor antagonists in long-term

secondary prevention after MI has not been established
Both US and European ACS practice guidelines currently recommend
treatment with a P2Y12 receptor antagonist for up to 1 year after MI47
CV, cardiovascular; MI, myocardial infarction
1. Bhatt DL et al. JAMA 2010;304:13501357
2. Fox KA et al. Eur Heart J 2010;31:27552764
3. Jernberg T et al. Eur Heart J 2015; pii: ehu505 [Epub ahead of print]
4. Amsterdam EA et al. Circulation 2014;130:23542394
5. Hamm CW et al. Eur Heart J 2011;32:29993054
6. O'Gara PT et al. Circulation 2013;127:e362425
7. Steg PG et al. Eur Heart J 2012;33:25692619

35

PEGASUS-TIMI 54: Rationale (2)

Ticagrelor is a potent, reversibly binding, direct-acting agent P2Y12

receptor antagonist that has low inter-individual variability1

Ticagrelor also increases endogenous adenosine levels via inhibition of

the equilibrative nucleoside transporter-12

When added to ASA for up to 1 year after an ACS event, ticagrelor

90 mg bid reduced the rate of major adverse CV events, including CV
death, as compared with clopidogrel 75 mg once daily, with an accrual
of benefit over time3

Building on these observations, the PEGASUS-TIMI 54 trial was

designed to test the hypothesis that long-term therapy with ticagrelor
added to low-dose ASA will reduce the risk of major adverse CV events
in high-risk patients with a history of MI

1. Husted S et al. Eur Heart J 2006;27:10381047

2. Cattaneo M et al. J Am Coll Cardiol 2014;63:25032509
3. Wallentin L et al. N Engl J Med 2009;361:10451057

36

PEGASUS-TIMI 54: Study Design

Patients aged 50 years with a history of spontaneous MI 13 years prior to
enrolment AND at least one additional atherothrombosis risk factor*
(N=21,162)

Ticagrelor 90 mg bid
+ ASA 75150 mg/day

Ticagrelor 60 mg bid
+ ASA 75150 mg/day

Placebo
+ ASA 75150 mg/day

Minimum of 12 months follow up:

Every 4 months in Year 1,
then semi-annually
Primary efficacy endpoint: CV death, MI or stroke
Primary safety endpoint: TIMI-defined major bleeding
*Age 65 years, diabetes mellitus, second prior MI, multivessel CAD or chronic non-end stage renal disease
bid, twice daily; CAD, coronary artery disease; TIMI, Thrombolysis in Myocardial Infarction
Bonaca MP et al. Am Heart J 2014;167:437444
Bonaca MP et al. N Engl J Med 2015 [Epub ahead of print]

37

PEGASUS-TIMI 54: Primary Endpoint

10

Placebo
Ticagrelor 90 mg bid
Ticagrelor 60 mg bid

Event rate (%)

9.04% Placebo

7.85% 90 mg bid

7.77% 60 mg bid

6
5
4
3

Ticagrelor 90 mg vs placebo
HR 0.85 (95% CI 0.750.96) P=0.008

Ticagrelor 60 mg vs placebo
HR 0.84 (95% CI 0.740.95) P=0.004

1
0
0
No. at risk
Placebo
90 mg bid
60 mg bid

12

15

18

21

24

27

30

33

36

5876
5921
5904

5157
5243
5222

4343
4401
4424

3360
3368
3392

2028
2038
2055

Months from randomisation

7067
7050
7045

6979
6973
6969

6892
6899
6905

6823
6827
6842

6761
6769
6784

6681
6719
6733

6508
6550
6557

6236
6272
6270

CI, confidence interval; HR, hazard ratio

Bonaca MP et al. N Engl J Med 2015 [Epub ahead of print]

38

PEGASUS-TIMI 54: Efficacy Endpoints

3-year KM event
rates (%)

Endpoint

Ticagrelor Placebo

Primary
(CV death, MI or stroke)
CV death

MI

Stroke

0.4

0.6

0.8

Ticagrelor better

1.25

HR (95% CI)

P value

7.85

9.04

0.85 (0.750.96)

0.008

7.77

9.04

0.84 (0.740.95)

0.004

7.81

9.04

0.84 (0.760.94)

0.001

2.94

3.39

0.87 (0.711.06)

0.15

2.86

3.39

0.83 (0.681.01)

0.07

2.90

3.39

0.85 (0.711.00)

0.06

4.40

5.25

0.81 (0.690.95)

0.01*

4.53

5.25

0.84 (0.720.98)

0.03*

4.47

5.25

0.83 (0.720.95)

0.005*

1.61

1.94

0.82 (0.631.07)

0.14*

1.47

1.94

0.75 (0.570.98)

0.03*

1.54

1.94

0.78 (0.620.98)

0.03*

1.67

Placebo better

Ticagrelor 90 mg bid
Ticagrelor 60 mg bid
Ticagrelor pooled

*Indicates nominal P value; P<0.026 indicates statistical significance

Bonaca MP et al. N Engl J Med 2015 [Epub ahead of print]

39

PEGASUS-TIMI 54: Estimates of First Efficacy

and Bleeding Events Prevented and Caused
50

Number of events per 10,000 patients

initiated on treatment for 1 year

41
40
31
30

20
10

CV death, MI or stroke

0
TIMI major bleeding

-10
-20
-30
-40
-50

Ticagrelor 90 mg bid
-40

-42

Ticagrelor 60 mg bid

Rates are annualised from 3-year Kaplan-Meier event rates in the intention-to-treat population
Bonaca MP et al. N Engl J Med 2015, Supplementary Appendix [Epub ahead of print]

40

Summary
Each Asia-Pacific country faces a unique set of barriers that prevent
optimal translation of evidence-based guideline recommendations into
practice
Establishing cardiac networks and local/individual hospital models/clinical
pathways will be central to optimization of ACS medical management in
the Asia-Pacific region
Validation study of ACS risk assessment should be encouraged onto our
own population
Reperfusion and DAPT are standard treatment in ACS management
Long-term DAPT strategy is promising strategy to reduce late restenosis
in stable CAD, with concerning to bleeding risk