Antiplatelet in acute coronary syndrome

The clinical decision-making
strategies for antiplatelet
therapy in ACS patients
Paiboon Chotnoparatpat, MD, FSCAI

www.themegallery.cohttp://www.scientific-art.com/GIF%20files/Medical/Atherosclerosishttp://www.scientific-art.com/portfolio%20medicine%20pages/atherosclerosis.

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

2014 AHA/ACC NSTE-ACS Guidelines
4
•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 Therapy
1. 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:
● 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 stenting
Initiate/continue antiplatelet and anticoagulant
therapy
1. 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:
● 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 care
1. 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)
CABG
Initiate/continue ASA therapy and
discontinue P2Y12 and/or GPI therapy
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
5
•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)
P2Y12
recommendation
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:
● Fondaparinux (Class I; LOE: B)
2. P2Y12 inhibitor (in addition to ASA) (Class I; LOE: B):
● Clopidogrel or
● Ticagrelor
3. Anticoagulant:
● 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)
6
•Invasive
management
(PCI)
Pathway
stage
•Initiate/continue ticagrelor or
clopidogrel, or initiate
prasugrel (only after
coronary anatomy has been
defined)
P2Y12
recommendation
PCI with stenting
Initiate/continue antiplatelet and anticoagulant
therapy
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:
● Bivalirudin (Class I; LOE: B) or
● Fondaparinux as the sole anticoagulant
(Class III: Harm; LOE: B) or
● UFH (Class I; LOE: B)
CABG
Initiate/continue ASA therapy and
discontinue P2Y12 and/or GPI therapy
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
7
Pathway
stage
P2Y12
recommendation
•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 care
1. 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 apply
1. Yusuf S et al. N Engl J Med 2001;345:494–502
2. Mehta SR et al. N Engl J Med 2010;363:930–942
3. Wallentin L et al. N Engl J Med 2009;361:1045–1057
4. James SK et al. BMJ 2011;342:d3527
Recommendation Class Level Evidence
P2Y12 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 B
CURE1, 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

Invasive management (PCI)
9
A 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 A
PLATO,1 TRITON,2 CREDO,3,4
EPISTENT,5 CLEAR PLATELETS,6
PCI-CLARITY7
Ticagrelor I B PLATO1
Clopidogrel I B
CREDO,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 –
2. Wiviott SD et al. N Engl J Med 2007;357:2001–2015
3. Steinhubl SR et al. JAMA 2002;288:2411–2420
4. Steinhubl SR & Deal DB. Circulation 2003;108(Suppl 1):I1742
5. Steinhubl SR et al. Circulation 2001;103:1403–1409
6. Gurbel PA et al. Circulation 2005;111:1153–1159
7. Sabatine MS et al. JAMA 2005;294:1224–1232
8. von Beckerath N et al. Circulation 2005;112:2946–2950
9. Siller-Matula JM et al. Heart 2011;97:98–105
10. Mangiacapra F et al. Am J Cardiol 2010;106:1208–1211

Duration of therapy
10
In 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 acid
1. Yusuf S et al. N Engl J Med 2001;345:494–502
2. Mehta SR et al. Lancet 2001;358:527–533
4. James SK et al. BMJ 2011;342:d3527
5. Shishehbor MH et al. Am J Cardiol 2006;97:1585–1590
6. Steinhubl SR et al. JAMA 2002;288:2411–2420
7. Wiviott SD et al. N Engl J Med 2007;357:2001–2015
8. 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 thepharmaceutical 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]
1
•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

•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
1
Executive summary

Top-line recommendations – STEMI
14
1. Montalescot G et al. Lancet 2009;373:723–731
2. Steg PG et al. Circulation 2010;122:2131–2141
3. Mehta S et al. Lancet 2010;376:1233–1243
4. Bellemain-Appaix A et al. JAMA 2012;308:2507–2516
5. Zeymer U et al. Clin Res Cardiol 2012;101:305–312
6. Koul S et al. Eur Heart J 2011;32:2989–2997
7. Dörler J et al. Eur Heart J 2011;32:2954–2961
A 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
ASA, acetylsalicylic acid

Top-line recommendations ‒ NSTE-ACS
15
A 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
5. Montalescot G et al. N Engl J Med 2013;369:999–1010

Revascularization in STEMI
Unchanged 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]

Guidelines?
NSTE-ACS
17
Revascularization in NSTE-ACS
Unchanged 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
*Ticagrelor should be stopped before elective surgery as per local label

Stable CAD*
18
*Note: Ticagrelor is not currently licensed for use in stable CAD; therefore, stable CAD guidelines
should only be discussed reactively with healthcare professionals
BMS, bare-metal stent; DES, drug-eluting stent
Revascularization in stable CAD
New/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
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
Ticagrelor
Dec 2010
July 2011

Thrombin
Thromboxane
A2
5HT
P2Y12
ADP ADPADP
5HT
PLATELET
ACTIVATION
P2Y1
5HT2A
PAR1
PAR4
Dense
granule
Thrombin
generation
Shape
change
aIIbb3
aIIbb3
Fibrinogen
aIIbb3
Aggregation
Amplification
Alpha
granule
Coagulation factors
Inflammatory mediators
TPa
Coagulation
GPVI
Collagen
ATPATP
P2X1
ASPIRIN
x TICLOPIDINE
CLOPIDOGREL
PRASUGREL
ACTIVE
METABOLITE
x
TICAGRELOR
(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.
Receptor
subtype
Molecular
structure
Secondary
messenger
system
Functional
response
P2Y12 Inhibitor
P2X1 P2Y1 P2Y12
G protein G protein
Intrinsic ion GPCR GPCR
channel 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 activity
Meadows 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
Hepatic
Metabolism
Clopidogrel
N
S
Cl
COOCH3
CYP 3A4(5)
CYP 2C9
CYP 2C19
CYP 2B6
CYP 1A2
CYP 2B6
CYP 2C19
Inactive Metabolites
carboxylic acid derivative
(85% of ingested
clopidogrel)
Esterases
Clopidogrel: Pro-drug to Active
Metabolite Formation
Active Metabolite
HOOC
* HS
N
O
Cl
OCH3
CH3
O
N
S
O
Cl
O
C
2-oxo Compound
Hepatic
Metabolism

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
0
Activemetaboliteconcentration
(ng/mL)
0 2 4 6 8 10 12 14 16 18 20 22 24
Time from dose (hours)
Prasugrel-AM
Clopidogrel-AM
100
80
60
20
0
Activemetaboliteconcentration
(ng/mL)
0 2 4
Time from dose (hours)
40
Prasugrel-AM
Clopidogrel-AM
Loading dose Maintenance dose

Balance of efficacy and safety in selected
subgroup
%ofSubjects
Wiviott et al. NEJM 2007;357:2001-2015
HR 1.54
P=0.04
HR 1.03
P=0.92
HR 0.99
P=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
platelets
Husted 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 aggregation
Coadminister 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-dependent
oxidation
CYP1A2
CYP2B6
CYP2C19
CYP-dependent
oxidation
CYP2C19
CYP3A4/5
CYP2B6
Active 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
100
Ticagrelor (n=54)
Clopidogrel (n=50)
Placebo (n=12)
Time (Hours)
InhibitionofPlateletAggregation
*P<0.0001 ticagrelor vs Clopidogrel
Loading
Dose
Ticagrelor 180-mg loading dose in Stable CAD patients
Clopidogrel 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
Argentina
Australia
Austria
Belgium
Brazil
Bulgaria
Finland
France
Georgia
Germany
Greece
Malaysia
Mexico
The Netherlands
New Zealand
Norway
Philippines
Poland
Portugal
Romania
Russia
Singapore
Slovakia
Spain
Sweden
Switzerland
South Africa
South Korea
Taiwan
Thailand
Turkey
Ukraine
United
Kingdom
United States
Canada
China
Czech
Republic
Denmark
Hong Kong
Hungary
India
Indonesia
Israel
Italy

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=18,624
Patients 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

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
12
11
10
9
8
7
6
5
4
3
2
1
0
13
CumulativeIncidence(%)
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
5.4
Clopidogrel
Ticagrelor
ARR=1.9%
RRR=16%
NNT=54*
P<0.001
HR: 0.84 (95% CI, 0.77–0.92)
0–12 Months

Months After Randomisation
0 2 4 6 8 10 12
6
5
4
3
2
1
0
7
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
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. Supplement.
Ticagrelor: Prescribing Information 2011.
ARR=1.1%
RRR=16%
Calculated NNT=91
P=0.005
HR: 0.84 (95% CI, 0.75–0.95)
ARR=1.1%
RRR=21%
NNT=91
P=0.001
HR: 0.79 (95% CI, 0.69–0.91)
Both groups included aspirin.

P=0.43
HR: 1.04 (95% CI, 0.95–1.13)
PLATO: Primary Safety Endpoint
PLATO-definedTotal
MajorBleeding(%)
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

PLATO: Bleeding
All values presented by PLATO criteria.
Major Bleeding Non-CABG-
Major Bleeding
Major and
Minor Bleeding
Life-threatening/
Fatal Bleeding
Fatal Bleeding CABG-Major
Bleeding
K-MEstimatedRate(%PerYear)
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
18
Ticagrelor(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-Mestimatedrate(%peryear)
†
[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 60 120 180 240 300 360
Days After Randomisation
James S, et al. ESC 2010; Poster #1353.
Cannon C, et al. Lancet. 2010;375:283–293.
10.7%
9%
Clopidogrel
Ticagrelor
6,676
6,732
6,129
6,236
6,034
6,134
5,881 4,815
4,889
3,680
3,735
2,965
3,0485,972Ticagrelor
Clopidogrel
Initial Invasive
72% of patients in PLATO
P<0.0025
HR: 0.84 (95% CI, 0.75–0.94)
Initial Non-Invasive
28% 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<0.045
HR: 0.85 (95% CI, 0.73–1.00)
14.3%
12%Clopidogrel
Ticagrelor
K-MEstimatedRatePrimary
CompositeofCVDeath/MI/Stroke(%)
No. at risk
Days After Randomisation
K-MEstimatedRatePrimary
CompositeofCVDeath/MI/Stroke(%)

Primary Efficacy Endpoint
Ticagrelor
Group
Clopidogrel
Group
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
9.0
12.0
9.3
10.5
8.4
14.1
8.8
8.6
11.7
10.7
14.5
11.0
12.6
10.2
16.2
10.0
11.2
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
<0.01
0.04
0.02
0.29
<0.05
>0.05
>0.05
<0.05
0.49
0.46
PLATO : Summary
* p for interaction

Primary Safety Endpoint
Ticagrelor
Group
Clopidogrel
Group
HR for
(95% CI) p p*
PLATO Major Bleed, K-M %
PLATO
PLATO-INVASIVE
PLATO-MEDICAL
PLATO-STEMI
PLATO-CABG
PLATO-DIABETES
No Diabetes
Diabetes
PLATO-GENETICS
No CYP2C19 loss of function allele
Any CYP2C19 loss of function allele
11.6
11.5
11.9
9.0
81.2
10.8
14.1
10.3
11.8
11.2
11.6
10.3
9.3
80.1
10.0
14.8
10.6
11.3
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
0.88
0.08
0.63
0.67
>0.05
>0.05
0.61
0.77
0.21
0.60
PLATO : Summary
* p for interaction

Updated ESC & ACCF
ACS 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 with
NSTE-ACS at moderate-to-high risk of ischemic events
2011 ESC Guidelines for the management of acute coronary syndromes in patients
presenting without persistent ST-segment elevation 1
OAP Recommendation
Recommended for all patients at moderateto-
high risk of ischemic events, regardless of
initial treatment strategy and including those
pre-treated with clopidogrel
Ticagrelor
Recommended for patients who cannot receive ticagrelor
or prasugrel
Clopidogrel (300-mg LD,
75-mg MD)
Clopidogrel 600-mg LD
(or supplementary 300-mg
dose at PCI following initial
300-mg LD)
Recommended for patients scheduled for an invasive strategy
when ticagrelor or prasugrel is not an option
OAP = Oral Anti-platelet, LD = Loading dose, MD = Maintenance dose
Ticagrelor and
clopidogrel
Should be considered to be (re) started after CABG surgery
as 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 PCI
Class* 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
elevation
2012 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 a
strict 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 for
ACS patients undergoing revascularization
C
2010 ESC/EACTS Guidelines on myocardial revascularization 2
OAP
NSTE-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 for
ACS patients undergoing percutaneous coronary intervention
2011 ACCF/AHA/SCAI Guidelines for Percutaneous Coronary Intervention3
At the time of PCI at least 12 months post-stenting
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 for
ACS 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
OAP
Ticagrelor
Clopidogrel
1 1A A
1 1A A
After PCI,
Recommended
aspirin 81 mg
per 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 stentOAP
Grade Grade
Ticagrelor
Clopidogrel
1B 1B
1B 1B
 For patients who do not undergo PCI, the guidelines suggest using ticagrelor before
clopidogrel (Grade 2B)
 For patients who undergo PCI and receive a stent, the guidelines suggest using
ticagrelor 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¥
Ticagrelor
Recommended in patients referred for elective
CABG should be discontinued for at least 5 days
before surgery
1 B
Clopidogrel
Recommended 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 A
Clopidogrel
(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.

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)
By Diagnosis By Treatment
UA/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 one
Ticagrelor tablet
in the evening (PM)
Take aspirin
(either in the
morning or at night)

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