The Importance Antiplatelet in ACS

1
The Importance Antiplatelet in ACS

• Pathophysiology ACS
• The importance of Antiplatelet
• Thrombus Formation
• Guidelines ACS
• Comparison of Antiplatelet – profile
• Switching Antiplatelet
• Length of DAPT

2
 Activated platelets are central to thrombus
formation in ACS

• Platelets do 3 things that promote thrombus formation

– Adhesion Activated platelets aggregate
and assemble a critical mass
– Activation 3 of activated, pro-thrombotic
platelet membrane at the site
– Aggregation of injury

Adherent platelet become activated

2

1
Plaque rupture
leads to platelet
adhesion to the
exposed
subendothelium

Vorchheimer DA, et al. Mayo Clin Proc. 2006;81:59-68; Davies MJ. Heart. 2000;83:361-366.
 ANTIPLATELET AGENT
Aspirin
Thienopyridine
• Ticlopidine
• Clopidogrel
• Prasugrel

Reversible
P2Y12 inhibitors
• Ticagrelor
• Cangrelor
• Elinogrel

GPIIb/Iia Antagonists

Angiolillo DJ. Drugs. 2012 Nov 12;72(16):2087-116 5

 Antiplatelet recommendation in Updated ACS Guidelines

46% odds reduction

Aspirin should be given to all patients without
on major vascular contraindications at an initial loading dose of 150–300 mg,
event and at a maintenance dose of 75–100 mg daily long-term
regardless of treatment strategy.

A P2Y12 inhibitor should be added to aspirin as soon as

possible and maintained over 12 months, unless there are
contraindications such as excessive risk of bleeding.

Clopidogrel Ticagrelor Prasugrel*

1.Kolh P et al. Eur Heart J August 29 2014; DOI:10.1093/eurheart/ehu278 [Epub ahead of *Not yet approved and
print]
2.Steg PG et al. Eur Heart J 2012;33:2569–2619; 3.Hamm CW et al. Eur Heart J 2011;32:2999 available in Indonesia
6 – 3054. 4. Amsterdam EA et al. J Am Coll Cardiol Sept 23, 2014 Epub ahead of print.
DOI:10.1016/j.jack.2014.09.017
 Metabolism P2Y12 inhibitor
(Pro drug vs active drug)

No in vivo
Active compound biotransformation
Intermediate metabolite
Pro-drug
CYP-dependent
oxidation
CYP3A4/5
Ticagrelor CYP2B6
(Active Drug) CYP2C19
Hydrolysis CYP2C9 Binding
by esterase CYP2D6
Prasugrel* Platelet
(Prodrug)

P2Y12
Clopidogrel
(Prodrug) CYP-dependent CYP-dependent
oxidation oxidation
CYP1A2 CYP2C19
CYP2B6 CYP3A4/5
CYP2C19 CYP2B6

*Prasugrel is not yet approved and available in Indonesia

Figure adapted from Schömig A (2009). CYP, cytochrome P450.
Schömig A. N Engl J Med 2009;361:1108–1111.
 DISPERSE: Greater and more consistent IPA with ticagrelor
than with clopidogrel (final extent)
Clopidogrel 75 mg od Ticagrelor 100 mg bd
10 10
0 0
8 80
0
6 DAY 1 60
0

Variable platelet 4 40

Mean Inhibition, %
Mean Inhibition, %

0
inhibition based on 2 20
genetic 0
polymorphisms 0 0
0 2 4 8 1 0 2 4 8 1
2 2
10 10
0 0
8 8
0 0
6 6
0 0
4
DAY 14 4
0 0
2 2
0 0 ↓ 2nd dose
0 0
0 2 4 8 1 2 0 2 4 8 1 2
2 4 2 4
Time, h Time, h
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.
CURE

Primary End Point - MI/Stroke/CV Death

Placebo 11.4%
+ ASA*
9.3%

Clopidogrel
+ ASA*

20% RRR
P < 0.001
N = 12,562

0 3 6 9 12
Months of Follow-Up
* In combination with standard therapy
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
CURE

Bleeding Results

Placebo Clopidogrel
+ ASA* + ASA*
End Point N = 6303 N = 6259
Major bleeding 2.7% 3.7%**
Life-threatening bleeding 1.8% 2.2% †
Non-life-threatening bleeding 0.9% 1.5% ‡
Minor bleeding2.4% 5.1% §

* In combination with standard therapy

** P = 0.001; † P = NS; ‡ P = 0.002; § P < 0.001.

The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
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

PLATO Study:
• 43 countries
18,624
43862
countries
patients
sites
• 862 sites
• 18,624 patients

STEMI Primary PCI NSTEACS Invasive NSTEACS Non invasive

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

 PLATO : Consistent CV event reduction Ticagrelor vs
clopidogrel regardless invasive or non invasive
20 Initially intended for non-invasive management
Ticagrelor (n=2601)
Clopidogrel (n=2615) p for interaction = 0.89

CV death, MI or stroke (%)

HR (95% CI) = 0.85(0.73–1.00); p=0.045
15
14.3%

12.0%
10.7%
10
9.0%

Initially intended for invasive management

5
Ticagrelor (n=6732)
Clopidogrel (n=6676)
HR (95% CI) = 0.84(0.75–0.94)
0
0 60 120 180 240 300 360
Number at risk
Initially intended for non-invasive management Days after randomisation
Ticagrelor 2601 2392 2326 2247 1854 1426 1099
Clopidogrel 2615 2392 2328 2243 1835 1416 1109
Initially intended for invasive management
Ticagrelor 6732 6236 6134 5972 4889 3735 3048
Clopidogrel 6676 6129 6034 5881 4815 3680 2965

CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction; NSTEMI, non-ST-segment elevated MI; UA, unstable angina.
James S, et al. BMJ 2011;342:d3527.
 PLATO: No increase major bleeding ticagrelor vs
clopidogrel in invasive or non invasive setting
20 Initially intended for non-invasive management
Ticagrelor (n=2584)
Clopidogrel (n=2601) p for interaction = NS
HR (95% CI) = 1.17(0.98–1.39); p=0.08
15

Major bleeding (%)

11.9%

10 10.3%

Initial intent for invasive management

5
Ticagrelor (n=6651)
Clopidogrel (n=6585)
HR (95% CI) = 0.90(0.79–1.02)
0
0 60 120 180 240 300 360
Number at risk
Initially intended for non-invasive management Days after randomisation
Ticagrelor 2584 2008 1878 1779 1399 1035 912
Clopidogrel 2601 2085 1945 1872 1453 1081 972
Initially intended for invasive management
Ticagrelor 6651 5238 4948 4766 3730 2748 2521
Clopidogrel 6585 5220 4985 4798 3756 2760 2507

CI, confidence interval; HR, hazard ratio; NSTEMI, non-ST-elevated myocardial infarction; UA, unstable angina.
James S, et al. BMJ 2011;342:d3527.
 1
PERKI Guideline 2018 for STEMI Primary PCI

Ticagrelor is preferred option over clopidogrel for STEMI Primary PCI

14
Reference: 1. Buku Pedoman Tatalaksana Sindrom Koroner Akut, Perki 2018
 PERKI Guideline 2018 for STEMI Fibrinolytic
Clopidogrel preferred options ; ticagrelor may be use post fibrinolytic who
will undergo PCI

15
Reference: 1. Buku Pedoman Tatalaksana Sindrom Koroner Akut, Perki 2018
 PERKI Guideline 2018 for NSTEACS

Ticagrelor is preferred option over clopidogrel

despite of treatment approach

16 Reference: 1. Buku Pedoman Tatalaksana Sindrom Koroner Akut, Perki 2018

 Antiplatelet based on treatment approach (on top of aspirin)

Acute coronary syndrome

UA / NSTEMI STEMI

Medical PCI Fibrinolytic PCI

Management
• Ticagrelor • Clopidogrel • Ticagrelor
• Ticagrelor • Prasugrel* • Ticagrelor** • Prasugrel*
• Clopidogrel • Clopidogrel (post fibrinolytic) • Clopidogrel

* Prasugrel is not yet approved and available in Indonesia; **

Roffi M et al. European Heart Journal 2015. doi:10.1093/eurheartj/ehv320; Steg PG et al. Eur Heart J
2012;33:2569–2619
17
 Dosage Antiplatelet
Antiplatelet Loading dose Maintenance dose

Aspirin 325 mg 75 – 100 mg

Clopidogrel

PCI 600 mg 75 mg once daily

Fibrinolytic (<75 years old) 300 mg 75 mg once daily

Fibrinolytic (> 75 years old) N/A 75 mg once daily

Medically Managed 300 mg 75 mg once daily

Ticagrelor

PCI

Fibrinolytic (< 75 years old) 180 mg 90 mg twice daily

Medically Managed

18 1. Roffi M et al. Eur Heart J 2016;37(3):267-315; 2. Ibanez B et al. European Heart Journal 2017; 00; 1–66
 DAPT for 12 months is standard care in ACS*

ACS

PCI (DES/BMS or DCB) Medical Treatment Alone

High Bleeding Risk

No Yes No Yes

A P A T A C or A T A T A C

or or
A C A C

12 month DAPT 6 month DAPT 12 month DAPT ≥1 month DAPT

(class I A) (class IIa B) (class I A) (class IIa C)

*If no high bleeding risk

Valgimigli M et al. European Heart Journal.2017; 0: 1–48
 ESC 2017 Focused Update DAPT in CAD :
Algorithm for switching between oral P2Y12 inhibitors
in ACUTE setting 1

Class I LOE B
Class Iib LOE C

Switch from Clopidogrel to Ticagrelor in Acute Setting is allowed

irrespective of prior clopidogrel timing and dosing (1B)
Reference: 1. Valgimigli M et al. European Heart Journal (2017) 0, 1–48 20
 :
ESC 2017 Focused Update DAPT in CAD
Algorithm for switching between oral P2Y12 inhibitors
in CHRONIC setting 1

• Swith after 24 hr last dose

• Clopidogrel to ticagrelor ~ no
loading dose
• Ticagrelor to clopidogrel ~
load 600 mg clopidogrel

Class IIb LOE C

Additional switching between oral P2Y12 inhibitors may be considered in

cases of side effects/drug intolerance according to the proposed algorithms.
Reference: 1. Valgimigli M et al. European Heart Journal (2017) 0, 1–48 21
Take Home Message
1. Aspirin indefinite
2. In pts with intracoronary stents, treatment with a P2Y12
antagonist is absolutely mandatory
• Minimum 1 month for BMS
• Minimum 6 months for DES (optimal duration isn’t known)
3. In pts with ACS who receive aspirin, P2Y12 antagonist
(Ticagrelor/Clopidogrel) is better than aspirin alone
4. Ticagrelor is better than clopidogrel for ACS pts with or w/o PCI