acs risk stratification and clinical management

CURRICULUM VITAEName Dr. Anwar Santoso, PhD, FIHA, FAsCC, FICA, FACCPlace & Date of

birth

Surabaya, 20 July

Official

designation

Lecturer in Dept. of Cardiology Faculty of Medicine ~ University of Indonesia,

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

background

1. Medical Doctor, Airlangga University, School of Medicine, Indonesia.

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

Society

Memberships

1. The Indonesian Medical Association, member, 1993 - now

2. Indonesian Heart Association, member, 1993 now

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

Anwar SantosoDept. of Cardiology Faculty of Medicine; University of Indonesia

National Cardiovascular Centre Harapan Kita HospitalPresident of Indonesian Heart Association

Jakarta - Indonesia

Acute Coronary Syndromes:

Risk stratification and how to deal with?

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

4

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


Overview of main international and AsPac ACS Guidelines

Accessibility/systems 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

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


Risk stratification

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


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


Education

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


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 Asia-

Pacific countries

Lack of familiarity with new drugs

amongst non-cardiac physicians

Adoption of newer, more potent P2Y12receptor antagonists is slow


Cost/affordability

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


User-funded healthcare systems in some

countries

Inequity in standards of care

Reimbursement systems Limited real-world access to optimal pharmacotherapy


Risk Stratification is important in NSTE-ACS

Management

TIMI SCORE GRACE SCORE

recommended as the preferred

classification to apply on admission and at

discharge in daily clinical routine practice

Less accurate in predicting events but its

simplicity makes it useful and widely

accepted

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

CLINICAL CONDITION1

2 3

PRIMARY

Relevant rise or fall in troponin Dynamic ST- or T-wave changes

(symptomatic or silent)

SECONDARY

Diabetes mellitus Renal insufficiency

(eGFR

TIMI SCORE

Age 65 years or older?

At least 3 risk factors for CAD?

Prior coronary stenosis of 50% or more?

ST-segment deviation on ECG 0.5mm?

Use of aspirin in prior 7 days

At least 2 anginal events in prior 24 hours?

Elevated serum cardiac markers?

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%

2 8.3%

3 13.2%

4 19.9%

5 26.2%

6- 7 40.9%

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

GRACE SCORE

Predictor Score

Age, years

< 40 0

40 - 49 18

50 - 59 36

60 - 69 55

70 - 79 73

80 91

Predictor Score

Heart Rate , beats/min

< 70 0

70-89 7

90-109 13

110 - 149 23

150 - 199 36

> 200 46

Predictor Score

Systolic Blood Pressure (mmHg)

< 80 63

80 99 58

100 - 119 47

120 - 139 37

140 - 159 26

160 - 199 11

> 200 0

Predictor Score

Creatinine (mol/L)

0 - 34 2

35 70 5

71 105 8

106 140 11

141 176 14

177 353 23

354 31

Predictor Score

Killip class

I 0

II 21

III 43

IV 64

Predictor Score

Cardiac

arrest at

admission

43

Elevated

cardiac

markers

15

ST Segment

deviation

30

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

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

GRACE risk score is underpredicted in Asian ACS management should be more agressive

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

Chan MY, et. al. Am Heart J 2011: 0: 1 - 9Lee JH, et. al. Am Heart J 2010: 159: 1012 - 19

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

instabilityAt least one < 2 hour

Urgent coronary angiography

Relevant rise or fall in troponin Dynamic ST- or T-wave changes

(symptomatic or silent)

Grace risk score > 140

none

none

Diabetes mellitus Renal insufficiency (eGFR

Initial Treatment

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

Initial Therapeutic Measures 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

5,50 5,10

Plasebo Clopidogrel

CURE1

2,40 2,10

Clopidogrel Prasugrel *

TRITON TIMI 382

5,10

4,00

Clopidogrel Ticagrelor

PLATO3

P = NS

n = 12.562

NNT = 250n = 13.608

NNT = 333

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

Ra

te o

f C

V d

ea

th (

%)

P = N/A P = 0.001

ESC 2012 STEMI guidelines:

periprocedural antiplatelet therapy in PPCI

Recommendations Class Level

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

An ADP receptor blocker is recommended in addition to ASA.

Options are:I A

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

stroke/TIA, age

ESC/EACTS 2014 Guidelines on

myocardial revascularization1

2

8

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

Recommendation in STEMI Class Level Evidence

A P2Y12 inhibitor is recommended in

addition to ASA and maintained over 12

months unless there are

contraindications such as excessive

bleeding

I A/B

PLATO

TRITON

CURRENT-OASIS 7

It is recommended to give P2Y12inhibitors at the time of first medical

contact

I B 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

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 post-

PCI 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

IB

IIaB

*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

Short-term (< 6 months) versus long-term (1 year) DAPT in post stent CAD?

Evolving issues?

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


Patient subgroups and DAPT duration

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 MI

47

CV, cardiovascular; MI, myocardial infarction

1. Bhatt DL et al. JAMA 2010;304:135013572. Fox KA et al. Eur Heart J 2010;31:275527643. Jernberg T et al. Eur Heart J 2015; pii: ehu505 [Epub ahead of print]

4. Amsterdam EA et al. Circulation 2014;130:235423945. Hamm CW et al. Eur Heart J 2011;32:299930546. 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 P2Y12receptor 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

36

1. Husted S et al. Eur Heart J 2006;27:103810472. Cattaneo M et al. J Am Coll Cardiol 2014;63:250325093. Wallentin L et al. N Engl J Med 2009;361:10451057

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 60 mg bid

+ 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

Placebo

+ ASA 75150 mg/dayTicagrelor 90 mg bid

+ ASA 75150 mg/day

*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;167:437444Bonaca MP et al. N Engl J Med 2015 [Epub ahead of print] 37

PEGASUS-TIMI 54: Primary Endpoint

38

CI, confidence interval; HR, hazard ratio

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

No. at risk

Placebo

90 mg bid

60 mg bid

7067

7050

7045

6979

6973

6969

6892

6899

6905

6823

6827

6842

6761

6769

6784

6681

6719

6733

6508

6550

6557

6236

6272

6270

5876

5921

5904

5157

5243

5222

4343

4401

4424

3360

3368

3392

2028

2038

2055

Eve

nt

rate

(%

)

Months from randomisation

Ticagrelor 60 mg vs placebo

HR 0.84 (95% CI 0.740.95) P=0.004

Ticagrelor 90 mg vs placebo

HR 0.85 (95% CI 0.750.96) P=0.008

9.04% Placebo

7.85% 90 mg bid

7.77% 60 mg bid

Placebo



0 3 6 9 12 15 18 21 24 27 30 33 36

0

1

2

3

4

5

6

7

8

9

10

PEGASUS-TIMI 54: Efficacy Endpoints

*Indicates nominal P value; P

-50

-40

-30

-20

-10

0

10

20

30

40

50

PEGASUS-TIMI 54: Estimates of First Efficacy

and Bleeding Events Prevented and Caused

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]



CV death, MI or stroke

TIMI major bleeding

Nu

mb

er

of e

ve

nts

pe

r 1

0,0

00

pa

tie

nts

initia

ted

on

tre

atm

ent fo

r 1

ye

ar

-40-42

41

31

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

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acs risk stratification and clinical management