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.

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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)