CONTROVERSIES FOR ASIAN PATIENTS

Antiplatelet for ACS patients:
Controversies for Asian
Patients
YUDI HER
OKTAVIONO

History of Dual Antiplatelet Therapy (DAPT) in Patients with Coronary
Artery Disease1
2
Reference: 1. Valgimigli M et al. European Heart Journal (2017) 0, 1–48

ESC 2020 NSTEMI GUIDELINE
Collet JP et al European Heart Journal (2020) 00, 1-79

ESC Guidelines (NSTEMI 2020;STEMI 2017)
Eur Heart J.2017;DOI: 10.1093/eurheartj/ehx393, Collet JP et al European Heart Journal (2020) 00, 1-79
NSTEMI
2020
STEMI
2017
Recommendations for antithrombotic treatment in non-ST-segment elevation acute
coronary syndrome patients without atrial fibrillation undergoing percutaneous
coronary intervention

AHA Guidelines
(NSTEMI.2014; STEMI.2013)
JACC.2013;61(4):e78-140; Circulation.2014;130:e344-426

PLATO Trial: Ticagrelor reduce CV Event on ACS Patients vs.
Clopidogrel1
6
*STEMI patients scheduled for primary PCI were randomised; however, they may not have received PCI.
†A loading dose of 300-mg clopidogrel was permitted in patients not previously 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.
<24h Month 1 Month 3 Month 6 Month 9 Month 12
Screening
Visit 2 Visit 3 Visit 4 Visit 5 Visit 6
N=18,624
• Patients with ACS
(UA, NSTEMI, or STEMI*)
• Initial treatment approaches
• Medically managed (28%)
• Invasively managed (72%)
Ticagrelor
180-mg
loading dose
Ticagrelor
90-mg bid + ASA
N=9,333
Clopidogrel
300-mg
loading dose
Clopidogrel
75-mg qd
+ ASA
N=9,291
Randomisation
• All patients were hospitalised with symptom onset <24 hours
• Patients could be taking clopidogrel at time of randomisation
 Primary efficacy
endpoint:
Composite of CV death,
MI (excluding silent MI),
or stroke
 Primary safety
endpoint:
Total PLATO major
bleeding‡
Reference: 1. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
ASA

PLATO Trial: Reduction CV event of ticagrelor starts early and continue until 12
months in ACS Patients vs. clopidogrel1
7
Reference: 1. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
No. at risk
Clopidogrel
Ticagrelor
9,291
9,333
Months After Randomization
8,521
8,628
8,362
8,460
8,124 6,650
6,743
5,096
5,161
4,047
4,147
8,219
0 2 4 6 8 10 12
12
11
10
9
8
7
6
5
4
3
2
1
0
13
Cumulative
Incidence
of
(Composite
of
CV
Death,
MI,
or
Stroke)
%
11.7 Clopidogrel
9.8 Ticagrelor
HR: 0.88 (95% CI, 0.77−1.00); P=0.045
0–30 Days
4.8
5.4
Clopidogrel
Ticagrelor
0–12 Months
at 1 month
ARR=0.6%
RRR=12%
HR: 0.84 (95% CI, 0.77–0.92); P<0.001
at 12 months
ARR=1.9%
RRR=16%

Ticagrelor versus Clopidogrel in Patients with Acute Coronary
Syndromes
Wallentin L, Becker RC, Budaj A, et al.N Eng J Med.2009;361(11)
Intracranial fatal bleeding is significantly higher in TICA

Ticagrelor versus Clopidogrel in Patients with Acute
Coronary Syndromes
Non-CABG related major bleeding is significantly higher in TICA

Syndromes
Discontinuation of the drug because of AE is higher in TICA

Clopidogrel is safer than ticagrelor in regard to bleeds : A closer look
at the PLATO trial
DiNicolantonio JJ, D’Ascenzo F, Tomek A, et al.Int J Cardiol.2013;168:1739-44.
• To compare hemorrhagic events between clopidogrel and ticagrelor in
PLATO
“Compared to clopidogrel, ticagrelor significantly increased spontaneous
bleeds, major bleeds, major plus minor bleeds, and major plus minor plus
minimal bleeds”
Major + minor bleeding (any bleeding requiring intervention Non-procedural (spontaneous) major + minor
bleeds

CHANGE DAPT Study :
Ticagrelor vs Clopidogrel in new generation
DES era

Impact of CHANGE DAPT in Clinical
Practice
• Based on international guidelines, ticagrelor has largely replaced
clopidogrel as a component of DAPT in ACS patients.
• CHANGE DAPT confirms that treatment with ticagrelor is associated
with more major bleedings. This increased bleeding risk should be
balanced against benefits in reducing ischaemic events.
• Nevertheless, in ACS patients treated by PCI with newer-generation
DES, the benefits of ticagrelor in reducing ischaemic events have not
yet been demonstrated and were not observed in this study. But we
cannot exclude that certain subgroups of PCI patients, treated with
contemporary DES, may benefit from ticagrelor use.
Zocca P, et al.EuroIntervention.2017;13(10):1168-76.

CHANGE STUDY

CP : clopidogrel period; TP : ticagrelor period

De-escalation strategy for ACS patients undergoing PCI

| 19
• TOPIC evaluated the effect of de-escalation from a new P2Y12 inhibitor to clopidogrel on clinical
outcomes and results were reported at EuroPCR in May 2017 and simultaneously published in the
European Heart Journal
• 646 ACS patients
undergoing PCI
• Without ischemic events or
bleeding (BARC ≥2) at
1-month follow-up after PCI
• Receiving DAPT with a new
P2Y12 inhibitor + aspirin
Randomization
1:1
De-escalation DAPT group
Clopidogrel + aspirin FDC
Composite primary endpoint
• Death, non fatal MI, stroke, all BARC
bleeding
Secondary endpoints
• Components of primary endpoint
• Death, MI, stroke, BARC bleeding ≥2
TOPIC: Timing Of Platelet Inhibition after acute Coronary Syndrome
FDC, fixed-dose combination; NCT02099422
Cuisset T et al. Eur Heart J. 2017 May 16. doi: 10.1093/eurheartj/ehx175. [Epub ahead of print]
Design Interventions Primary endpoint
Prospective, randomized trial in
646 ACS patients
• Prasugrel or ticagrelor
• Clopidogrel
Death, non-fatal MI, stroke, all BARC bleedings at 12
months
TOPIC: RCT study design
Unchanged DAPT group
New P2Y12 inhibitor + aspirin
1- year follow-up
1- year follow-up

Better Prognosis with switched DAPT
Cuisset T, et al.Eur Heart J.2017;0:1-9
Primary Endpoint
Death, Urgent revasc., Stroke, BARC ≥ 2
TOPIC (Timing Of Platelet Inhibition after acute Coronary
Syndrome) randomized study : To evaluate the benefit of
switching DAPT from aspirin plus a newer P2Y12 blocker to aspirin
plus clopidogrel 1 month after ACS.

No difference for ischemic events
Any ischemic endpoint
TOPIC (Timing Of Platelet Inhibition after acute Coronary Syndrome)
randomized study : To evaluate the benefit of switching DAPT from
aspirin plus a newer P2Y12 blocker to aspirin plus clopidogrel 1 month after
ACS.

TOPIC (Timing Of Platelet Inhibition after acute Coronary Syndrome)
randomized study : To evaluate the benefit of switching DAPT from
aspirin plus a newer P2Y12 blocker to aspirin plus clopidogrel 1 month after
ACS.
Higher Rate of BARC bleeding ≥ 2 with Unchanged DAPT
BARC bleedings ≥ 2

2018 ESC/EACTS Guidelines on
Myocardial Revascularization
Recommendation Class Level
De-escalation of P2Y12 inhibitor treatment (e.g. with a switch from
ticagrelor to clopidogrel) guided by platelet function testing may be
considered as an alternative DAPT strategy, especially for ACS
patients deemed unsuitable for 12-month potent platelet inhibition
IIb B
DAPT scenario in the
guideline
Duration of
treatment
Shortened (< 12 month)
Extended (> 12 month)
P2Y12inh
switching
De-escalation
Escalation
‘ Triggers for DAPT de-escalation include clinical (bleeding events or
presumed high bleeding risk) and socio-economic factors’
Neumann FJ, et al.Eur Heart J.2018;00:1-96.

Recommendations for post-interventional and
maintenance treatment in patients with
non-ST-segment elevation acute coronary
syndrome

A New Phenomenon : ‘East Asian Paradox’
Unique Characteristics
of East Asians
Compared to their Caucasian counterparts, East Asian patients treated with
dual antiplatelet therapy have a similar or lower rate of post-PCI ischaemic
events in spite of having a higher level of platelet reactivity
Huo Y, et al.Science Bulletin.2019;64:166-79.

A New Phenomenon : ‘East Asian Paradox’
World Heart Federation
Expert Consensus :
• Large, phase III, randomized,
controlled trials of the P2Y12
inhibitors (clopidogrel, ticagrelor,
prasugrel) only included few East
Asian patients.
• Data suggests that East Asian
patients have DIFFERENT risk
profiles for both thrombophilia and
bleeding compared with white
patients  different ‘therapeutic
window’ of on-treatment platelet
reactivity (see figure)
Levine GN, et al. Nat Rev Cardiol.2014. doi:10.1038/nrcardio.2014.104; Huo Y, et al.Science Bulletin.2019;64:166-79.

Ticagrelor vs. Clopidogrel in Japanese, Korean and Taiwanese Patients with Acute Coronary Syndrome
‘Randomized, Double-Blind, Phase III PHILO Study compared the safety and efficacy of ticagrelor vs
clopidogrel’
Goto S, Huang CH, Park SJ, et al.Circ J.2015;79:2452-60.
Patients : ACS with planned PCI. Inclusion and exclusion
criteria were similar to those for PLATO
Result :
• No difference in the composite of cardiac death, MI,
stroke, at 12 months (tica vs clopi : 9.0% vs 6.3%; p=ns)
• No difference in major bleeding (PLATO-defined) (tica vs
clopi 10.3% vs 6.8%; p=ns)
• Higher composite of major and minor bleeding in tica vs
clopido (23.8% vs 14.7%; HR 1.72 95%CI 1.23 – 2.40)
Conclusions: East Asian patients with ACS undergoing PCI who received
ticagrelor had a non-significantly higher rate of major bleeding events and more,
albeit not significantly, major CV events (CV death, MI or stroke), compared with
clopidogrel. This may be explained by the small sample size, imbalance in baseline
demographics and clinical characteristics, and the generally low number of events
in the PHILO population.
Randomized
n=801
Ticagrelor
90mg bid
(n=401)
Completed
study
n=335; 83.5%
Clopidogrel 75
mg od (n=400)
Completed
study
n=337; 84.3%
ACS : acute coronary syndrome; PCI, percutaneous coronary intervention, MI, myocardial infarction, HR, hazard ratio

“The PLATO and PHILO randomized trials did not show efficacy
superiority of ticagrelor vs clopidogrel in East Asian Patient” – 2018
WHF Consensus
Kang HJ, et al Ticagrelor versus clopidogrel in Asian patients with acute coronary syndrome: A retrospective analysis from PLATO trial.Am Heart
J.2015;169:899-905.e1.
1,106 patients
out of 18,621
(5.9%) of
PLATO study
population
were Asian

Comparison of short-term clinical outcomes between ticagrelor versus clopidogrel in patients with acute
myocardial infarction undergoing successful revascularization; from Korea Acute Myocardial Infarction
Registry—National Institute of Health
Park KH, Jeong MH, Ahn Y, et al.International Journal of Cardiology.2016;215:193-200.
Efficacy and safety comparison between ticagrelor
and clopidogrel in AMI patients without increased
bleeding risk among East Asian patients.
Result :
• No difference in the composite of cardiac death,
MI, stroke, or target vessel revascularization at
6 months (tica vs clopid : 4.2% vs 4.9%;
p=0.499)
• Higher TIMI major bleeding in ticagrelor arm
(2.6% vs 1.2%; p=0.008)
• In hospital mortality was higher in patients with
major bleeding (11.3% vs 0.9%; p<0.001)
Conclusions: Our study shows that ticagrelor did not reduce ischemic
events yet, however, was associated with increased risk of bleeding complications
compared with clopidogrel. Further large-scale, long-term, randomized trials should
be required to assess the outcomes of ticagrelor for East Asian patients with AMI
AMI : acute myocardial infacrtion; MI, myocardial infarction

Safety and Effectiveness of Contemporary P2Y12 Inhibitors in an East
Asian Population With Acute Coronary Syndrome: A Nationwide
Population-Based Cohort Study’
Yun JE, Kim YJ, Park JJ,et al.J Am Heart Assoc.2019;8:e012078.
An observational cohort study comparing safety and efficacy of P2Y12inh in 70,715 patients with ACS
(mostly undergoing PCI). Median follow-up : 18.0 mo
Safety endpoint
HR
1.23

Safety and Effectiveness of Contemporary P2Y12 Inhibitors in an East
Asian Population With Acute Coronary Syndrome: A Nationwide
Population-Based Cohort Study’
Yun JE, Kim YJ, Park JJ,et al.J Am Heart Assoc.2019;8:e012078.
An observational cohort study comparing safety and efficacy of P2Y12inh in 70,715 patients with ACS
(mostly undergoing PCI). Median follow-up : 18.0 mo
Efficacy endpoint
HR
0.76
“Compared with clopidogrel, ticagrelor was associated with an increased risk of
bleeding but a decreased risk of mortality in East Asian patients.”

TICAKOREA
• Number of sample: 800 Korean patients with ACS (STEMI and N-STEMI)
• Method: multicenter, open-label, randomized, controlled trial
• Drug: 1:1 ratio
• ticagrelor (180 mg loading dose, 90 mg twice daily thereafter) OR clopidogrel (600 mg loading dose, 75 mg daily thereafter).
• Primary End Point: clinically significant bleeding (a composite of major
bleeding or minor bleeding according to PLATO (Platelet Inhibition and
Patient Outcomes) criteria at 12 months.
• Result:
• At 12 months, the incidence of clinically significant bleeding Ticagrelor 11.7% vs
Clopidogrel 5.3% (p=0.002; higher in the ticagrelor).
• The incidence of death from cardiovascular causes, myocardial infarction, or stroke
was not significantly different (Ticagrelor 9.2% vs Clopidogrel 5.8%, p=0.07)
Park DW, et al. Circulation. 2019;140:00–00

2018 World Heart Federation Expert Consensus
Statement
East Asian Paradox : East Asian patients show a similar or even a lower rate
of ischemic event occurrence and higher bleeding risk compared with
Caucasian patients
Consensus statement :
• Clopidogrel in combination with aspirin is a reasonable DAPT choice
for elective PCI or ACS (during the chronic phase) in East Asian population.
• Use of standard-dose potent P2Y12 inhibitors needs attention to the
increased risk of bleeding when used in East Asian ACS population (e.g.,
prior stroke, old age, low body weight, and recurrent episodes of nuisance
bleeding).
• After considering the risk-benefit profile, a reduced-dose strategy of potent
P2Y12 receptor inhibitors (especially, prasugrel) may be a considerable
choice in East Asian population with ACS.
Huo Y, et al.Science Bulletin.2019;64:166-79.

CONCLUSION
• Choice of antiplatelet should be based on careful review on the balance
between antiplatelet efficacy and risk of bleeding (individualized).
• Tolerability, safety, compliance to treatment, patient’s preference and cost
should also be considered
• Use of more potent P2Y12 inhibitors (ticagrelor) in place of clopidogrel
results in decreased ischemic risk but also increased bleeding risk,
particularly in East Asian patient population.
• East Asian paradox, TOPIC study, and recent CHANGE DAPT study
warrants further challenge to existing guidelines, taking into
consideration other important factors, such as race difference and newer
generation DES era.

Hasil penilaian dari bleeding criteria lebih baik
dengan Clopidogrel

What is NEW?

The rationale behind dual antiplatelet therapy
Colombo A, et al.N Eng J Med.2014;371(23):2225-6.
1. The stented segment requires protection
from stent thrombosis that occurs as a
result of inflammation during healing.
 the stented segment requires protection
from stent thrombosis that occurs as a result of
inflammation during healing.
2 indications for DAPT after successful stenting :
2. the areas inside and outside the stented
section require protection from the
development of progressive atherosclerosis
and plaque rupture

Leonardi S, et al. European Heart Journal: Acute Cardiovascular Care

New ESC NSTEMI Guideline

Major Changes in Recommendation

Acuity Score
Mehran R, et al. A risk score to predict bleeding in patients with acute coronary syndromes. J Am Coll Cardiol 2010;55:2556-2566

CRUSADE SCORE
CRUSADE Score for Post-MI Bleeding Risk, downloaded from https://www.mdcalc.com/crusade-score-post-mi-bleeding-risk#use-
cases, accessed on 11 Sep 2020. Xi S. Thromb Haemost 2017;117:2186–2193.

Major Changes in Recommendation
An alternative to these scores may be the
assessment of bleeding risk according to the
Academic Research Consortium for High
Bleeding Risk (ARC-HBR).
ARC-HBR criteria may be difficult to apply in
routine clinical practice as several of the
criteria are quite detailed and so far, this
score has not been validated.
In order to estimate bleeding risk in this setting,
scores such as the Can Rapid risk stratification of
Unstable angina patients, CRUSADE and the Acute
Catheterization and Urgent Intervention Triage
strategy (ACUITY) bleeding risk scores have been
developed.
CRUSADE bleeding risk score may be
considered in patients undergoing coronary
angiography to quantify bleeding risk.
Among HBR patients based on PRECISE-DAPT
(i.e. PRECISE-DAPT score >_25), prolonged
DAPT was associated with no ischaemic benefit
but a large bleeding burden

Clopidogrel for NSTEMI ESC
2020

Algorithm for antithrombotic therapy in non-ST-segment elevation
acute coronary syndrome patients without atrial fibrillation
undergoing PCI

DAPT in patients undergoing fibrinolytic treatment
Recommendations (2017 ESC guideline DAPT) Clas
s
Lev
el
Clopidogrel (300 mg loading dose in patients aged ≤ 75,
75 mg o.d.) is recommended on top of aspirin in STEMI
patients receiving thrombolysis
IA A
Valgimigli M, et al.Eur Heart J.2018;39:213-54; Ibanez B, et al.Eur Heart J.2017;00:1-66.
- Clopidogrel added to aspirin reduces the risk of cardiovascular events
and overall mortality in patients treated with fibrinolysis and should be
added to aspirin as an adjunct to lytic therapy.
- Prasugrel and ticagrelor have not been studied as adjuncts to fibrinolysis.
2017 ESC guidelines for STEMI

Duration of DAPT after fibrinolytic (without PCI)
• Clopidogrel is recommended for 1 month in patients treated with
fibrinolysis without subsequent PCI.
• Expanding the duration of DAPT up to 12 months should be considered
in these patients.
2017 ESC guidelines for STEMI
• Clopidogrel should be continued for a minimum of 14 days (Class I – A)
and ideally at least 12 months. Expanding the duration of DAPT up to
12 months should be considered in these patients (Class I – C-EO)
• In patients who have tolerated DAPT without bleeding complication and
who are not at high bleeding risk continuation of DAPT for longer than
12 months may be reasonable (Class IIb – A)
2016 ACC/AHA guidelines for STEMI
Ibanez B, et al.Eur Heart J.2017;00:1-66; Levine GN, et al.Circulation.2016;133:000-000.

CURE COMMIT
CLARITY
CURE
COMMIT
CURE
DAPT
CHARISMA
PEGASUS
Class 1:
> 12 mo
(CPG,
ticagrelo
r)
Class 1:
> 14 d &
Ideally > 12
mo
(CPG)
Class 1:
> 12 mo
(CPG,
ticagrelor,
prasugrel)
Class 1:
After CABG,
resume
P2Y12
inhibitor to
complete 1
yr of DAPT
No high risk of bleeding
& no significant bleeding on DAPT
High
bleedin
g risk
or
signific
ant
overt
bleedin
g
Class II b:
Discontinuatio
n after
6 mo may be
reasonable
2016 ACC/AHA DAPT Guideline Recommendations In ACS:
Duration Of Antiplatelet Therapy
Algoritma Durasi Manajemen ACS

Antiplatelet effect vs Bleeding risk
“Use of more potent P2Y12 inhibitors (ticagrelor or prasugrel) in place of
clopidogrel also results in decreased ischemic risk and increased bleeding
risk” – Levine GN, et al 2016 ACC/AHA Guideline
Antithrombotic Bleeding

INHIBITION OF PLATELET AGGREGATION
RISK
OF
ANY
EVENT
“Sweet Spot” Bleeding risk
Ischemic risk
Ferreiro Jl, et al. Thromb Haemost 2010; 103: 1128–1135
History of bleeding
• Therapy OAC
• Female
• Advanced Age
• Low body weight
• CKD
• Diabetes
• Anemia
• Chronic steroid or
NSAID
High risk ischemic patient = high risk for bleeding
Factors Associated With Increased Ischemic And
Bleeding Risk
High Ischemic risk
• Advanced age
• ACS
• Multiple prior MI
• Extensive CAD
• DM
• CKD
High risk Stent
Thrombosis
• ACS
• Diabetes
• LVEF < 40%
• DES 1st generation
• Stent technique
suboptimal
• Stent Type

Syndromes/ PLATO STUDY
• Method :
• multicenter, double-blind, randomized trial, comparing ticagrelor (180-mg LD  90 mg
BID) and clopidogrel (300-to-600-mg LD  75 mg OD) for the prevention of
cardiovascular events
• Results : n=18,624

Clopidogrel is safer than ticagrelor in regard to bleeds : A closer
look at the PLATO trial
DiNicolantonio JJ, D’Ascenzo F, Tomek A, et al.Int J Cardiol.2013;168:1739-44.
• To compare hemorrhagic events between clopidogrel and ticagrelor in
the PLATO trial

Summary from PLATO study
Choice between clopidogrel and ticagrelor : Other
things to consider for clinical practice
Keypoints Description
Clopidogrel loading
dose
Only 19.6% of subjects randomized to clopidogrel received
loading dose of clopidogrel as recommended by ESC
guideline.
Drug compliance • Ticagrelor : 2x/day; clopidogrel 1x/day
• Premature discontinuation is higher in ticagrelor arm
(7.4% vs 6.0%; p<0.001)
Other adverse event Incidence of dyspnea is higher in ticagrelor arm (13.8% vs
7.8%; p<0.001)
Wallentin L, Becker RC, Budaj A, et al.N Eng J Med.2009;361:1045-57.

Bleeding complications with clopidogrel or
ticagrelor in ST-elevation
myocardial infarction patients – A real life cohort
study of two treatment strategies
Method: We identified 330 consecutive STEMI patients with a
clopidogrel-based and 330 with a ticagrelor-based DAPT strategy
RESULT:
• In discharge period from hospital, there were more than twice as
many bleeding events with a ticagrelor-based compared with a
clopidogrel-based strategy (13.3% vs.6.5%, p = 0.005).
• Bleeding events included significantly more severe bleeding
complications (TIMI major/minor [5.8 vs. 1.0, p = 0.001]) during the
ticagrelor-based period.
• There was no significant difference in the composite of death, MI or
stroke (7.8% vs. 7.1%, p = 0.76).
Alfredson J, et al. IJC Heart & Vasculature 27 (2020) 100495. https://doi.org/10.1016/j.ijcha.2020.100495

In patients discharged
alive, there were more
than twice as many
bleeding events during the
ticagrelor-based period as
compared with the
clopidogrel-based period
(13.3% vs. 6.5%,
p = 0.005).
Bleeding complications with clopidogrel or ticagrelor in ST-
elevation
myocardial infarction patients – A real life cohort study of two
treatment strategies
Alfredson J, et al. IJC Heart & Vasculature 27 (2020) 100495. https://doi.org/10.1016/j.ijcha.2020.100495

TOPIC study :
In patients without adverse event 1 month after stented ACS, a switched DAPT is
superior to an unchanged DAPT strategy to prevent bleedings without increased risk of
ischemic events
ENDPOINTS Switched DAPT
(n=322)
Unchanged
DAPT
(n=323)
HR (95%IC)
P-value
Net clinical benefit 43 (13.4%) 85 (26.3%) 0.48 (0.34 - 0.68) <0.01
Any ischaemic event 30 (9.3%) 37 (11.5%) 0.48 (0.34 - 0.68 0.36
Cardiovascular Death 1 (0.3%) 4 (1.2%) 0.30 (0.05 - 1.73) 0.18
Unplanned revascularization 28 (8.7%) 30 (9.3%) 0.93 (0.56 - 1.55) 0.78
Stent Thrombosis 4 (1.2%) 3 (0.9%) 1.34 (0.30 – 6.0) 0.72
Stroke 1 (0.3%) 3 (0.9%) 0.37 (0.05 – 2.60) 0.32
All Bleedings 30 (9.3%) 76 (23.5%) 0.39 (0.27 - 0.57) <0.01
BARC Bleedings ≥ 2 13 (4%) 48 (14.9%) 0.30 (0.18 - 0.50) <0.01
TIMI Major 1 (0.3%) 4 (1.2%) 0.30 (0.05 - 1.73) 0.18
TIMI Minor 9 (2.8%) 26 (8%) 0.37 (0.19 - 0.71) <0.01
TIMI Minimal 20 (6.2%) 46 (14.2%) 0.44 (0.27 - 0.71) <0.01

Discussion
• Mengapa pasien Asia lebih beresiko mengalami
perdarahan?
• Perbedaan profil reaktivitas platelet (platelet reactivity)
 in Asian, higher exposure to ticagrelor and its active
metabolite (AR-C124910XX) led to higher levels of
inhibition for platelet aggregation.
• Perbedaan genetic dari faktor pembekuan darah
 (genetic DNA of coagulation factor) such as: factor V
Leiden [G1691A] and prothrombin [G20210A] gene
mutations), plasma hemostatic factors (i.e., fibrinogen, D-
dimer, and factor VIII), and endothelial activation markers
(i.e., von Willebrand factor, intercellular adhesion molecule
1, and E-selectin).

Specific Population:
ICU Patients and Elderly Patients

Bleeding risk of ticagrelor compared to
clopidogrel in intensive care unit patients with ACS
Charpentier T et al, PLoS ONE 15 (5): e0232768. https://doi.org/10.1371/journal.pone.0232768
All patients with ACS hospitalized in the ICU of a French university hospital
between January 2013 and January 2017 were included in the study
A total of 155 patients were
included in the study, 57
with ASA + TICA and 57
with ASA + Clopidogrel
61.4%
21.1%
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
Ticagrelor group Clopidogrel group
Bleeding during ICU Stay
Bleeding during ICU Stay
p<0.0001

Ticagrelor Vs Clopidogrel:
both TIMI major bleeding (12.3% vs. 35.1%, p = 0.004) and TIMI minor bleeding (8.8% vs. 26.3%, p = 0.01).
35.1%
12.3%
26.3%
8.8%
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
Ticagrelor Clopidogrel
Bleeding Risk Ticagrelor Vs Clopidogrel
TIMI Major TIMI Minor

• The relative risk of bleeding occurrence during ICU
stay was 2.60 (confidence interval 95%: 1.55–4.35)
for ticagrelor compared to clopidogrel.
• No significant difference in ICU mortality was found
between the two groups (45.6% in the clopidogrel
group vs. 29.8% in the ticagrelor group, p = 0.08).

Clopidogrel vs Ticagrelor or Prasurgel in
Patients of 70 years / older with NSTEMI ACS
(Elderly Patients)
• POPULAR AGE ESC CONGRESS 2019
Gimbel M, et al. Lancet 2020; 395: 1374–81

Secondary Safety Outcomes of POPULAR
AGE Study
Bleeding
events in
Clopidogre
l group is
lower for
PLATO
major
bleeding
and fatal
bleeding

Secondary Efficacy Outcomes of POPULAR
AGE Study
In patients aged 70 years or older presenting with NSTE-ACS, clopidogrel is a favourable alternative
to ticagrelor, because it leads to fewer bleeding events without an increase in the combined endpoint
of all-cause death, myocardial infarction, stroke, and bleeding.
Clopidogrel could be an alternative P2Y12 inhibitor especially for elderly patients with a higher
bleeding risk.

Loading Dose Clopidogrel in PCI
Patients
MAT-ID-2000533-v1.0 (09/2020)

CURRENT OASIS 7: A 2X2 Factorial Randomized Trial of Optimal
Clopidogrel and Aspirin Dosing in Patients with ACS Undergoing an
Early Invasive Strategy with Intent For PCI
• Clopidogrel
• Clopidogrel 300 mg followed by 75 mg daily reduces
major CV events across the spectrum of ACS and PCI
• Recent data suggest that doubling the loading and
maintenance doses of clopidogrel results in a higher and
more rapid antiplatelet effect
• Aspirin
• Dose of ASA varies between Europe and North America
• No large-scale RCT’s have compared high (300-325 mg)
versus low (75-100) dose aspirin in patients with ACS
undergoing PCI Mehta SR, et al. Lancet 2010; 376: 1233–43

Relative Risk Reduction
PCI No PCI
CURE: Clopidogrel 300/75 mg v Placebo (CVD/MI) 30%1 19%2
STEMI: Clopidogrel 300/75 mg v Placebo
(CVD/MI)
46%3 9%4
TRITON: Prasugrel v clopidogrel 300/75mg
(CVD/MI/Stroke)
19%5 Not evaluated
Benefits of Antiplatelet Therapy in ACS are
Greater in Patients Undergoing PCI
1. Mehta SR, et al. Lancet 2001; 358(9281):527-33.
2. Fox KAA, et al. Circulation 2004;110:1202-8
3. Sabatine MS, et al. JAMA 2005; 294(10):1224-32.
4. Chen ZM Lancet 2005;366:1607-21
4. Boersma E et al. Lancet 2002; 359:189
5. Wiviott S et al. N Engl J Med 2007; 357: 2001–15.

Study Design, Flow and Compliance
25,086 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)
 Planned Early (<24 h) Invasive Management with intended PCI
 Ischemic ECG Δ (80.8%) or ↑cardiac biomarker (42%)
PCI
17,232
(70%)
Angio 24,769
(99%)
No PCI 7,855 (30%)
No Sig. CAD 3,616 CABG 1,809 CAD 2,430
Randomized to receive (2 X 2 factorial):
CLOPIDOGREL: Double-dose (600 mg then150 mg/d x 7d then 75 mg/d) vs Standard dose (300 mg then 75 mg/d)
ASA: High Dose (300-325 mg/d) vs Low dose (75-100 mg/d)
Efficacy Outcomes: CV Death, MI or stroke at day 30
Stent Thrombosis at day 30
Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major)
Key Subgroup: PCI v No PCI
Clop in 1st 7d (median) 7d 7 d 2 d 7d
Complete
Follow up
99.8%
Compliance:
Mehta SR, et al. Lancet 2010; 376: 1233–43
Disclaimer: The approved loading dose for Plavix in PI is 300 mg

Kaplan-Meier curves for the primary outcome of CV death, MCI, or
stroke, for the clopidogrel dose comparison
This benefit was mainly attributable to a lower rate of myocardial infarction;
rates of cardiovascular death and stroke in the two groups were similar

Kaplan-Meier curves for clopidogrel dose comparison for
definite stent thrombosis in patients receiving a drug-eluting
stent
The rate of definite or probable stent thrombosis was 31% lower and that of
definite (angiographically confirmed) stent thrombosis was 46% lower with the
double-dose than with the standard-dose clopidogrel regimen.

Clopidogrel Dose Comparison
• Compared with the standard dose, double-dose clopidogrel
reduced the rate of the primary outcome (330 events [3·9%]
vs 392 events [4·5%]; adjusted hazard ratio 0·86, 95% CI
0·74–0·99, p=0·039) and definite stent thrombosis (58 [0·7%]
vs 111 [1·3%]; 0·54 [0·39–0·74], p=0·0001).
• High-dose and low-dose aspirin did not differ for the primary
outcome (356 [4·1%] vs 366 [4·2%]; 0·98, 0·84–1·13,
p=0·76).
• Major bleeding was more common with double-dose than with
standard-dose clopidogrel (139 [1·6%] vs 99 [1·1%]; 1·41,
1·09–1·83, p=0·009)

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