5 years after PLATO –

Experience from the Daily

Clinical Practice

Dual Antiplatelet Therapy:

Time for a Paradigm Shift?

Hans Rickli

Goals with antithrombotic treatment

Acute coronary syndrome

Risk reduction of cardiovascular events

Myocardial infarction

Death

Stroke

Risk reduction of stent thrombosis

Prehospital treatment to achieve rapid and

effective platelet inhibition and anticoagulation

Minimizing the risk of bleeding18.06.2015

Complications and outcome in STEMI patients (N=27’207)

*developing during hospitalization

Reduction of time delays Better risk stratification Invasive approach Antithrombotic therapy ……

Reperfusion therapy in STEMI patients (N=27’207)

P<0.001

P2Y12 inhibitors at discharge in ACS patients (N=12,278)

Clopidogrel across spectrum of CAD

Biotransformation Mode of ActionClopidogrel,

Prasugrel und Ticagrelor

Schomig AS. Ticagrelor — Is There Need for a New Player in the Antiplatelet-Therapy Field? New Eng J Med 2009; 361(11): 1108-1111

Antiplatelet therapy: efficacy vs. safety

or Ticagrelor

Cuisset; Euro PCR 2010, Paris

5 years after PLATO: Antiplatelet therapy in

NSTEMI Guidelines

ESC Guidelines for the management of acutecoronary syndromes in patients presenting without

persistent ST-segment elevation; Europ Heart J 2011

18.06.2015

Antiplatelet therapy in patients with STEMI(STEMI 2012)

5 years after PLATO: ESC guidelines 2014

myocardial revascularization

NSTE-ACS undergoing PCI

STEMI undergoing PCI

Windecker et al. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J. 2014 Oct 1;35(37):2541-619

For

med

ical

use

on

ly–

may

con

tain

off

lab

leto

pic

s

Guidelines are usefull but don’t stop

thinking

Prasugrel Ticagrelor

Study design PCI study “All-Comers”-study

invasive invasive or conservative

conservative 0 % 28 %

Revascularization strategy: PCI PCI or CABG

CABG: 1 %10 % of the study group

and 14% of the invasive gr.

PCI: 99 % 62 %

STEMI: 26 % 38 %

Loading with Clopidogrel:Relatively late

300 mg

early

300- 600 mg

Important points to consider:

Triton-TIMI 38: New Engl J Med 2007;357:2001-2015

Plato: N Engl J Med 2009;361:1045-57

0,5 1,0 1,5

Risk increase as compared

Clopidogrel

Risk reduction as compared

to Clopidogrel

Primary endpoint:

Ticagrelor

Triton-TIMI 38: New Engl J Med 2007;357:2001

Plato: N Engl J Med 2009;361:1045-57

0,5 1,0 1,5

Risk increase as compared

Clopidogrel

Risk reduction as compared

to Clopidogrel

Conservative management:

Total mortality

Prasugrel Clopidogrel

--- ---

Ticagrelor Clopidogrel

6,1 %

(signifikant)

8,2 %in PLATO:

n = 5216 = 28%

in TRITON

no conservative group!

Trilogy ACS

Without benefit as

compared to

Clopidogrel

0,5 1,0 1,5

Risk increase as compared

Clopidogrel

Major bleedings: („TIMI major“)

without CABG-Patients

Prasugrel Clopidogrel

2,4 %

(significant)

1,8 %

Ticagrelor Clopidogrel

2,8 %

(significant)

2,2 %

Risk reduction as compared

to Clopidogrel

PLATO Trial PLATO CABG substudy

Wallentin L et al. NEJM 2009;361:1045-57.

11.7%

9.8%

11.6%11.2%

9.7%

4.7%

Held C et al. JACC 2011;57:672-84.

Primary endpoint (MACCE)

Major bleeding

Overall mortality

Major bleeding

trial stopped early when a

planned interim analysis

showed that

pretreatment was

associated with an

increased risk of major

bleeding

7d: (2.6% vs. 1.4%,

p=0.006)

30 days (2.9% vs. 1.5%,

p=0.002)

Clopidogrel vs Prasugrel/Ticagrelor –

Key messages

Prasugrel and Ticagrelor: net clinical benefit over

Clopidogrel in ACS patients

Ticagrelor evaluated in allcomers study (PLATO)

Benefit through all subgroups

CABG/Conservative tx

No restriction in elderly (>75yrs), weight < 60kg and history of

TIA/Stroke

Prasugrel in PCI study (TRITON)

Good results in STEMI pts, diabetic population

No benefit in patients with conservative management (Trilogy ACS)

Elevated bleeding risk with pretreatment (Accoast)

not recommended, if history of Stroke - dose reduction if age > 75

yrs, weight < 60kg)

Major adverse CV events up to 30 days

Definite stent thrombosis up to 10 days

Definite stent thrombosis up to 30 days

Conclusion

Pre-hospital ticagrelor administration a short time before PCI in patients with ongoing STEMI is safe but does not improve pre-PCI coronary reperfusion. It may, however, reduce the risk of post-PCI stent thrombosis.

Windecker et al. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) Developed with the special contribution of the European Association of PercutaneousCardiovascular Interventions (EAPCI). Eur Heart J. 2014 Oct 1;35(37):2541-619

5000 Heparin i.v.

Ticagrelor (Brillique®) Loading Dose 2x90 mg/d

Triage im Spital/PCI-Zentrum

Keep it simple in network treatment

RivaroxabanApixabanEdoxaben

Dabigatran

5 years after PLATO: What else…?

Cangrelor

Different Clinical conditions

ACS

– NSTEMI conservative

– NSTEMI/STEMI with

PCI/CABG

Stable CAD with Stents

RCTs with Ticagrelor or

Prasugrel lacking

Important co-factors to consider

• Triple therapy for newer drugs not

approved

• Impact of Age, Diabetes, other

comorbidity….

5 years after PLATO: What else…?

Trends in triple antithrombotic therapy at discharge in ACS patients with atrial fibrillation at admission (n=294)

Increasing rate of Combination of

newer P2Y12 inhibitors together with

OAC

- In hospital bleeding, in hospital-

outcome, at 1 yr?

Increasing rate of triple tx with NOACs

Unpublished data

5 years after PLATO: What else…?

5 years after PLATO – Experience from the

Daily Clinical Practice

• Risk reduction of cardiovascular events remains still a

goal (balance between thrombotic and bleeding risk)

– newer antithrombotics are integrated in daily practice in ACS

– Management of ACS patients in regional networks: need of

simple and clear strategy

– In contrast to the guidelines – a substantial number of ACS patients

is treated with Prasugrel or Ticagrelor in combination with

anticoagulation (VKA or NOACs)

18.06.2015

Thank you!

L.C

H.H

C.1

1.2

011.0

079-E

N

18.06.2015

Fallbeispiel 1a

• 71-jährige Patientin

• Bekannte Koronare und hypertensive Herzkrankheit

• St. n. inferiorem Myokardinfarkt vor Jahren (Stent)

• Beschwerdefrei (keine Angina) und ordentlich belastbar

• Medikation: Bisoprolol (Concor®)

Ramipril (Triatec®)

Atorvastatin (Sortis®)

Aspirin

• Colon-Carcinom: Hemikolektomie links

Gerstein NS, et al. Anesth Analg 2015; 120: 5670-5

Kardiovaskuläres Manual KSSG 2015

Gurbel PA et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable

coronary artery disease: the ONSET/OFFSET study. Circulation. 2009;120:2577–2585

* P<0.05, ** P<0.001, *** P<0.0001

Ticagrelor vs. Clopidogrel

ONSET/OFFSET – Studie

Ticagrelor 180-mg Initialdosis in stabilen KHK-Patienten

Clopidogrel 600-mg Initialdosis in stabilen KHK-Patienten