Oral P2Y12 inhibitors in Acute Myocardial Infarction
: Are they all equal ?
Cardiovascular Division, Department of Internal Medicine
Kangnam Sacred Heart Hospital, Hallym University Medical
Center, Seoul, Korea
Jung Rae Cho, MD, PhD
The Current Bottom Line – To start with potent P2Y12
inhibitor in ACS (ESC 2017 recommendation)
European Heart Journal (2017) 0, 1–48. doi:10.1093/eurheartj/ehx419
Clinical need for “de-escalation”
• Economical issue (reduced cost with clopidogrel)
• Increased bleeding risk with the use of prasugrel or
ticagrelor (such as older age, lower body weight,
previous TIA/stroke, in-hospital treatment of CABG,
atrial fibrillation or concurrent use of oral anti-
coagulant)
• Non-bleeding side effects – dyspnea with ticagrelor
• TOPIC trial – Despite limitation, it showed reduced
bleeding complications with de-escalation
• TROPICAL-ACS – Only RCT utilizing PFT to adjust
antiplatelet therapy (either escalation or de-
escalation) to meet its primary end point
TRANSLATE-ACS population
4/4/2010 to 8/17/2012
8149 patients from 217 hospitals
Initial 1st gen ADPri
(n=6077)
Initial 2nd gen ADPri
(n=2072)
No Switch
(n=5408)
(89%)
Switch to 1st
gen (n=271)
(13%)
No Switch
(n=1801)
(87%)
Switch to 2nd
gen (n=669)
(11%)
In-Hospital Switching of ADP Receptor Inhibitor in Myocardial Infarction
Patients Treated with Percutaneous Coronary Intervention:
Insights from the TRANSLATE-ACS Study
Switch from 2nd to 1st gen:
associated with older age,
anticoagulant use at discharge,
preserved LV systolic function,
and prior TIA/stroke.
Switch from 1st to 2nd gen:
associated with clinical and
socio-economic factors:
younger age, prior PCI, PFT,
and private health insurance.
Bagai et al. ACC 2012
In-hospital ADPri switching is not associated with early (6-weeks) MACE and
hospitalization for bleeding . Future investigation will examine longer term effects.
In-hospital de-escalation from potent
P2Y12 inhibitor to less potent P2Y12
inhibitor is not uncommon in real world.
1/3 patients poor
responders
PD Effects of De-escalation from
Ticagrelor or Prasugrel to Clopidogrel
Kerneis M et al.
JACC Cardiovasc Interv. 2013;6:158–165
Gurbel P A et al.
Circulation 2010; 121:1188-99
De-escalation inevitably leads to an increase in platelet reactivity and HPR rates
Pharmacodynamic Effects of Switching from Ticagrelor to Clopidogrel in
Patients with Coronary Artery Disease: Results of the SWAP -4 Study
Results
PRU levels were similar between C-600mg-24h and C-75mg-24h (p=0.29), including at 48
hours (primary endpoint; LSM difference: -6.9; 95% CI: -38.1 to 24.3; p=0.66). PRU levels
were lower with C-600mg-12h versus C-75mg-24h (p=0.024)
Franchi F, et al. Circulation, 2018
VerifyNow P2Y12
PD studies showed rebound of platelet
activity after de-escalation.
Ce document de formation strictement confidentiel est la propriété unique d’AstraZeneca. Il doit être lu en lien avec le RCP en vigueur. Il ne peut être ni remis, ni dupliqué, ni utilisé en visite médicale. Document exclusivement réservé à la formation des délégués médicaux habilités à présenter des produits AstraZeneca.
Document interne. Seule la version figurant sur Nucleus est en vigueur. CAR/BRI/SU/01 2017/Bri Lésions complexes Janv2017 V1
8,688
8,763
0 10 20 30
8
6
4
2
0
Cu
mu
lati
ve
in
cid
en
ce
(%
)
Clopidogrel
Ticagrelor
4.77
5.43
HR 0.88 (95% CI 0.77–1.00), p=0.045
No. at risk
Clopidogrel
Ticagrelor
9,291
9,333
8,875
8,942
8,763
8,827
Days after randomisation
31 90 150 210 270 330
8
6
4
2
0
Clopidogrel
Ticagrelor
5.28
6.60
8,688
8,763
8,286
8,397
6,379
6,480
Days after randomisation*
HR 0.80 (95% CI 0.70–0.91), p<0.001
8,437
8,543
6,945
7,028
4,751
4,822
Cu
mu
lati
ve
in
cid
en
ce
(%
) *Excludes patients with any primary event during the first 30 days
PLATO : Primary Endpoint Over Time Time to first primary efficacy event (composite of CV death, MI or stroke)
Wallentin et al. New Eng J Med 2009; 361(11): 1045-1057
Ce document de formation strictement confidentiel est la propriété unique d’AstraZeneca. Il doit être lu en lien avec le RCP en vigueur. Il ne peut être ni remis, ni dupliqué, ni utilisé en visite médicale. Document exclusivement réservé à la formation des délégués médicaux habilités à présenter des produits AstraZeneca.
Document interne. Seule la version figurant sur Nucleus est en vigueur. CAR/BRI/SU/01 2017/Bri Lésions complexes Janv2017 V1
No. at risk
Clopidogrel
Ticagrelor
9,291
9,333
8,560
8,678
8,405
8,520
8,177
Days after randomisation
6,703
6,796
5,136
5,210
4,109
4,191
0 60 120 180 240 300 360
6
5
4
3
2
1
0
7 C
um
ula
tive
in
cid
en
ce
(%
) Clopidogrel
Ticagrelor
5.8
6.9
8,279
HR 0.84 (95% CI 0.75–0.95), p=0.005
0 60 120 180 240 300 360
6
4
3
2
1
0
Clopidogrel
Ticagrelor
4.0
5.1
HR 0.79 (95% CI 0.69–0.91), p=0.001
7
5
9,291
9,333
8,865
8,294
8,780
8,822
8,589
Days after randomisation
7079
7119
5,441
5,482
4,364
4,419 8,626
Myocardial infarction
Cardiovascular death
Cu
mu
lati
ve
in
cid
en
ce
(%
)
PLATO : Secondary Endpoints Time to first myocardial infarction or cardiovascular death
Wallentin et al. New Eng J Med 2009; 361(11): 1045-1057
0
5
10
15
0 30 60 90 180 270 360 450
HR 0.81
(0.73-0.90)
P=0.0004
Prasugrel
Clopidogrel
HR 0.80
P=0.0003
HR 0.77
P=0.0001
Days
Pri
ma
ry E
nd
po
int
(%)
12.1
(781)
9.9
(643)
Primary Endpoint
CV Death,MI,Stroke
NNT= 46
ITT= 13,608 LTFU = 14 (0.1%)
0
2
4
6
8
0 1 2 3
1
0
30 60 90 180 270 360 450
HR 0.82
P=0.01
HR 0.80
P=0.003
5.6
4.7
6.9
5.6
Days
Pri
ma
ry E
nd
po
int
(%)
Prasugrel
Clopidogrel
Prasugrel
Clopidogrel
Loading Dose Maintenance Dose
Timing of Benefit
(Landmark Analysis)
From the landmark analyses in both
PLATO and TRITON TIMI 38 studies, de-
escalation of P2Y12 inhibitor may sacrifice
continued ischemic benefit of potent
P2Y12 inhibitor after de-escalation.
Similar P2Y12-Associated Complications
in Patients with ACS in Real World Practice
J Manag Care Spec Pharm. 2017
11,629 ACS patients (USA big data)
0.3 3
Net clinical benefit of ticagrelor in Asian ACS patients:
Efficacy and safety analyses (PLATO) No significant interaction between Asian/non-Asian ethnicity and
clinical outcomes was observed in PLATO
End point HR (95% CI) p for interaction
Net clinical benefit Asian 0.85 (0.65–1.11) 0.521
Non-Asian 0.93 (0.86–0.99)
CV death, MI or stroke Asian 0.84 (0.61–1.17) 0.974
Non-Asian 0.85 (0.77–0.93)
All-cause death Asian 0.77 (0.51–1.17) 0.931
Non-Asian 0.79 (0.69–0.90)
CV death Asian 0.75 (0.49–1.16) 0.792
Non-Asian 0.80 (0.69–0.93)
CV death or MI Asian 0.83 (0.59–1.16) 0.972
Non-Asian 0.82 (0.74–0.91)
Stroke Asian 1.01 (0.44–2.32) 0.701
Non-Asian 1.19 (0.91–1.57)
Probable/definite stent thrombosis Asian 0.91 (0.37–2.25) 0.638
Non-Asian 0.73 (0.57–0.93)
PLATO major bleeding Asian 1.02 (0.70–1.49) 0.938
Non-Asian 1.04 (0.95–1.14)
Non-CABG major bleeding Asian 1.21 (0.67–2.19) 0.947
Non-Asian 1.19 (1.01–1.39)
Dyspnoea Asian 1.77 (1.18–2.66) 0.894
Non-Asian 1.82 (1.66–2.00)
Bradycardia Asian 1.16 (0.64–2.07) 0.856
Non-Asian 1.09 (0.95–1.26)
1 Favours ticagrelor Favours clopidogrel
CABG, coronary artery bypass graft; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction.
1. Kang HJ et al. Am Heart J. 2015 Jun;169(6):899-905.e1. doi: 10.1016/j.ahj.2015.03.015. Epub 2015 Mar 31
Ticagrelor Regulatory Post-marketing surveillance* (rPMS) in Korea
• Study design
Multicenter, open-label, prospective, observational study
• Re-examination period*
22 July 2011 – 21 July 2017
• Participating investigators
71 investigators from 49 centers across Korea
ENCORE Seoul 2017 Moderated E-Poster III (Coronary)
• Safety end points
Incidence of AE/ADR/SAE/SADR
Incidence of hemorrhagic events*
• Efficacy end point
Composite end point - CV death, MI, Stroke
AE, Adverse Event; ADR, Adverse Drug Reaction; SAE, Serious Adverse Event; SADR, Serious Adverse Drug Reaction;
* The outcomes were collected during the study period but all data about hemorrhage was collected from the administration start date to 7 days after the
administration end date of ticagrelor or 7 days after final observation date.
• Objective
To evaluate safety and efficacy of ticagrelor in real clinical practice
Results: Haemorrhagic events & Efficacy endpoints
Variables (N=3,108) No. of AEs (%)
Hemorrhagic events 409 (13.2)
Major fatal/life-threatening hemorrhage
0 (0.0)
Other major hemorrhage Bruise 7 Melena 5 GI hemorrhage 4 Epistaxis 3 Post procedural hematoma 2 Cerebral hemorrhage 1 Ecchymosis 1 Hematuria 1
24 (0.8)
Minor hemorrhage 99 (3.2)
Minimal bleeding 286 (9.2)
• Major Fatal/life-threatening hemorrhage Fatal, or intracranial, or intrapericardial bleed with cardiac tamponade, or hypovolaemic shock or severe hypotension due to bleeding and requiring pressors or surgery, or clinically overt or apparent bleeding associated with a decrease in haemoglobin of more than 50 g/L, or transfusion of 4 or more units (whole blood or PRBCs) for bleeding.
• Other major hemorrhage Significantly disabling(e.g., intraocular with permanent vision loss), or clinically overt or apparent bleeding associated with a decrease in haemoglobin of 30 to 50g/L, or transfusion of 2-3 units (whole blood or PRBCs) for bleeding.
• Minor hemorrhage Requires medical intervention to stop or treat bleeding (e.g., epistaxis requiring visit to medical facility for packing).
• Minimal bleeds Includes all other bleeds
ADR: Adverse Drug Reaction
ENCORE Seoul 2017 Moderated E-Poster III (Coronary)
Variables (N=2,343) No. of patients (%)
Composite end point 11 (0.5)
Cardiovascular death 0 (0.0)
Myocardial infarction 5 (0.2)
Stroke 6 (0.3)
Ticagrelor plus low-dose aspirin was associated with a low rate of major bleeding events and a low incidence of major CV events (CV death, myocardial infarction, stroke) in Korean patients with ACS.
Introduction of ticagrelor in Sweden
(SWEDEHEART Registry)
Sahlen A et al. Eur Heart J 2016;37:3335-3342.
Outcomes in Patients Treated With Ticagrelor or Clopidogrel After ACS:
Real world evidence from SWEDEHEART Registry
Clopidogrel
Clopidogrel
Clopidogrel
Clopidogrel
Clopidogrel
Ticagrelor
Ticagrelor Ticagrelor
Ticagrelor
Ticagrelor
adj HR:0.85 (0.78 – 0.93)
adj HR:0.89 (0.78 – 1.01)
adj HR:0.83 (0.75 – 0.92)
adj HR:0.81 (0.65 – 1.01)
adj HR:1.20 (1.04 – 1.40)
Sahlen A et al. Eur Heart J 2016;37:3335-3342.
45,073 ACS patients between Jan 2000 and Dec 2013
14 Centre study with 1230 AMI patients recruited, randomized to either Prasugrel or Ticagrelor
Study prematurely terminated for futility
Although prematurely terminated and
underpowered, PRAGUE-18 RCT
demonstrated similar ischemic/bleeding
outcomes between prasugrel and
ticagrelor.
Taiwan National Health Insurance Database
Lee CH et al. Circ J 2018;82(3):747-756.
Composite of all cause death, MI or stroke
0
5
10
15
20
Composite endpoint All cause death MI Stroke
Ticagrelor, n = 2,389
Clopidogrel, n = 19,112
10.6% vs. 16.2%
2.2% vs. 6.9%
7.5% vs. 9.0%
1.7% vs. 2.9%
%
Adjusted HR 0.80; CI 0.68 - 0.94
• The Taiwan National Health Insurance Research Database between January 2012 and December 2014
Taiwan National Health Insurance Database
Lee CH et al. Circ J 2018;82(3):747-756.
Composite of ICH and major GI bleeding
0
5
10
Composite endpoint ICH Major GI bleeding
Ticagrelor, n = 2,389
Clopidogrel, n = 19,112
3.2% vs. 4.1%
0.3% vs. 0.4%
2.9% vs. 3.7%
% Adjusted HR 1.01; CI 0.74-1.37
• The Taiwan National Health Insurance Research Database between January 2012 and December 2014
Comparison between the effects of ticagrelor and clopidogrel in Korean patients with AMI
Park KH et al. IJC 2016
Equipotent ischemic benefit with increased bleeding with ticagrelor compared with clopidogrel
Consistently less bleeding with clopidogrel than ticagrelor across all subgroups
Park KH et al. IJC 2016
J.C. Choe et al. / International Journal of Cardiology
MACEs and CV mortality Safety and Efficacy Endpoints in Entire Cohort
J.C. Choe et al. / International Journal of Cardiology
Efficacy Endpoints According to Different Adjustment
Methods.
Antiplatelet therapy for AMI in Korea
(HIRA database)
CK Kim et al. Korean Circ J. 2017 Nov;47(6):888-897
Antiplatelet therapy for AMI in Korea 1-year
outcomes from HIRA database
DH Shin Presented at TCTAP 2018
Different patient groups, statistical methods as
well as limitation of registry data may have
affected the different study results
The solution…
1) We need RCT (idealistic)
or
1) Prescribe P2Y12 inhibitor according to
individual characteristics (believe in
yourself !)
Summary • Dual antiplatelet therapy with potent P2Y12 inhibitors in
conjunction with aspirin has become the standard of care in patients with acute coronary syndrome.
• However, due to its increased bleeding, switching back to clopidogrel (a.k.a “de-escalation”) has gained popularity in clinical practice as evidenced from 2 notable RCTs, which unfortunately has several limitations.
• However, de-escalation might not be suitable for patient subsets such as prior stent thrombosis, multiple implanted stents or complex coronary lesion etc.
• In the real-world data, potent P2Y12 inhibitors showed not much adverse effects than expected, but also demonstrated promising results in terms of reducing MACE.
• Therefore, the decision-making to use particular P2Y12 inhibitor at the beginning of ACS according to individual ischemic/bleeding risk is of utmost importance. If chosen, it might be better to keep going with same medication up to 1 year unless there is a demand for de-escalation.
Thank you for your attention !!!
Sapporo, Japan (Oct 6, 2017)