STEMI Management: Choice for reperfusion

and the role of ticagrelor based on update

guideline

Dr. dr. Muzakkir Amir Sp.JP, FIHA

1
 Chest pain

ST elevation ST depression
ECG ST segment

Bio-chemistry Troponin rise / Troponin

fall normal

Diagnosis

STEMI NSTEMI UA
2 Adapted from Hamm CW et al. Eur Heart J 2011;32:2999 3054
 Diagnosis ECG in 10 minutes

In the absence of LVH and LBBB In the presence LBBB or ST depression

New ST elevation at the J point in 2
contiguous leads with 0.2 mV in men
(>40 years old) or 0.15 mV in women
in leads V2-V3 and/or 0.1 mV in other
leads
New LBBB, and symptoms suggestive of
ACS
ST depression in leads V1V3 indicate
inferobasal myocardial ischemia
(especially when the terminal T-wave is
positive)

In suspected posterior (circumflex artery-

related) or right ventricle-related infarction

ST elevation in V7,V8 and V9 using a cut-point

>0.05 mV.
ST elevation in V3R and V4R, using a cut-off
point >0.05 mV, and >0.1 mV in men <30
years.
ST Segment LBBB
Elevation

Steg G et al. Eur Heart J. 2012;33:2569-619

3
 ECG CHANGES OF INJURY ACUTE MYOCARDIAL INFARCTION

In early stage of AMI , ECG may be

normal or near normal

5- 30 min after onset of

infarction

Changes
< 1 mm - > 10 mm

1-2 hours of onset

symptoms

ST resolves - anterior up to 2 weeks;

posterior > 2 weeks
T wave : many months

Morris F, Brady WJ. BMJ 2002 Apr 6;;324(7341) :831-4

4
 Challenge in STEMI Management

80% onset > 12 jam

Dharma S et al. Neth Heart J 2012; 20:254-259

 Time to Treatment is Critical in STEMI

Mensah GA et al. Circulation. 2007;116:e33-e38

6
 Component of any delay in STEMI

Importance to identify Symptom Onset in STEMI

7 Steg G et al. Eur Heart J. 2012;33:2569-619
 STEMI Management

STEMI Diagnosis

Primary-PCI capable EMS or non primary-

center PCI capable center

Preferably PCI possible < 120 min?

< 60 min
Immediate transfer to
PCI center
Primary-PCI Yes No
Preferably 90 min
( 60 min in early
Preferably
Rescue-PCI presenters)
30 min
Immediately Immediate transfer to
No PCI center
Succesful Immediate
fibrinolysis ? fibrinolysis ?
Yes
Preferably 3-24 h

Coronary angiography Steg G et al. Eur Heart J. 2012;33:2569-619

8
 Reperfusion and target goal
I IIa IIb III
Reperfusion therapy should be administered to all eligible patients
with STEMI with symptom onset within the prior 12 hours.

I IIa IIb III

Primary PCI is the recommended method of reperfusion when it
can be performed in a timely fashion by experienced operators.

I IIa IIb III

In the absence of contraindications, fibrinolytic therapy should be
administered to patients with STEMI at nonPCI-capable hospitals
when the anticipated FMC-to-device time at a PCI-capable hospital
exceeds 120 minutes because of unavoidable delays.

I IIa IIb III

Reperfusion therapy is reasonable for patients with STEMI and
symptom onset within the prior 12 to 24 hours who have clinical
and/or ECG evidence of ongoing ischemia. Primary PCI is the
preferred strategy in this population.

9 OGara PT et al. Circulation. 2013;127:e362-e425

 In large registries, shorter delays to reperfusion
result in improved mortality outcomes

Delayed hospital care is associated with increased mortality in-hospital through 1 year (NIAP data, UK)1*

Call to balloon time In-hospital 30 days 1 year

60120 min 2.7% 2.9% 5.1%
120180 min 4.5% 4.9% 8.7%
>180 min 11.4% 12.2% 15.9%
*Analysis of call to balloon times in relation to patient follow-up data

PPCI appears to be less sensitive to delay than thrombolysis (Vienna STEMI registry, in-hospital mortality,
20032004)2
35

20 No reperfusion 30 28.6
18.4
PPCI
Thrombolysis 25

Mortality (%)
Mortality (%)

15
20
10 8.1 8.2 15 12.5
10.6
5 10 7.8 6.7
5.1
0 5
Total
0
02 hours 26 hours 612 hours
1. Treatment of Heart Attack National Guidance, NIAP report, October 2008 Hours from onset of pain
10 2. Kalla K et al. Circulation 2006;113:23982405
Important time delays with a pharmaco-invasive strategy vs primary
percutaneous coronary intervention (PCI) are shown.

Sinnaeve PR, Van de Werf F, Circulation. 2014;129:1623-1625

Fibrinolytic vs. Primary PCI

Fibrinolytic Primary PCI

Symptom onset < 12 hrs Within 120 minutes

Primary PCI > 90 minutes Patient has contraindication to

fibrinolytic
No contraindication Door to-balloon 90 minutes
30 min (door-to-needle time) STEMI Patient with cardiogenic
shock and severe heart failure
STEMI Diagnosis in doubt

1.Steg PG, et al. European Heart Journal. 2012;33:2569-2619 ; 2. Anderson JL, et al. Circulation. 2007;116:e148-e304.
 Check list contraindication fibrinolytic therapy
Absolute Relative
Previous intracranial hemorrhage or stroke
of unknown origin at any time Transient ischemic attack in the
preceding 6 months
Ischemic stroke in the preceding 6 months
Oral anticoagulant therapy
Central nervous system damage or
neoplasms or arteriovenous malformation Pregnancy or within 1 week postpartum

Recent major trauma/surgery/head injury

(within the preceding 3 weeks) Refractory hypertension

Gastrointestinal bleeding within the past Advanced liver disease

month
Infective endocarditis
Known bleeding disorder (excluding
menses) Active peptic ulcer

Aortic dissection Prolonged or traumatic resuscitation

Non-compressible punctures in the past 24

h (e.g. liver biopsy, lumbar puncture)

Ischemic stroke more than 6 months ago

13 Steg G et al. Eur Heart J. 2012;33:2569-619
 Fibrinolytic Complication and its management

Hypotention Allergic reaction Bleeding Arythmia

Patient position Mild allergic Minor Bleeding Refer to ACLS
supine Antihistamin Pressure to guidelines
Reduce or stop injection bleeding area
streptokinase (difenhidramin 10 Major Bleeding Reperfusion sign
drops mg i.v) eg ICH Premature
Provide Ringer Severe allergic Stop streptokinase Ventricular
Lactate / NaCL Dexamethasone and refer patient Contraction
100 ml (10 injection 5 mg for further bleeding Idiophatic
minutes) management Ventricular
Stop vasodilator Rhytm
drug (eg.
Nitrate)
Streptokinase Parameter Successful Fibrinolytic Therapy
drop continue if
systolic 1. Reduction of chest pain
pressure > 90 2. Decrease ST elevation > 50%
mmHg 3. Arrhythmia reperfusion
14 Reference : iSTEMI Indonesia Video
 STEMI treatment Primary PCI
First 24 hours and days 2-7

15 Steg G et al. Eur Heart J. 2012;33:2569-619

 Profile of P2Y12 inhibitors

Profile Clopidogrel Ticagrelor

Class Thienopyridine Triazolopyrimidine

Binding Irreversible Reversible

Reversibility

Metabolism Pro drug Active drug

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

 Faster Onset and offset ticagrelor vs clopidogrel
(based on inhibition platelet aggregation)
Last maintenance dose
Loading 90 mg bid
100 75 mg qd Ticagrelor (n=54)
Dose
90
* * * * *
180 mg
600 mg
* * Clopidogrel (n=50)
80
* * P<0,0001
70 P<0,005
P<0,05
60
IPA %

50
*
40

30

Catatan : penelitian ini dilakukan pada pasien CAD yang
20 mengkonsumsi aspirin tanpa riwayat ACS <1 tahun
BRILINTA belum mendapatkan persetujuan untuk populasi
10 pasien ini.

0 0.5 1 2 4 8 24 6 weeks 0 2 4 8 24 48 72 120 168 240

Onset Maintenance Offset

17
Time (hours)) Time (hours)
Adapted from Gurbel PA, et al. Circulation. 2009;120:25772585. IPA : Inhibition of Platelet Aggregation
 PLATO: Study Design

Primary efficacy
Ticagrelor (n=9,333) endpoint:
Composite of CV
death, MI (excluding
silent MI), or stroke
180-mg loading dose 90 mg bid + ASA maintenance dose

All patients were hospitalised with symptom onset <24 hours

N=18,624 Patients could be taking clopidogrel at time of randomisation
Patients with ACS
(UA, NSTEMI, or Primary safety
STEMI*) 300-mg loading dose 75 mg qd + ASA maintenance dose endpoint:
Total PLATO major
bleeding
Clopidogrel (n=9,291)

Randomisation
Visit 2 Visit 3 Visit 4 Visit 5 Visit 6

Screening <24h Month 1 Month 3 Month 6 Month 9 Month 12

*STEMI patients scheduled for primary PCI were randomised; however, they may not have received PCI.
Initial Treatment approaches A loading dose of 300-mg clopidogrel was permitted in patients not previously treated with clopidogrel,
Medically managed (n=5,216 28.0%) with an additional 300 mg allowed at the discretion of the investigator.
Invasively managed (n=13,408 72.0%) The PLATO study expanded the definition of major bleeding to be more inclusive compared with

previous studies in ACS patients. The primary safety endpoint was the first occurrence of any major
bleeding event.

Wallentin L, et al. N Engl J Med. 2009;361:10451057.

James S, et al. Am Heart J. 2009;157:599605. Confidential for AstraZeneca Discussion Purposes Only
 PLATO: Primary Efficacy Endpoint
(Composite of CV Death, MI, or Stroke)

13 030 Days 012 Months

12 11.7 Clopidogrel
Cumulative Incidence (%)

11
10 9.8 Ticagrelor
9 Clopidogrel
8 5.4
7
6
5
4 ARR=0.6% ARR=1.9%
4.8
RRR=12% RRR=16%
3 Ticagrelor
P=0.045 NNT=54*
2 HR: 0.88 (95% CI, 0.771.00) P<0.001
1 HR: 0.84 (95% CI, 0.770.92)
0
0 2 4 6 8 10 12
No. at risk Months After Randomization
Ticagrelor 9,333 8,628 8,460 8,219 6,743 5,161 4,147

Clopidogrel 9,291 8,521 8,362 8,124 6,650 5,096 4,047

Both groups included aspirin.
*NNT at one year.

Wallentin L, et al. N Engl J Med. 2009;361:10451057. Confidential for AstraZeneca Discussion Purposes Only
 PLATO K-M estimates of time to
secondary efficacy endpoints* [Wallentin 2009-2:D]

Myocardial infarction Cardiovascular death

7 6.9 7
Clopidogrel

6 5.8 6
Clopidogrel

Cumulative incidence (%)

5.1
Cumulative incidence (%)

5 Ticagrelor 5

4.0
4 4
Ticagrelor
3 3

2 2

1 1

HR 0.84 (95% CI, 0.75-0.95) P=0.005 0 HR 0.79 (95% CI, 0.69-0.91) P=0.001
0

0 2 4 6 8 10 12 0 2 4 6 8 10 12
Months after randomization Months after randomization
No. at risk
Ticagrelor 9333 8678 8520 8279 6796 5210 4191 9333 8294 8822 8626 7119 5482 4419
Clopidogrel 9291 8560 8405 8177 6703 5136 4109 9291 8865 8780 8589 7079 5441 4364

*The rate of stroke did not differ significantly between the two treatment groups
Wallentin L. Presented at the European Society of Cardiology Congress 2009-2, Barcelona, Spain. August 29-September 2: 179.
http://spo.escardio.org/eslides/view.aspx?eevtid=33&id=179 -2. Confidential for AstraZeneca Discussion Purposes Only
 Stent Thrombosis

HR for
Ticagrelor Clopidogrel ticagrelor p
(n=6,732) (n=6,676) (95% CI) value*

Stent thrombosis, %

Definite 1.0 1.6 0.62 (0.450.85) 0.003

Probable or definite 1.7 2.3 0.72 (0.560.93) 0.01

Possible, probable, or definite 2.2 3.1 0.72 (0.580.90) 0.003

Evaluated in patients with any stent during the study

Time-at-risk is calculated from the date of first stent insertion in the study or date of randomization
* By univariate Cox model

Cannon C et al. Lancet 2010;375:283293

 PLATO: Time to major bleeding:
primary safety endpoint*

15 [Wallentin 2009:I,J]
K-M estimated rate (% per year)

Ticagrelor
11.6%
11.2% P=NS
10 Clopidogrel

5 (HR 1.04; 95% CI, 0.95-1.13; P=0.43)

0
0 60 120 180 240 300 360
Days from first IP dose
No. at risk

Ticagrelor 9235 7246 6826 6545 5129 3783 3433

Clopidogrel 9186 7305 6930 6670 5209 3841 3479

*Both groups included aspirin
Wallentin L, et al. N Engl J Med. 2009;361:1045-1057.
Confidential for AstraZeneca Discussion Purposes Only
 PLATO: Major bleeding

P=0.43 [Wallentin 2009:K]

12 11.6
11.2 Ticagrelor, n=9235
11 Clopidogrel, n=9186
P=0.96
K-M estimated rate (% per year)

10
*Both groups included aspirin
P=0.57 8.9 8.9
9
7.9
8 7.7

7 P=0.70
5.8 5.8
6
5
4
3
2
P=0.66
1 0.3 0.3
0
PLATO Major TIMI Major Red cell PLATO Life- Fatal bleeding
bleeding bleeding transfusion* Threatening/
*Proportion of patients (%) Fatal bleeding

Wallentin L, et al. N Engl J Med. 2009;361:1045-1057.

Confidential for AstraZeneca Discussion Purposes Only
 ESC/EACTS 2014 Guidelines on myocardial
revascularization1
Recommendation in STEMI Class Level
ASA is recommended for all patients without
contraindications at an initial oral loading dose of 150300
I A
mg (or 80150 mg i.v.) and at a maintenance dose of 75
100 mg daily long-term regardless of treatment strategy.
It is recommended to give P2Y12 inhibitors at the time of
I B
first medical contact
A P2Y12 inhibitor is recommended in addition to ASA and
maintained over 12 months unless there are
I A
contraindications such as excessive risk of bleeding.
Options are:
Prasugrel (60 mg loading dose, 10 mg daily dose) if no
I B
contraindication

Ticagrelor (180 mg loading dose, 90 mg twice daily) if

I B
no contraindication
Clopidogrel (600 mg loading dose, 75 mg daily dose),
only when prasugrel or ticagrelor are not available or I B
are contraindicated.

Windecker S et al. Eur Heart J 2014;35: 2541 2619 24

 Guidelines ACS PERKI 2015
Antiplatelet in STEMI Management

25 Buku Pedoman Tatalaksana Sindrom Koroner Akut, Perki 2015

 Summary

Right Diagnosis
Timely diagnosis of STEMI is key to successful management
Right Antiplatelet
Ticagrelor is preferred for patient received Primary PCI while clopidogrel is
preffered for patient received fibrinolytic therapy
Right Reperfusion
Primary PCI is preferred options if conduct within guidelines mandated times, by
experience team, regardless patient goes to PCI capable or not.
Right Referral Hospital
Considered symptom onset and look for hospital where treatment delay is
minimal
Right Bleeding Management
Assessing bleeding risk , recognizing bleeding early and considering
management modification will reduce bleeding event in ACS patients

26