Antiplatelet in acute coronary syndrome

The clinical decision-making strategies for antiplatelet therapy in ACS patients

Paiboon Chotnoparatpat, MD, FSCAI

www.themegallery.com

http://www.scientific-art.com/GIF%20files/Medical/Atherosclerosis.jpghttp://www.scientific-art.com/portfolio%20medicine%20pages/atherosclerosis.htm

• 2014 AHA/ACC guidelines for the management of patients with non-ST-elevation ACSA focus on DAPT in NSTE-ACS

2014 AHA/ACC NSTE-ACS Guidelines

44

•NB: Continuation of ticagrelor or prasugrel beyond 12 months is outside the label of both drugs

Recommended treatment algorithm in NSTE-ACS

• Early management (angiography or initial medical management)

• Invasive management (PCI)

• Late/post- hospital care

Pathway stage

• Initiate ticagrelor or clopidogrel, preferably ticagrelor

• (NB: prasugrel is not a recommended option at this stage)

• Initiate/continue ticagrelor or clopidogrel, or initiate prasugrel (only after coronary anatomy has been defined)

P2Y12 recommendation

• Medically managed: Ticagrelor or clopidogrel for up to 12 months, preferably ticagrelor

• Stent: Ticagrelor, prasugrel or clopidogrel for at least 12 months, preferably ticagrelor or prasugrel

NSTE-ACS:Definite or Likely

Ischemia-Guided strategy Early Invasive Strategy

Initiate DAPT and Anticoagulant Therapy1. ASA (Class I; LOE: A)

2. P2Y12 inhibitor (in addition to ASA) (Class I; LOE B):

● Clopidogrel or● Ticagrelor

3. Anticoagulant:● UFH (Class I; LOE B) or● Enoxaparin (Class I; LOE: A) or● Fondaparinux (Class I; LOE: B)


2. P2Y12 inhibitor (in addition to ASA) (Class I; LOE: B):● Clopidogrel or● Ticagrelor

3. Anticoagulant:● UFH (Class I; LOE B) or

● Enoxaparin (Class I; LOE: A) or● Fondaparinux (Class I; LOE B) or● Bivalirudin (Class I; LOE B)

Can consider GPI in addition to ASA and P2Y12 inhibitor in high-risk (eg, troponin positive) patients (Class IIb; LOE B)

● Eptifibatide● Tirofiban

Medical therapy chosen based on cath

findings

Therapy Ineffective

Therapy Effective

PCI with stentingInitiate/continue antiplatelet and anticoagulant

therapy1. ASA (Class I; LOE: B)

2. P2Y12 inhibitor (in addition to ASA):● Clopidogrel (Class I; LOE: B) or● Prasugrel (Class I; LOE: B) or● Ticagrelor (Class I: LOE: B)

3. GPI (if not treated with bivalirudin at time of PCI)

● High risk features, not adequately pretreated with clopidogrel (Class I; LOE: A)

● High-risk features adequately pretreated with clopidogrel (Class IIa; LOE: B)

4. Anticoagulant:● Enoxaparin (Class I; LOE: A) or● Bivalirudin (Class I; LOE: B) or● Fondaparinux as the sole anticoagulant

(Class III: Harm; LOE: B) or● UFH (Class I; LOE: B)

Late hospital/post hospital care1. ASA indefinitely (Class I; LOE: A)

2. P2Y12 inhibitor (clopidogrel or ticagrelor), in addition to ASA, up to 12 mo if medically treated (Class I; LOE: B)

3. P2Y12 inhibitor (clopidogrel, prasugrel or ticagrelor), in addition to ASA, at least 12 mo if treated with coronary stenting (Class I; LOE: B)

CABGInitiate/continue ASA therapy and

discontinue P2Y12 and/or GPI therapy1. ASA (Class I; LOE: B)

2. Discontinue clopidogrel/ticagrelor 5 d before, and prasugrel at least 7 d before elective CABG

3. Discontinue clopidogrel/ticagrelor up to 24 h before urgent CABG (Class I; LOE: B). May perform urgent CABG <5 d after clopidogrel/ticagrelor and <7 d after prasugrel discontinued

4. Discontinue eptifibatide/tirofiban at least 2–4 h before, and abciximab ≥12 h before CABG (Class I; LOE: B)


Recommended treatment algorithm: Early management

55

• Early management (angiography or initial medical management)

Pathway stage

• Initiate ticagrelor or clopidogrel, preferably ticagrelor

• (NB: prasugrel is not a recommended option at this stage)


Confidential – for AstraZeneca Medical use only

Ischemia-Guided strategy


2. P2Y12 inhibitor (in addition to ASA) (Class I; LOE B):

● Clopidogrel or● Ticagrelor

3. Anticoagulant:● UFH (Class I; LOE B) or● Enoxaparin (Class I; LOE: A) or● Fondaparinux (Class I; LOE: B)


2. P2Y12 inhibitor (in addition to ASA) (Class I; LOE: B):● Clopidogrel or● Ticagrelor

3. Anticoagulant:● UFH (Class I; LOE B) or

● Enoxaparin (Class I; LOE: A) or● Fondaparinux (Class I; LOE B) or● Bivalirudin (Class I; LOE B)

Can consider GPI in addition to ASA and P2Y12 inhibitor in high-risk (eg, troponin positive) patients (Class IIb; LOE B)

● Eptifibatide● Tirofiban

Early Invasive Strategy


Recommended treatment algorithm: Invasive management (PCI)

66

• Invasive management (PCI)

Pathway stage

• Initiate/continue ticagrelor or clopidogrel, or initiate prasugrel (only after coronary anatomy has been defined)


PCI with stentingInitiate/continue antiplatelet and anticoagulant

therapy1. ASA (Class I; LOE: B)

2. P2Y12 inhibitor (in addition to ASA):● Clopidogrel (Class I; LOE: B) or● Prasugrel (Class I; LOE: B) or● Ticagrelor (Class I: LOE: B)

3. GPI (if not treated with bivalirudin at time of PCI)

● High risk features, not adequately pretreated with clopidogrel (Class I; LOE: A)

● High-risk features adequately pretreated with clopidogrel (Class IIa; LOE: B)

4. Anticoagulant:● Enoxaparin (Class I; LOE: A) or● Bivalirudin (Class I; LOE: B) or● Fondaparinux as the sole anticoagulant

(Class III: Harm; LOE: B) or● UFH (Class I; LOE: B)

CABGInitiate/continue ASA therapy and

discontinue P2Y12 and/or GPI therapy1. ASA (Class I; LOE: B)

2. Discontinue clopidogrel/ticagrelor 5 d before, and prasugrel at least 7 d before elective CABG

3. Discontinue clopidogrel/ticagrelor up to 24 h before urgent CABG (Class I; LOE: B). May perform urgent CABG <5 d after clopidogrel/ticagrelor and <7 d after prasugrel discontinued

4. Discontinue eptifibatide/tirofiban at least 2–4 h before, and abciximab ≥12 h before CABG (Class I; LOE: B)



Recommended treatment algorithm: Duration of therapy

77

Pathway stage



• Late/post- hospital care

• Medically managed: Ticagrelor or clopidogrel for up to 12 months, preferably ticagrelor

• Stent: Ticagrelor, prasugrel or clopidogrel for at least 12 months, preferably ticagrelor or prasugrel

Late hospital/post hospital care1. ASA indefinitely (Class I; LOE: A)

2. P2Y12 inhibitor (clopidogrel or ticagrelor), in addition to ASA, up to 12 mo if medically treated (Class I; LOE: B)

3. P2Y12 inhibitor (clopidogrel, prasugrel or ticagrelor), in addition to ASA, at least 12 mo if treated with coronary stenting (Class I; LOE: B)•NB: Continuation of ticagrelor or prasugrel

beyond 12 months is outside the label of both drugs


Top-line recommendations in NSTE-ACS

8

Contraindications and other label requirements still apply1. Yusuf S et al. N Engl J Med 2001;345:494–5022. Mehta SR et al. N Engl J Med 2010;363:930–9423. Wallentin L et al. N Engl J Med 2009;361:1045–10574. James SK et al. BMJ 2011;342:d3527

Recommendation Class Level EvidenceP2Y12 inhibitor (either clopidogrel or ticagrelor) in addition to aspirin, for up to 12 months in patients treated initially with either an early invasive or ischaemia-guided strategy

I BCURE1, CURRENT-OASIS 72, PLATO3, PLATO non-invasive substudy4

It is reasonable to choose ticagrelor in preference to clopidogrel for patients treated with an early invasive or ischaemia-guided strategy

IIa B PLATO3, PLATO non-invasive substudy4

Early management strategy (initial ischaemia-guided or early invasive strategy) before definition of coronary anatomy


Top-line recommendations in NSTE-ACSInvasive management (PCI)

9

Recommendation Class Level EvidenceA loading dose of a P2Y12 receptor inhibitor (ticagrelor, clopidogrel or prasugrel) should be given before the procedure in patients undergoing PCI with stenting. Options include:

I APLATO,1 TRITON,2 CREDO,3,4 EPISTENT,5 CLEAR PLATELETS,6 PCI-CLARITY7

Ticagrelor I B PLATO1

Clopidogrel I BCREDO,3,4 EPISTENT,5 CLEAR PLATELETS,6 ISAR-CHOICE,8 Siller-Matula 2011,9 Mangiacapra 201010

Prasugrel (only after coronary anatomy defined) I B TRITON2

Continuation of DAPT beyond 12 months may be considered in patients undergoing stent implantation

NB: Continuation of ticagrelor or prasugrel beyond 12 months is outside the label of both drugs

IIb C –

Contraindications and other label requirements still apply1. Wallentin L et al. N Engl J Med 2009;361:1045–10572. Wiviott SD et al. N Engl J Med 2007;357:2001–20153. Steinhubl SR et al. JAMA 2002;288:2411–24204. Steinhubl SR & Deal DB. Circulation 2003;108(Suppl 1):I17425. Steinhubl SR et al. Circulation 2001;103:1403–14096. Gurbel PA et al. Circulation 2005;111:1153–1159

7. Sabatine MS et al. JAMA 2005;294:1224–12328. von Beckerath N et al. Circulation 2005;112:2946–29509. Siller-Matula JM et al. Heart 2011;97:98–10510. Mangiacapra F et al. Am J Cardiol 2010;106:1208–1211


Top-line recommendations in NSTE-ACSDuration of therapy

10

Recommendation Class Level EvidenceIn addition to ASA, a P2Y12 inhibitor (clopidogrel or ticagrelor) should be continued for up to 12 months in all patients treated with an ischaemia-guided strategy

I B CURE,1 PCI-CURE,2 PLATO,3 PLATO non-invasive substudy4

P2Y12 inhibitor therapy (clopidogrel, prasugrel or ticagrelor) should be given for at least 12 months in patients receiving a stent

I B TARGET,5 PCI-CURE,2

CREDO,6 TRITON,7 PLATO3

It is reasonable to choose ticagrelor over clopidogrel for maintenance P2Y12 treatment in patients with NSTE-ACS treated with an early invasive strategy and/or PCI

IIa B PLATO,3 PLATO non-invasive substudy4

It is reasonable to choose prasugrel over clopidogrel for maintenance P2Y12 treatment in patients with NSTE-ACS who undergo PCI who are not at high risk for bleeding complications

IIa B TRITON,7 TRILOGY-ACS8

Continuation of DAPT beyond 12 months may be considered in patients undergoing stent implantation

NB: Continuation of ticagrelor or prasugrel beyond 12 months is outside the label of both drugs

IIb C –

ASA, acetylsalicylic acidContraindications and other label requirements still apply1. Yusuf S et al. N Engl J Med 2001;345:494–5022. Mehta SR et al. Lancet 2001;358:527–5333. Wallentin L et al. N Engl J Med 2009;361:1045–10574. James SK et al. BMJ 2011;342:d3527

5. Shishehbor MH et al. Am J Cardiol 2006;97:1585–15906. Steinhubl SR et al. JAMA 2002;288:2411–24207. Wiviott SD et al. N Engl J Med 2007;357:2001–20158. Roe MT et al. N Engl J Med 2012;367:1297–1309

and NSTE-ACS

• 2014 ESC/EACTS Guidelines on Myocardial Revascularization

2014 ESC/EACTS Guidelines on Myocardial Revascularization

Executive summary

What are the new ESC/EACTS guidelines on myocardial revascularization?•These joint guidelines were developed by the Task Force on Myocardial Revascularization of the ESC and EACTS (without involvement of the pharmaceutical or device industries)•The guidelines were presented at ESC 2014 and simultaneously published in the European Heart Journal1 and the European Journal of Cardio-Thoracic Surgery2•These guidelines replace those published in 20103•This slide deck provides top-line information on new recommendations relating to DAPT in STEMI and NSTE-ACS (and stable CAD); for further information, refer to the ESC website [here]

1212

•Windecker S et al. Eur Heart J 2014;doi: 10.1093/eurheartj/ehu278:[Epub ahead of print]

Windecker S et al. Eur J Cardiothorac Surg 2014;doi: 10.1093/ejcts/ezu366:[Epub ahead of print]

. Wijns E et al. Eur Heart J 2010;31:2501–2555

CAD, coronary artery disease; DAPT, dual antiplatelet therapy; NSTE-ACS, non-ST-segment elevation acute coronary syndromes; STEMI, ST-segment elevation myocardial infarction

http://www.escardio.org/guidelines-surveys/esc-guidelines/Pages/percutaneous-coronary-interventions.aspx


•LOE, level of evidence; PPCI, primary percutaneous coronary intervention

How do the new recommendations compare with existing guidelines?•For patients with STEMI or NSTE-ACS in whom a revascularization strategy is planned, the recommendations are generally consistent with existing ACS treatment guidelines:‒Class I LOE in favour of 12 months’ DAPT‒Class I LOE in favour of using ticagrelor (or prasugrel) over clopidogrel•Pre-treatment with prasugrel is not recommended in NSTE-ACS patients in whom the coronary anatomy is unknown‒This Class III B recommendation follows the results of ACCOAST and is specific to prasugrel‒In the PLATO study, oral antiplatelet treatment with ticagrelor or clopidogrel could be initiated before coronary angiography was performed

How might the new recommendations impact ticagrelor use in clinical practice?•The new STEMI PPCI recommendation to treat at ‘first medical contact’ is consistent with the ATLANTIC results, which showed that ticagrelor has the flexibility to be used either pre- or in-hospital, with no adverse impact on efficacy or bleeding rates

1313

Executive summary


Top-line recommendations – STEMI2014 ESC/EACTS Guidelines on Myocardial Revascularization

14

1. Montalescot G et al. Lancet 2009;373:723–731 2. Steg PG et al. Circulation 2010;122:2131–21413. Mehta S et al. Lancet 2010;376:1233–12434. Bellemain-Appaix A et al. JAMA 2012;308:2507–2516

5. Zeymer U et al. Clin Res Cardiol 2012;101:305–3126. Koul S et al. Eur Heart J 2011;32:2989–2997 7. Dörler J et al. Eur Heart J 2011;32:2954–2961

Recommendation Class Level EvidenceA P2Y12 inhibitor is recommended in addition to ASA and maintained over 12 months unless there are contraindications such as excessive risk of bleeding

I A –

- Prasugrel I B • TRITON STEMI1

- Ticagrelor I B • PLATO STEMI2

- Clopidogrel I B • CURRENT-OASIS 73

Give P2Y12 inhibitors at the time of first medical contact I B

• Bellemain-Appaix, Zeymer, Koul, Dörler4–7

Contraindications and other label requirements still apply ASA, acetylsalicylic acid


Top-line recommendations ‒ NSTE-ACS2014 ESC/EACTS Guidelines on Myocardial Revascularization

15

Recommendation Class Level EvidenceA P2Y12 inhibitor is recommended in addition to ASA and maintained over 12 months unless there are contraindications such as excessive risk of bleeding

I A• TRITON Diabetes1

• PLATO2

• PCI-CURE3

- Prasugrel I B • TRITON Diabetes1

- Ticagrelor I B • PLATO2

- Clopidogrel I B • CURRENT-OASIS 73

• PCI-CURE4

Pre-treatment with prasugrel in patients in whom coronary anatomy is not known, is not recommended

III B • ACCOAST5

1. Wiviott SD et al. Circulation 2008;118:1626–1636 2. Wallentin L et al. N Engl J Med 2009;361:1045–10573. Mehta S et al. Lancet 2010;376:1233–12434. Mehta S et al. Lancet 2001;358:527–533 5. Montalescot G et al. N Engl J Med 2013;369:999–1010

Contraindications and other label requirements still apply


Revascularization in STEMIUnchanged from 2010• Initiate treatment with a P2Y12 inhibitor (as part of DAPT) and maintain DAPT for 12 months• Class IB recommendation for ticagrelor• Class IB recommendation for prasugrel

New/updated• Specific recommendation (Class IB) to initiate P2Y12 at first medical contact added• Clopidogrel recommendation changed from Class IC to Class IB and wording updated

to specify use only when ticagrelor or prasugrel are unavailable or contraindicated• In patients undergoing PPCI, the recommendation for bivalirudin has dropped to IIa/A

(new guidelines now reflect data from the HORIZONS-AMI, EuroMAX and HEAT-PPCI studies)

What has changed in the new 2014 ESC/EACTS Guidelines?

16

STEMI

Windecker S et al. Eur Heart J 2014;doi: 10.1093/eurheartj/ehu278:[Epub ahead of print]

Contraindications and other label requirements still apply


What has changed in the new 2014 ESC/EACTS Guidelines?NSTE-ACS

17

Revascularization in NSTE-ACSUnchanged from 2010• The recommended duration of treatment with a P2Y12 inhibitor remains at 12 months unless

there are contraindications such as excessive risk of bleeding• Class IB recommendation for clopidogrel only when ticagrelor or prasugrel are unavailable

or contraindicated

New/updated• Pre-treatment with prasugrel is not recommended in patients with unknown coronary

anatomy (Class IIIB), following results of the ACCOAST study• Ticagrelor retained its Class IB recommendation; wording updated to specify use in patients

at moderate-to-high risk of ischaemic events, regardless of initial treatment strategy (including those pre-treated with clopidogrel), if no contraindication*

• Prasugrel recommendation changed from Class IIa/B to Class IB, and wording added to specify that recommendation applies to patients in whom the coronary anatomy is known and who are proceeding to PCI


Contraindications and other label requirements still apply*Ticagrelor should be stopped before elective surgery as per local label


Stable CAD*

18

Contraindications and other label requirements still apply *Note: Ticagrelor is not currently licensed for use in stable CAD; therefore, stable CAD guidelines should only be discussed reactively with healthcare professionalsBMS, bare-metal stent; DES, drug-eluting stent

Revascularization in stable CADNew/updated• Recommended duration of DAPT after DES implantation has been reduced to 6 months

(Class IB) – this was previously 6–12 months• Shorter DAPT duration (<6 months) may be considered after DES in patients at high

bleeding risk (Class IIb/A)– However, the guidelines also recommend DAPT for >6 months in stable CAD patients

at high ischaemic risk and low bleeding risk (Class IIb/C) • Note: DAPT is still indicated for at least 1 month after BMS implantation (Class IA)• Recommendation for clopidogrel pre-treatment in stable CAD has been changed

(from Class IC to Class IIb/C) and wording added to specify that this is recommended where there is a high probability of significant CAD


What has changed in the new 2014 ESC/EACTS Guidelines?

Evolution of P2Y12 Inhibitors

ERA OF THIENOPYRIDINES

1990 1995 2000 2005 2010 2011

ERA OF THIENOPYRIDINES

Oct 1991

Nov 1997 Jun 2009

BIRTH OF NON-THIENOPYRIDINES

TicagrelorDec 2010July 2011

Thrombin

ThromboxaneA2

5HT

P2Y12

ADP ADPADP

5HT

PLATELETACTIVATION

P2Y15HT2A

PAR1

PAR4

Densegranule

Thrombingeneration

Shapechange

aIIbb3

aIIbb3

FibrinogenaIIbb3

Aggregation

AmplificationAlpha

granule

Coagulation factorsInflammatory mediators

TPa

Coagulation

GPVI

Collagen

ATPATP

P2X1

ASPIRIN

x TICLOPIDINECLOPIDOGRELPRASUGREL

ACTIVE METABOLITE

xTICAGRELOR (AZD6140)

GP IIb/IIIa ANTAGONISTS

xx

Storey RF. Curr Pharm Des. 2006;12:1255-59.

Platelet Activation Mechanisms

21

Inhibition of Platelet Purinergic Receptors

Storey F, et al. Platelets. 2001;12:197.

Receptorsubtype

Molecularstructure

Secondarymessengersystem

Functionalresponse

P2Y12 Inhibitor

P2X1 P2Y1 P2Y12

G protein G protein

Intrinsic ion GPCR GPCRchannel Gq Gi

↓ ↓ ↓ ↑[Na+/Ca2+]i ↑PLC/IP3 ↓AC

↑[Ca2+]i ↓[cAMP]↓ ↓ ↓

Shape change Shape change Sustained aggregation transient aggregation aggregation

secretion

Biotransformation and Mode of Action of Clopidogrel, Prasugrel and Ticagrelor

Schomig AS. New Eng J Med 2009; 361(11): 1108-1111

Molecular Structure of Antiplatelet agents

ticagrelor

ADPATP

Springthorpe et al. Bio Med Chem Letts 2007, 17: 6013–18

clopidogrel

Bioactivation of ThienopyridinesBioactivation of Thienopyridines

Mechanism of action of thienopyridines

Irreversible, covalent binding to P2Y12 receptor

Hydrolysis by esterases

Active drug

Inactive metabolites elimination by

urine/feces Platelets require replacement for return to activityMeadows TA, et al. Circ Res. 2007;100(9):1261-1275; Beitelshees A, et al. Arterioscler Thromb Vasc Biol. 2006;26:1681-1683; Wiviott S, et al. Circulation. 2010; 122: 394-403; Cattaneo M. Eur Heart J. 2008;10(Suppl I):I33-I3; Ibanez B, et al. Eur Heart J. 2006:8:G.3

Variable proportion of prodrug metabolized to active drug by

cytochrome P450

ADP

[Meadows 2007:B; Wiviott 2010:A,B; Cattaneo 2008: A; Ibanez 2006:A; Beitelshees 2006:A]

Characteristics of Thienopyridines• All are prodrugs (indirect effect)

– Slow onset• Requiring bioactivation by CYP450

– Subject to genetic variation• Irreversible competitive inhibitors

– Slow offset, bleeding risk• Wide interpatient variability

– Significant proportion of low responders

28

HepaticMetabolism

Clopidogrel

N

SCl

COOCH3

CYP 3A4(5)CYP 2C9CYP 2C19CYP 2B6

CYP 1A2CYP 2B6CYP 2C19

Inactive Metabolitescarboxylic acid derivative(85% of ingested clopidogrel)

Esterases

Clopidogrel: Pro-drug to Active Metabolite Formation

Active Metabolite

HOOC* HS

N

O

Cl

OCH3

CH3

ON

S

O

Cl

OC

2-oxo Compound

HepaticMetabolism

Clopidogrel and prasugrel:Exposure of active metabolite• The active metabolite of prasugrel demonstrates earlier

and higher peak concentrations than the clopidogrel active metabolite

• Both active metabolites are eliminated within 2–4 hours post-dose

AM, active metabolite.Wallentin L, et al. Eur Heart J 2008;29:21–30.

400

300

200

100

0Act

ive

met

abol

ite c

once

ntra

tion

(ng/

mL)

0 2 4 6 8 10 12 14 16 18 20 22 24

Time from dose (hours)

Prasugrel-AMClopidogrel-AM

100

80

60

20

0Act

ive

met

abol

ite c

once

ntra

tion

(ng/

mL)

0 2 4

Time from dose (hours)

40

Prasugrel-AMClopidogrel-AM

Loading dose Maintenance dose

Balance of efficacy and safety in selected subgroup

% o

f Sub

ject

s

Wiviott et al. NEJM 2007;357:2001-2015

HR 1.54P=0.04

HR 1.03P=0.92

HR 0.99P=0.89

Ticagrelor: important characteristics

• Ticagrelor is a cyclopentyltriazolopyrimidine (CPTP): direct acting and reversibly interacts with the platelet P2Y12

• Phase 1 and 2 studies demonstrated:– A rapid onset of inhibitory effect

• Important for urgent management in ACS– Greater and more consistent platelet inhibition than

clopidogrel• Less variability in individual response• Higher average inhibition of platelet aggregation

• Reversibly binding to the P2Y12 receptor• Faster offset of platelet inhibition than clopidogrel in a

pharmacodynamic (PD) and pharmacokinetic (PK) study in stable coronary artery disease (CAD) patients– Predictable and reliable offset reflecting the gradual fall

in plasma concentration– Recovery of platelet function does not depend on

generation of new plateletsHusted SE, et al. Eur Heart J. 2006;27:1038-1047; Cannon CP. J Am Coll Cardiol. 2007;50:1844-51; Storey RF, et al. J Am Coll Cardiol. 2007;50:1852-1856; Gurbel PA, et al. Circulation. 2009;120:2577-2585.

Husted S, et al. Cardiovasc Ther. 2009;27:259-274.

Ticagrelor: mechanism of action

A B

C D

[Husted 2009:A]

Ticagrelor: First and Only Approved CPTP

• Ticagrelor, a new chemical class, is a cyclo-pentyl-triazolo-pyrimidine (CPTP)

• Ticagrelor is direct acting (not a prodrug and does not require metabolic activation)

• It binds directly to P2Y12 receptors and reversibly interacts with the receptor, to prevent platelet activation and aggregation

• Thienopyridines bind covalently to P2Y12 ADP binding site for the life of the platelet

P2Y12 receptor on platelet

Ticagrelor

ADP binding site

Husted S, et al. Eur Heart J. 2006;27:1038–1047.Gurbel PA, et al. Expert Opin Drug Metab Toxicol. 2009;5(8):989–1004. Van Giezen JJ, et al. J Thromb Haemost. 2009;7:1556-1565.

Ticagrelor: a new chemical class

Hepatic metabolism not required for

activity

Rapid intestinal absorption

Reversibly binds to P2Y12

receptor

Husted S, et al. Cardiovasc Ther. 2009;27:259-274.

Ticagrelor – pharmacokinetic parameters

Absorption • Rapidly absorbed in the small intestine[Husted 2009:B; EMEA Label:A]

Distribution • ~99.7% bound to human plasma protein[EMEA Label:B]

Metabolism

• Predominantly metabolized by CYP3A4/5 in the liver, which may account for drug/drug interactions[Teng 2010:A; EMEA Label:C]

• Metabolized to active metabolite (AR-C124910XX) and/or inactive metabolites[Teng 2010:A; EMEA Label:A,D]

Elimination• Primarily eliminated via biliary secretion[EMEA Label:E]

• Less than 1% excreted in urine[EMEA Label:E; Husted 2009:F]

Pharmacokinetics

• Peak plasma concentrations and steady state are dose-proportional and occur between 1.5 and 3 hours[EMEA Label:A; Butler 2008:A]

• Half life ~8 hours[EMEA Label: E; Teng 2010:B]

• Dosing with food increases the area under the curve (AUC) ~20%[EMEA Label: F; Butler 2008:B]

• AR-C124910XX (half-life ~10 hrs) accounts for ~30% to 40% of total activity[EMEA Label: D,E;Teng 2010:B]

Husted S , et al. Cardio Ther. 2009;27:259-274; Butler K et al, Can J Clin Pharmacol. 2008;15:e684-e685 [Abstract 562]; Teng R. Eur J Clin Pharmacol. 2010;66:487-496. Data on File, Investigator’s Brochure.

Key drug interactions

Data on file, Investigator’s Brochure.

Drug Primary usage Effect Warning on ticagrelor label

Ketoconazole(strong CYP3A4 inhibitor) Antifungal Ticagrelor Cmax 2.4x and AUC 7.3xa Coadministration is

contraindicated

Diltiazem(moderate CYP3A4 inhibitor)

Vasodilation; angina; hypertension Ticagrelor Cmax by 69% and AUC 2.7xb Can be coadministered

Rifampin (CYP3A inducer) Antibacterial Ticagrelor Cmax by 73% and AUC by 86%c Coadministration is

discouraged

Desmopressin/heparin/ enoxaparin/aspirin Alter hemostasis No effect on ticagrelor or on ADP-induced

platelet aggregationCoadminister with

caution

Verapamil(potent P-gp inhibitor)

Antihypertensive; antianginal Unknownd Coadminister with

caution

Simvastatin(CYP3A4 substrate)

Control hypercholesterolemia

Simvastatin Cmax by 81% and AUC by 56%;no effect on ticagrelor

Coadministration with > 40 mg simvastatin is not recommended

Atorvastatin(CYP3A4 substrate)

Control hypercholesterolemia

Atorvastatin acid Cmax by 23% and AUC by 36% None

Levonorgesterol+ethinyl estradiol Oral contraceptive

Ethinyl estradiol exposure by ≈20%;no effect on levonorgesterol

None

Digoxin(P-gp substrate)

Strengthen cardiac contractions;

congestive heart failure

Digoxin Cmax by 75% and AUC by 28%;no effect on ticagrelor

Close clinical and laboratory monitoring is

recommendede

aSimilar effects would be expected for other strong inhibitors of CYP3A4 (eg, clarithromycin, nefadozone, ritonavir, atazanavir)bSimilar effects would be expected for other moderate inhibitors of CYP3A4 (eg, amprenavir, aprepitant, erythromycin, fluconazole)cSimilar effects would be expected for other inducers of CYP3A (eg, dexamethasone, phenytoin, carbamazepine, phenobarbitol)dData are also unavailable for other potent P-gp inhibitors (eg, quinidine, cyclosporine)eAppropriate monitoring is also recommended when giving other narrow therapeutic index P-gp dependent medications (eg, cyclosporine) ; AUC, area under the concentration vs time curve; Cmax, maximum plasma concentration; P-gp, P-glycoprotein

[EMEA Label: G, H, I, J, K, L, M, N, O]

• Recommended dosing: – 180 mg LD + 90 mg BID

• No need to adjust dose in elderly, renal impairment and mild hepatic impairment

• No difference in gender & ethnicity• Not adequately studied in moderate to severe

hepatic impairment

Dosing & Special Populations

Unmet Need and Ticagrelor Clinical Pharmacology

Summary• Regardless of ACS presentation, mortality remains high 1 year

post-admission (~15%)• There are a number of challenges with clopidogrel• Ticagrelor is a new chemical class, CPTP• Ticagrelor is direct acting and the first reversibly binding, oral ADP

receptor antagonist• Ticagrelor has a more rapid onset of platelet activity compared to

clopidogrel– 30 minutes: 41% vs 8% IPA, respectively– 2 hours: 88% vs 38% IPA, respectively

Fox KA, et al. Nat Clin Pract Cardiovasc Med. 2008;5:580–589.Gurbel PA, et al. Circulation. 2009;120:2577–2585.Ticagrelor: Approved Prescribing Information on November 30, 2011.

Adapted from Schomig A. N Engl J Med. 2009;361:1108–1111.

Ticagrelor: Does NOT require metabolic activation to

become active drug

Clopidogrel: A prodrug; requires metabolism to

become active drug

CYP-dependentoxidationCYP1A2CYP2B6CYP2C19

CYP-dependentoxidationCYP2C19 CYP3A4/5

CYP2B6Active compound

Intermediate metabolite

Prodrug

Ticagrelor

Clopidogrel

Binding

P2Y12

Ticagrelor: Does Not Require Hepatic Metabolism for Activation

Platelet

Clinical Pharmacology: Ticagrelor and Clopidogrel

Gurbel PA, et al. Circulation. 2009;120:2577–2585. Ticagrelor: Approved Prescribing Information on November 30, 2011.Clopidogrel: Approved Prescribing Information

Ticagrelor Clopidogrel

Chemical class CPTP Thienopyridine

Reversible Inhibition of P2Y12 receptor Yes No

PD variability with CYP2C19 genotype No Yes

Dosing Twice daily (bid) Once daily (qd)

Mean inhibition of platelet aggregation (IPA) at 30 minutes 41% 8%

Mean IPA at 2 hours 88% 38%

Inhibition of Platelet Aggregation: Onset

0

20

40

60

80

100Ticagrelor (n=54)

Clopidogrel (n=50)

Placebo (n=12)

Time (Hours)

Inhi

bitio

n of

Pla

tele

t Agg

rega

tion

*P<0.0001 ticagrelor vs ClopidogrelLoading Dose

Ticagrelor 180-mg loading dose in Stable CAD patientsClopidogrel 600-mg loading dose in Stable CAD patients

* * **

Adapted from Gurbel PA, et al. Circulation. 2009;120:2577–2585.

*

*

• The PLATelet inhibition and patient Outcomes (PLATO) study was designed to test the hypothesis that ticagrelor, compared with clopidogrel, will result in a lower risk of recurrent thrombotic events in a broad patient population with ACS and that this result can be achieved with a clinically acceptable bleeding rate and overall safety profile

PLATO

James et al. Am Heart J 2009; 157: 599-605

• The primary objective of PLATO was to test the hypothesis that ticagrelor is superior to clopidogrel for the prevention of vascular events (death from vascular causes, MI, or stroke) in patients with non–ST elevation ACS or ST-elevation ACS, with a clinically acceptable bleeding rate and overall safety profile

PLATO : Objective



PLATO : Study Design

ArgentinaAustralia AustriaBelgiumBrazil Bulgaria

FinlandFranceGeorgia

GermanyGreece

MalaysiaMexicoThe NetherlandsNew Zealand

NorwayPhilippinesPolandPortugal RomaniaRussiaSingapore

SlovakiaSpainSweden SwitzerlandSouth AfricaSouth KoreaTaiwan

ThailandTurkeyUkraineUnited KingdomUnited States

CanadaChinaCzech RepublicDenmark

Hong KongHungaryIndiaIndonesiaIsraelItaly

180-mg loading dose

Ticagrelor (n=9,333)

*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.

90 mg bid + ASA maintenance dose

300-mg loading dose† 75 mg qd + ASA maintenance dose

Clopidogrel (n=9,291)

Primary efficacy endpoint:Composite of CV death, MI (excluding silent MI), or stroke

Primary safety endpoint:Total PLATO major bleeding‡

N=18,624Patients with ACS(UA, NSTEMI, or

STEMI*)

<24h Month 1 Month 3 Month 6 Month 9 Month 12Screening

Visit 2 Visit 3 Visit 4 Visit 5 Visit 6

Initial Treatment approaches• Medically managed (n=5,216 — 28.0%)• Invasively managed (n=13,408 —

72.0%)

Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.James S, et al. Am Heart J. 2009;157:599–605.

Randomisation

• All patients were hospitalised with symptom onset <24 hours• Patients could be taking clopidogrel at time of randomisation

PLATO: Study Design

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

Both groups included aspirin.*NNT at one year.

PLATO: Primary Efficacy Endpoint(Composite of CV Death, MI, or Stroke)

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

4,1478,219

0 2 4 6 8 10 12

1211109876543210

13

Cum

ulat

ive

Inci

denc

e (%

) 11.7 Clopidogrel

9.8 Ticagrelor

ARR=0.6%RRR=12%P=0.045

HR: 0.88 (95% CI, 0.77−1.00)

0–30 Days

4.8

5.4Clopidogrel

TicagrelorARR=1.9%RRR=16%NNT=54*P<0.001

HR: 0.84 (95% CI, 0.77–0.92)

0–12 Months

Months After Randomisation0 2 4 6 8 10 12

6

5

4

3

2

1

0

7

Cum

ulat

ive

Inci

denc

e (%

)

Clopidogrel

Ticagrelor

5.8

6.9

0 2 4 6 8 10 12

6

4

3

2

1

0

Clopidogrel

Ticagrelor

4.0

5.1

7

5

Months After Randomisation

Myocardial Infarction Cardiovascular Death

Cum

ulat

ive

Inci

denc

e (%

)

PLATO: Secondary Efficacy Endpoints

Rate of stroke for ticagrelor was not different from clopidogrel (1.3% vs 1.1% ), P=0.225.

Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. Supplement.Ticagrelor: Prescribing Information 2011.

ARR=1.1%RRR=16%

Calculated NNT=91P=0.005

HR: 0.84 (95% CI, 0.75–0.95)

ARR=1.1%RRR=21%NNT=91P=0.001

HR: 0.79 (95% CI, 0.69–0.91)

Both groups included aspirin.

P=0.43HR: 1.04 (95% CI, 0.95–1.13)

PLATO: Primary Safety EndpointPL

ATO

-def

ined

Tot

al

Maj

or B

leed

ing

(%)


Days From First Dose

10

5

0

15

0 60 120 180 240 300 360

Clopidogrel

Ticagrelor

11.2%11.6% P=NS

No. at risk

Clopidogrel

Ticagrelor

9,186

9,235

7,305

7,246

6,930

6,826

6,670 5,209

5,129

3,841

3,783

3,479

3,4336,545

Both groups included aspirin.

PLATO: Bleeding


All values presented by PLATO criteria. Both groups included aspirin.

Major Bleeding Non-CABG-Major Bleeding

Major and Minor Bleeding

Life-threatening/Fatal Bleeding

Fatal Bleeding CABG-Major Bleeding

K-M

Est

imat

ed R

ate

(% P

er Y

ear)

NS

P = 0.03

P = 0.008

NS

NS

NS

11.6

5.8

0.3

16.1

4.5

7.4

11.2

5.8

0.3

14.6

3.8

7.9

0

2

4

6

8

10

12

14

16

18Ticagrelor (n=9,235)

Clopidogrel (n=9,186)

Total fatal bleeding in PLATO*

Total Fatal Fatal ICH† Fatal GI bleed† Other Fatal

Ticagrelor (N=9235) 20 11 0 9

Clopidogrel (N=9186) 23 2 5 16

*Both groups included aspirin; †Data on file: Table 43 E, numbers are for % of patients

Wallentin L, et al. N Engl J Med. 2009;361:1045-1057; Data on file.

ICH, intracranial hemorrhage; GI, gastrointestinal

†

K-M

est

imat

ed ra

te (%

per

yea

r)

†

[Wallentin 2009:G; Data on file Table 43: F]

PLATO Primary Endpoint: Initial Invasive vs Initial Non-Invasive Management

0

2

4

6

8

10

12

14

16

0 60 120 180 240 300 360Days After Randomisation

James S, et al. ESC 2010; Poster #1353.Cannon C, et al. Lancet. 2010;375:283–293.

10.7%

9%

Clopidogrel

Ticagrelor

6,6766,732

6,1296,236

6,0346,134

5,881 4,8154,889

3,6803,735

2,9653,0485,972Ticagrelor

Clopidogrel

Initial Invasive72% of patients in PLATO

P<0.0025HR: 0.84 (95% CI, 0.75–0.94)

Initial Non-Invasive28% of patients in PLATO

2,615

2,601

2,392

2,392

2,328

2,326

2,243 1,835

1,854

1,416

1,426

1,109

1,0992,247Ticagrelor

Clopidogrel

P<0.045HR: 0.85 (95% CI, 0.73–1.00)

14.3%

12%Clopidogrel

Ticagrelor

K-M

Est

imat

ed R

ate

Prim

ary

Com

posi

te o

f CV

Dea

th/M

I/Str

oke

(%)

No. at riskDays After Randomisation

K-M

Est

imat

ed R

ate

Prim

ary

Com

posi

te o

f CV

Dea

th/M

I/Str

oke

(%)

Primary Efficacy Endpoint

TicagrelorGroup

ClopidogrelGroup

HR for (95% CI) p p*

MI / CV Death / Stroke, K-M %

PLATO (n=18,624)

PLATO-INVASIVE (n=13,408)PLATO-MEDICAL (n=5,216)PLATO-STEMI (n=8,430)PLATO-CABG (n=1,261)PLATO-DIABETES No Diabetes (n=13,951) Diabetes (n=4,662)PLATO-GENETICS No CYP2C19 loss of function allele (n=3554) Any CYP2C19 loss of function allele (n=1384)

9.8

9.012.09.3

10.5

8.414.1

8.88.6

11.7

10.714.511.012.6

10.216.2

10.011.2

0.84 (0.74-0.92)

0.84 (0.75-0.97)0.85 (0.73-1.00)0.85 (0.74-0.97)0.84 (0.60-1.16)

0.83 (0.74-0.93)0.88 (0.76-1.03)

0.86 (0.74-1.01)0.77 (0.60-0.99)

<0.001

<0.010.040.020.29

<0.05>0.05

>0.05<0.05

0.49

0.46

PLATO : Summary

* p for interaction

Primary Safety Endpoint

TicagrelorGroup

ClopidogrelGroup

HR for (95% CI) p p*

PLATO Major Bleed, K-M %

PLATO

PLATO-INVASIVEPLATO-MEDICALPLATO-STEMIPLATO-CABGPLATO-DIABETES No Diabetes DiabetesPLATO-GENETICS No CYP2C19 loss of function allele Any CYP2C19 loss of function allele

11.6

11.511.99.0

81.2

10.814.1

10.311.8

11.2

11.610.39.3

80.1

10.014.8

10.611.3

1.04 (0.95-1.13)

0.99 (0.89-1.10)1.17 (0.98-1.39)0.96 (0.83-1.12)1.07 (0.80-1.43)

1.08 (0.97-1.20)0.95 (0.81-1.12)

0.96 (0.83-1.12)1.04 (0.82-1.30)

0.43

0.880.080.630.67

>0.05>0.05

0.610.77

0.21

0.60

PLATO : Summary

* p for interaction

Updated ESC & ACCFACS guidelines

NSTE-ACS

2011 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation

2012 ACCF/AHA Focused Update of the Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction

ESC guidelines recommended ticagrelor for all patients withNSTE-ACS at moderate-to-high risk of ischemic events

2011 ESC Guidelines for the management of acute coronary syndromes in patientspresenting without persistent ST-segment elevation 1

OAP Recommendation

Recommended for all patients at moderateto-high risk of ischemic events, regardless ofinitial treatment strategy and including thosepre-treated with clopidogrel

Ticagrelor

Recommended for patients who cannot receive ticagreloror prasugrel

Clopidogrel (300-mg LD,75-mg MD)

Clopidogrel 600-mg LD(or supplementary 300-mgdose at PCI following initial300-mg LD)

Recommended for patients scheduled for an invasive strategywhen ticagrelor or prasugrel is not an option

OAP = Oral Anti-platelet, LD = Loading dose, MD = Maintenance dose

Ticagrelor andclopidogrel

Should be considered to be (re) started after CABG surgeryas soon as considered safe

1

1

1

2a

B

A

B

B

Hamm, Christian W., Jean-Pierre Bassand, Stefan Agewall, Jeroen Bax, Eric Boersma, Hector Bueno, Pio Caso, et al. 2011. ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. European Heart Journal (August 26).

Class* Level¥

Hali Jneid, Jeffrey L.Anderson, R.Scott Wright, Cynthia D. Adams, Charles R. Bridges, et al.2012.ACCF/AHA Focused Update of the Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction (Updating the 2007 Guideline and Replacing the 2011 Focused Update) : A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines(July 16)

ACCF/AHA guidelines recommended ticagrelor for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction

2012 ACCF/AHA Focused Update of the Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction 2

Invasive Strategy (Undergoing PCI)

OAP Before PCI At the time of PCIClass* Level¥

Ticagrelor

Clopidogrel

1 B

1 B 1 A

1 B

Loading dose of ticagrelor 180 mg or clopidogrel 600 mg should be given as early as possible

Maintenance dose of ticagrelor 90mg twice daily or clopidogrel 75 mg daily should be given for at least 12 months 1 B

Non-invasive Strategy

Ticagrelor or clopidogrel should be added to aspirin and anticoagulant therapy as soon as possible after admission and administered for up to 12 months 1 B

Class* Level¥

Class* Level¥

Class* Level¥

1 B 1 B

STEMI

2012 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation

2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction

ESC guidelines recommended ticagrelor the management of acute myocardial infarction in patients presenting with ST-segment elevation2012 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation

Periprocedural antithrombotic medication in primary PCI

OAP Recommendation Ticagrelor For all patients presenting with STEMI Clopidogrel Preferably when ticagrelor not

available or contraindicated I C

Recommendation

Routine therapies in the acute, subacute and long term phase of STEMI

DAPT with a combination of aspirin and ticagrelor is recommended (over aspirin and clopidogrel) in patients treated with PCI.DAPT with aspirin and an oral ADP receptor antagonist must be continued for up to 12 months after STEMI, with astrict minimum of:

• 1 month for patients receiving BMS

• 6 months for patients receiving DES

I A

I C

I C

IIb B

I B

Ph.Gabriel S., Stefan K.James, Dan Atar, Luigi P. Badano, Carina B. Lundqvist, Michael A. Borger, et al. 2012. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. European Heart Journal (August 28).

Class*

Level¥

Class*

Level¥

Patrick T. O'Gara, Frederick G, et al.2013. ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction (December 17)

Revascularization

2010 ESC/EACTS Guidelines on myocardial revascularization

2011 ACCF/AHA/SCAI Guidelines for Percutaneous Coronary Intervention

62

ESC/EACTS guidelines recommended ticagrelor forACS patients undergoing revascularization

C

2010 ESC/EACTS Guidelines on myocardial revascularization 2

OAPNSTE-ACS STEMI

Ticagrelor

Clopidogrel (600 mg LD ASAP)

Clopidogrel (9-12 months after PCI)

1 1B B

1 1C

1 B - -

Wijns, William, Philippe Kolh, Nicolas Danchin, Carlo Di Mario, Volkmar Falk, Thierry Folliguet, Scot Garg, et al. 2010. Guidelines on myocardial revascularization. European Heart Journal (August 29)

Class* Level¥ Class* Level¥

63

ACCF/AHA/SCAI guidelines recommended ticagrelor forACS patients undergoing percutaneous coronary intervention

2011 ACCF/AHA/SCAI Guidelines for Percutaneous Coronary Intervention3

At the time of PCI at least 12 months post-stentingClass* Level¥ Class* Level¥

OAP

Ticagrelor

Clopidogrel

1 1B B

1 1B B

Levine, Glenn N., Eric R. Bates, James C. Blankenship, Steven R. Bailey, John A. Bittl, Bojan Cercek, Charles E. Chambers, et al. 2011. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: Executive summary: A report of the american college of cardiology Foundation/American heart association task force on practice guidelines and the society for cardiovascular angiography and interventions. Journal of the American College of Cardiology 58 (24) (December 6): 2550-83

64

AHA/ACCF guidelines recommended ticagrelor forACS patients undergoing percutaneous coronary intervention

2011 AHA/ACCF Guidelines for 2nd Prevention and Risk Reduction Therapy for Patients with Coronary and Other Atherosclerosis Vascular Disease4

Patients after PCI PCI with Stent Placement

Class* Level¥ Class*

Level¥OAP

Ticagrelor

Clopidogrel

1 1A A

1 1A A

After PCI,Recommendedaspirin 81 mgper day(Class IIa levelB)

*For patients receiving BMS or DES during PCI for ACS, clopidogrel 75 mg daily,or ticagrelor 90 mg twice daily should be given for at least 12 months

Smith, Sidney C., Emelia J. Benjamin, Robert O. Bonow, Lynne T. Braun, Mark A. Creager, Barry A. Franklin, Raymond J. Gibbons, et al. 2011. AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update. Circulation 124 (22) (November 29): 2458-73.

65

ACCP guidelines recommended ticagrelor for patients in the 1st year after an ACS

2012 ACCP Guidelines for Primary and Secondary Prevention of Cardiovascular Disease5

Without PCI With stentOAPGrade Grade

Ticagrelor

Clopidogrel

1B 1B

1B 1B

For patients who do not undergo PCI, the guidelines suggest using ticagrelor beforeclopidogrel (Grade 2B) For patients who undergo PCI and receive a stent, the guidelines suggest usingticagrelor before clopidogrel (Grade 2B)

Vandvik, Per Olav, A. Michael Lincoff, Joel M. Gore, David D. Gutterman, Frank A. Sonnenberg, Pablo Alonso-Coello, Elie A. Akl, Maarten G. Lansberg, Gordon H. Guyatt, and Frederick A. Spencer. 2012. Primary and secondary prevention of cardiovascular disease. Chest 141 (2 suppl) (February 01): e637S-668S.

66

ACCF/AHA CABG guidelines recommend Ticagrelor as a Preoperative Antiplatelet for patients referred for elective CABG

2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft (CABG) Surgery 7

RecommendationOAP Class*Level¥

TicagrelorRecommended in patients referred for elective CABG should be discontinued for at least 5 days before surgery 1 B

ClopidogrelRecommended in patients referred for elective CABG should be discontinued for at least 5 days before surgery

1 B

L. David Hillis, Peter K. Smith, Jeffrey L. Anderson, John A. Bittl, Charles R. Bridges, John G. Byrne, Joaquin E. Cigarroa, Verdi J. DiSesa, et al. 2011. ACCF/AHA Guideline for Coronary Atery Bypass Graft Surgery : A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011 December 06;124(23):e652-e735.

67

OAP Class*Level¥Recommendation

ESC guidelines recommend Ticagrelor over clopidogrel as a 1st-line therapy for patients with ACS at early invasive strategy is planned

2012 European Guidelines on Prevention of Cardiovascular Disease in Clinical Practice 6

Recommended in the acute phase of coronary artery syndromes and for the following 12 moths, dual antiplatelet therapy with a P2Y12 inhibitor (ticagrelor or prasugrel) added to aspirin is reccommended unless contraindication due to such as excessive risk of bleeding.

Ticagrelor 1 B

1 AClopidogrel (600-mg LD, 75-mg MD)

Recommended for patients who cannot receive ticagrelor or prasugrel

Joep Perk, Guy De Backer, Helmut Gohlke, Ian Graham, Zeljko Reiner, Monique Verschuren,Christian Albus, Pascale Benlian, et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012): The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts) * Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur.Heart J. 2012 May 3

68

2011 CCS Guideline for post-discharge management of ACS (12 month)

OAP NSTE-ACS STEMI

Medically managed PCI Medically managed PCI

Ticagrelor IB IB IIBC IB

Clopidogrel IA IA IIBC IB

Canadian Cardiovascular Society Guidelines recommend ticagrelor for ACS patients

Bell AD, Roussin A, Cartier R, Chan WS, Douketis JD, Gupta A, et al. The Use of Antiplatelet Therapy in the Outpatient Setting: Canadian Cardiovascular Society Guidelines. Can.J.Cardiol. 2011 05/01;27.0828-282X(3):S1-S59.

69

70

71

Appropriate Use of ticagrelor

Ticagrelor Indication

• Ticagrelor, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of thrombotic events in adult patients with acute coronary syndromes (unstable angina, non–ST-elevation myocardial infarction [NSTEMI] or ST-elevation myocardial infarction [STEMI]); including patients managed medically, and those who are managed with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG)

Ticagrelor: Prescribing Information 2011.

By Diagnosis By TreatmentUA/NSTEMI STEMI Medical

management PCI CABG

If clinically indicated, ticagrelor should be used with caution in the following patient groups: Patients with concomitant administration of medicinal products that may increase the risk of bleeding (eg, non-steroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants and/or fibrinolytics) within 24 hours of ticagrelor dosing

Drug Interaction and Contraindication

Effect of other drugs on ticagrelor

Strong CYP3A4 inhibitors(e.g. ketoconazole, clarithromycin,nefazadone,atanazavir)

Recommendations

Should not be given concomitantly

Effect of Ticagrelor on other drugs

Metabolised by CYP3A4(e.g. simvastatin, atorvastatin)

Recommendations

-Increase exposure to simvastatin-Consider clinical consequences in patients requiring > 40 mg simvastatin- Increase in exposure not considered clinically relevant with atorvastatin

Review the full approved Product Information for a complete list of interactions

Contraindications

- Hypersensitivity to ticagrelor or any of the excipients - Active pathological bleeding - History of intracranial haemorrhange - Severe hepatic impairment

Dosing and Administration

• Treatment with ticagrelor is recommended for at least12 months unless discontinuation is clinically indicated

• Ticagrelor can be administered with or without food

Initial treatment: 180 mg

Morning – Take one

LOADING

Continued treatment: 90 mg twice daily + Aspirin: 75–100 mg once daily

MAINTENANCE

Two 90-mg tablets

Initiate ticagrelor with a loading dose of aspirin.

Ticagrelor tablet in the morning (AM)

Night – Take oneTicagrelor tablet in the evening (PM)

Take aspirin(either in themorning or at night)

Ticagrelor: Prescribing Information 2011.

Thank you

Health & Medicine

Antiplatelet in acute coronary syndrome