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Ticagrelor Use In ACS Management

RSU DR Wahidin Sudirohusodo

Dr. Abdul Hakim Alkatiri, SpJP


Patient profile:
• Background and physical profile
• 52th, Makasar, Laki-laki 90 kg
• Nyeri dada

• Medical history
• Dyslipidemia
• Smoker
• Obesitas
• Family History
Clinical investigation :

– BP 100/80 , HR 80, LDL-C : 170


– ECG : Sinur Rhythm T inverse, V1 – V4
– Hasil lab:
• Trop T : Positif
• CrCl : 100 µmol/L
– Hasil Echo : hipokinetik Septal EF 50%
EKG
Diagnosis Acording EKG

ACS NSTEMI
Mortality in hospital based on GRACE
RISK SCORE NSTEMI 2011

6
Hamm CW, et al. European Heart Journal (2011) 32, 2999–3054
NSTEMI :
When Invasive Strategy better

1. Ongoing Ischemia despite optimal MT


2. Impending Heart Failure
3. Haemodynamic instability
Strategi Invasif
• Strategi invasif (dalam 72 jam setelah awal masuk) diindikasikan pada
pasien-pasien dengan IA
– Paling tidak satu kriteria risiko tinggi
– Simptom rekuren

• Angiografi koroner segera (<2 jam) direkomendasikan untuk pasien dengan


risiko iskemia sangat tinggi (angina refrakter, disertai dengan gagal jantung, IC
aritmia ventrikuler mengancam jiwa ataupun stabilitas hemodinamik)

• Strategi invasif dini (<24 jam) direkomendasikan pada pasien skor risiko
GRACE >140 atau dengan paling tidak satu kriteria risiko tinggi primer
1A

Hamm CW, et al. European Heart Journal (2011) 32, 2999–3054


Management ( Cathlab
Available)
• Treatment decision:
– Invasive Strategy

• Medication choice in ER
– Loading Dose BRILINTA (Ticagrelor) 180 mg
– Trombo Aspilet 160 mg
– Fondapainux 2,5 mg SL
– Atorvastatin 40 mg
– Cedocard SL
Before PTCA
After PTCA
Treatment - Maintenance

– BRILINTA (Ticagrelor) 90mg BID (1 year)


– Trombo Aspilet 80mg OD
– Atovastatin 40mg OD
– Fondaparinux 2,5mg SL
– Farsorbid 1mg/jam
P2Y12 inhibitors

Hamm CW, et al. European Heart Journal (2011) 32, 2999–3054


Limitation of clopidogrel
• Dual antiplatelet therapy (DAPT) with aspirin & clopidogrel is
the current standard treatment in patients with ACS1
– With or without ST segment elevation1
• Poor platelet inhibition response to clopidogrel is seen in
approximately 15% - 40% of patients2
– Contribute to residual high risk of recurrent results
• Clopidogrel has slow onset of action1
– Prodrug that requires conversion to active metabolite 1
• Variable metabolism results in interindividual variability in
inhibition of platelet agregation1

1. Bassand JP . European Heart Journal Supplements (2008) 10 (Supplement D), D3–D11; 2. Gurbel
PA, Tantry US. Thrombosis Research. 2007;120: 311–321
Ticagrelor : Does Not Require Hepatic Metabolism
for Activation
Ticagrelor:
Does NOT require metabolic activation to
become active drug

Ticagrelor
Binding

Platelet

P2Y12
Clopidogrel
CYP-dependent CYP-dependent
oxidation oxidation
CYP1A2 CYP2C19
Active compound CYP2B6 CYP3A4/5
CYP2C19 CYP2B6
Intermediate metabolite
Prodrug
Clopidogrel:
A prodrug; requires metabolism to
become active drug

Adapted from Schomig A. N Engl J Med. 2009;361:1108–1111.


DISPERSE: Greater and More
Consistent IPA with Ticagrelor than
Clopidogrel
AZD6140 100 mg BD (Ticagrelor) Clopidogrel
Day 1 Day 14 Day 1 Day 14
100 100

80 80

Mean % inhibition
Mean % inhibition

60 60

40 40

20 20

24 8 12 2 4 8 12 24 24 8 12 2 4 8 12 24
Time, hours Time, hours

IPA = inhibition of platelet aggregation; od = once daily; bd = twice daily.


Adapted from Husted SE, et al. Presented at: European Society of Cardiology Annual Congress 2005; 3-7 September, 2005; Stockholm, Sweden.
ONSET/OFFSET:
Pharmacodynamics in Stable CAD Patients

Last
Maintenance
Dose 90 mg bid
100 Loading
Dose 75 mg qd Ticagrelor (n=54)
90
* * * * * †
180 mg
600 mg
* * Clopidogrel (n=50)
80
 * *
P<0.0001
70 †
P<0.005
‡ P<0.05

60
IPA %

50
* 
40

30

20

10

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

Onset Maintenance Offset


Time (Hours) Time (Hours)
Adapted from Gurbel PA, et al. Circulation. 2009;120:2577–2585.
Checklist of treatments when ACS diagnosis appears likely

NEW

18
Hamm CW, et al. European Heart Journal (2011) 32, 2999–3054
PERKI Guideline 2014 : P2Y12 Inhibitor
International guidelines recommend ticagrelor
as 1st line treatment
ESC NSTEMI 2011
Ticagrelor (180-mg loading dose, 90 mg twice
daily) is recommended for all patients at moderate- Class Level
to-high risk of ischaemic events (e.g. elevated
troponins) , regardless of initial treatment strategy
and including those pre-treated with clopidogrel
(which should be discontinued when ticagrelor is
commenced)

AHA NSTEMI 2012

For UA/NSTEMI patients in whom an initial


conservative (ie, noninvasive) strategy is selected, Class Level
clopidogrel or ticagrelor (loading dose followed by
daily maintenance dose) should be added to
aspirin and anticoagulant therapy as soon as
possible after admission and administered for up
to 12 months

Hamm CW et al. Eur Heart J 2011;32:2999 – 3054; 2 Jneid H et al. Circulation 2012; 126: 875 - 910
Rekomendasi Oral Antiplatelet
Aspirin harus diberikan pada semua tipe pasien tanpa
Class Level
kontraindikasi dengan loading dose 150 – 300 mg dan dosis
maintenance jangka panjang 75-100 mg OD tidak terkait strategi 1 A
terapi
Penghambat P2Y12 inhibitor harus diberikan bersamaan dengan Class Level
aspirin secepatnya dan dilanjutkan sampai 12 bulan, kecuali
kontraindikasi misalnya risiko perdarahan. 1 A

Penghentian berkepanjangan atau tetap penghambat P2Y12 dalam Class Level


12 bulan setelah kejadian penyebab tidak disarankan kecuali ada
1 c
indikasi klinis
Ticagrelor (180 mg loading dose, 90 mg dua kali sehari Class Level
direkomendasikan untuk semua pasien dengan risiko kejadian
iskemik sedang – tinggi, terlepas strategi penatalaksanaan awal dan 1 B
yang telah mendapatkan clopidogrel sebelumnya (clopidogrel
harus dihentikan bila ticagrelor diberikan)

Hamm CW, et al. European Heart Journal (2011) 32, 2999–3054


Rekomendasi Oral Antiplatelet
Clopidogrel (300 mg loading dose, 75 mg satu kali sehari) Class Level
direkomendasikan untuk pasien yang tidak dapat diberikan
ticagrelor atau prasugrel 1 A

Loading dose clopidogrel 600 mg (atau peningkatan dosis 300 mg


pada saat PCI, setelah pemberian loading dose 300 mg) Class Level
direkomendasikan untuk pasien yang direncanakan menjalani
strategi invasif pada saat ticagrelor atau prasugrel tidak dapat 1 B
diberikan

Hamm CW, et al. European Heart Journal (2011) 32, 2999–3054


PLATO : Only Ticagrelor provide mortality benefit vs
clopidogrel in ACS

P = N/A P = NS P < 0.001

n = 12.562 n = 13.608 n = 18.624


NNT = 250 NNT = 333 NNT = 91

1.Yusuf S et al. N Engl J Med 2001;345; Wiviott SD e tal. N Engl J Med 2007;357:2001-15; Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
PLATO Study
PLATO study tested the hypothesis that…
ticagrelor will result in a lower risk of recurrent thrombotic events in a broad patient
population with ACS as compared to clopidogrel and this would be achieved with a clinically
acceptable bleeding rate and overall safety profile 1

PLATO Study2:
• 43 countries
• 862 sites
• 18,624 patients

1. James S et al. Am Heart J 2009;157: 599 – 605


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

N=18,624 • All patients were hospitalised with symptom onset <24 hours
Patients with ACS
(UA, NSTEMI, or STEMI*) • Patients could be taking clopidogrel at time of randomisation
Primary safety
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
Initial Treatment approaches have received PCI.
• Medically managed (n=5,216 — 28.0%) †
A loading dose of 300-mg clopidogrel was permitted in patients not previously
• Invasively managed (n=13,408 — 72.0%) treated with clopidogrel, with an additional 300 mg allowed at the discretion of the
investigator.

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;361:1045–1057.


James S, et al. Am Heart J. 2009;157:599–605.
PLATO: Primary Efficacy Endpoint
(Composite of CV Death, MI, or Stroke)
13 0–30 Days 0–12 Months
12 11.7 Clopidogrel
11
Cumulative Incidence (%)

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, 0.77−1.00) P<0.001
1 HR: 0.84 (95% CI, 0.77–0.92)
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;361:1045–1057.


PLATO: Secondary Efficacy Endpoints
Myocardial Infarction Cardiovascular Death

7 Clopidogrel 6.9 7
6 5.8 6

Cumulative Incidence (%)


Cumulative Incidence (%)

Clopidogrel 5.1
5 Ticagrelor 5
4 4 4.0
Ticagrelor
3 3
ARR=1.1% ARR=1.1%
2 RRR=16% 2 RRR=21%
Calculated NNT=91 NNT=91
1 P=0.005 1 P=0.001
HR: 0.84 (95% CI, 0.75–0.95) HR: 0.79 (95% CI, 0.69–0.91)

0 0
0 2 4 6 8 10 12 0 2 4 6 8 10 12
Months After Randomisation Months After Randomisation

Rate of stroke for ticagrelor was not different from clopidogrel (1.3% vs 1.1% ), P=0.225.
Both groups included aspirin.

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


Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. Supplement.
BRILINTA ® Indonesia Prescribing Information 2012
PLATO Substudy NSTEMI : Primary Endpoint (Composite of CV
Death, MI, or Stroke) with or without Revascularization

HR= 0,85

Interaction P= 0,98

HR= 0,86

Daniel Lindholm et al. Ticagrelor vs clopidogrel in patient with NSTEMI with or without Revascularization: result from the PLATO trial
European Heart Journal/ doi:10.1093/eurheartj/ehu16
PLATO substudy NSTEMI : All-Cause Death with or without
revascularization

HR= 0,84

Interaction P= 0,94

HR= 0,85

Daniel Lindholm et al. Ticagrelor vs clopidogrel in patient with NSTEMI with or without Revascularization: result from the PLATO trial
European Heart Journal/ doi:10.1093/eurheartj/ehu160
SAFETY : Major Bleeding with or without revascularization

Interaction P= 0,82

Daniel Lindholm et al. Ticagrelor vs clopidogrel in patient with NSTEMI with or without Revascularization: result from the PLATO trial European Heart
Journal/ doi:10.1093/eurheartj/ehu160
Major Bleeding Definitions
TIMI CURE PLATO
[Rao 1988:A] [Yusuf 2001:A] [James 2009:B]

Major Major (fatal/life- Major (fatal/life-threatening)


threatening)
Fatal/life-threatening Fatal Fatal
(related to
instrumentation,
spontaneous, trauma)
ICH ICH ICH
↓ >5 g/dL hemoglobin ↓ ≥5 g/dL hemoglobin ↓ ≥5 g/dL hemoglobin
↓ 15% absolute ≥4 unit transfusion ≥4 unit transfusion
hematocrit
Hypotension Hypotension
requiring inotropes; requires requiring pressors or surgery;
surgical intervention intrapericardial with tamponade;
hypovolemic shock

Other Major Other Major


Substantially disabling Substantially disabling
(eg, intraocular with vision (eg, intraocular with permanent vision
loss) loss)

2-3 unit transfusion 2-3 unit transfusion


↓ 3-5 g/dL hemoglobin

ICH, intracranial hemorrhage; N/S, not specified


Rao SV et al . J Am Coll Cardiol 2006;47:809 –16; James S, et al. Am Heart J. 2009;157:599-605.
Minor and Minimal Bleeding
Definitions
TIMI CURE PLATO
[Rao 1988:A] [Yusuf 2001:A] [James 2009:B]

Minor* Minor Minor


Observed blood loss: Hemorrhages leading Requires medical
clinically overt sign of to interruption of intervention to stop or
hemorrhage with medication treat bleeding
↓hemoglobin 3-5 g/dL or
>10% decrease in
hematocrit*
No observed blood loss:
↓hemoglobin ≥4 g/dL or
12% decrease in
hematocrit

Minimal Minimal Minimal


Clinically overt sign of None defined All others not requiring
hemorrhage with intervention
↓hemoglobin <3 g/dL or (eg, bruising, bleeding
<9% decrease in gums, oozing from
hematocrit injection sites, etc)

*TIMI minor bleeding resembles PLATO major bleeding by hemoglobin drop

Rao SV et al . J Am Coll Cardiol 2006;47:809 –16; James S, et al. Am Heart J. 2009;157:599-605.


ESC NSTEMI – Bleeding
Complication
Interruption and/or neutralization of both CLASS LEVEL
anticoagulant and antiplatelet therapies
is indicated in case of major bleeding, 1 C
unless it can be adequately controlled by
specific haemostatic measures

CLASS LEVEL
Minor bleeding should preferably be
managed without interruption of active
1 C
treatments.

CLASS LEVEL
Co-medication of PPI and antithrombotic
agents is recommended in patients at
1 B
increased risk of GI haemorrhage.

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


Confidential for AstraZeneca Discussion Purposes Only
Supporting Evidence for choosing
Ticagrelor
• Rapid onset of action
• Predictable effect on IPA
• Plato Study : Reduced CV mortality, Myocardial Infarction
or Stroke
• Sub Study Plato NSTEMI: Mortality Benefit CV Death
• SubStudy Plato NSTEMI : No difference in Bleeding Risk
• Pedoman Talaksanaan Sindrom koroner Akut PERKI 2014
• Guidelines NSTEMI ESC 2011 dan AHA 2012
TAKE HOME MESSAGE
• There is an important unmet need for defining optimal antiplatelet therapy
in those patients with ACS who undergo medical management (including
issue on clopidogrel resistance or suboptimal platelet inhibition)
• Substudy of the PLATO trial in medically managed patients show consistent
benefit in reduction cv event including mortality benefit ticagrelor vs
clopidogrel
• In this substudy of the PLATO trial, ticagrelor compared with clopidogrel
consistently reduced the rates of ischaemic events and mortality without
any difference in overall major bleeding in patients with anentry diagnosis of
NSTE-ACS, and this effect was independent of whether or not early
revascularization was performed.
• These results harmonize with the European Society of Cardiology (ESC)NSTE-
ACS guidelines, which recommend ticagrelor in all patientsat moderate-to-
high risk of ischaemic events, regardless of initialtreatment strategy.