Eduardo S. Caguioa, MD., FPCP, FPCC, FACCEduardo S. Caguioa, MD., FPCP, FPCC, FACCAsst. Professor, UST Faculty of Medicine and Surgery, Dept of Medicine, Section of CardiologyAsst. Professor, UST Faculty of Medicine and Surgery, Dept of Medicine, Section of Cardiology

Medical Director, UST HospitalMedical Director, UST Hospital

Acute Coronary Syndrome:Acute Coronary Syndrome:Antiplatelets and AntithromboticsAntiplatelets and Antithrombotics

DisclosuresDisclosures

Member of Advisory Member of Advisory Board:Board:

•Astra-ZenecaAstra-Zeneca

•MSDMSD

•PfizerPfizer

•ServierServier

Receives honorarium for Receives honorarium for lectures or drug trialslectures or drug trials

Have no financial interest Have no financial interest in any drug company.in any drug company.

SYNERGY

LMWHLMWH

ESSENCEESSENCE

19941994 19951995 19961996 19971997 19981998 19991999 20002000 20022002 20032003 20042004 20052005 2006200620012001

CURECURE

ClopidogrelClopidogrel

Bleeding riskBleeding risk

Ischemic riskIschemic risk

GP IIb/IIIa GP IIb/IIIa blockersblockers

PRISM-PLUSPRISM-PLUS

PURSUITPURSUIT

ACUITYTACTICS TIMI-18TACTICS TIMI-18

Early invasiveEarly invasive

PCIPCI ~ 5% stents~ 5% stents ~85% stents~85% stents Drug-eluting stentsDrug-eluting stents

ISAR-REACT 2

Milestones in ACS Management

OASIS-5

[ Fondaparinux ]

Anti-Thrombin Rx

Anti-Platelet Rx

Treatment Strategy

HeparinHeparin

AspirinAspirin

ConservativeConservative

ICTUS

BivalirudinBivalirudin

REPLACE 2REPLACE 2

Adapted from and with the courtesy of Steven Manoukian, MDAdapted from and with the courtesy of Steven Manoukian, MD

Evolution of ACS TherapiesEvolution of ACS Therapies

Adapted from White HD et al. Lancet 2008; 372: 570–84

AspirinAspirin

HeparinHeparin

1990 19961996 19971997 20002000 20012001 20052005 20072007 20082008

YearYear

Low molecularLow molecularweight heparinweight heparin

IIb/IIIa receptorIIb/IIIa receptorantagonistantagonist

Early invasive managementEarly invasive management

CLOPIDOGRELCLOPIDOGRELAtorvastatin

FondaparinuxFondaparinux

BivalirudinBivalirudin

IntegratedIntegratedstrategystrategy

DABIGATRANDABIGATRAN

Proportional effects of antiplatelet therapy on Proportional effects of antiplatelet therapy on Vascular events in five main high risk categoriesVascular events in five main high risk categories

Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.

Absolute effects of antiplatelet therapy on Absolute effects of antiplatelet therapy on vascular events in five main high risk categoriesvascular events in five main high risk categories

Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.

Clopidogrel in NSTE ACS: CUREClopidogrel in NSTE ACS: CURE

CURE. NEJM 2001;345:494-502

12,563 Pts, GP IIb/IIIa & early invasive approach discouraged

RR 0.80, p<0.001

Clopidogrel(9.3%)

Placebo(11.4%)

CV

Dea

th, M

I, S

tro

ke

Months of follow-up

0 3 6 9 120.0

0.02

0.04

0.06

0.08

0.10

0.12

0.14

Yusuf S et al. Circulation 2003;107:966-972

CURE: Very Early Efficacy of CURE: Very Early Efficacy of Clopidogrel in NSTE ACSClopidogrel in NSTE ACS

Hours After Randomization

0.0

0.005

0.010

0.015

0.020

0.025

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

P=.003

Placebo+ Aspirin(n=6303)

Clopidogrel+ Aspirin(n=6259)

34%Relative

RiskReduction

CV Death, MI, Stroke, Severe Ischemia Within First 24 Hours

Cu

mu

lati

ve H

aza

rd R

ate

Clopidogrel in STEMIClopidogrel in STEMI

Fibrinolytic, ASA, Heparin

Clopidogrel300 mg + 75 mg qd

Coronary Angiogram(2-8 days)

Primary endpoint:Occluded

artery (TIMI Flow Grade 0/1)or D/MI by time

of angio

randomize

Placebo

Double-blind, randomized, placebo-controlled trial in3491 patients, age 18-75 yrs with STEMI < 12 hours

StudyDrug

30-day clinical follow-up

Open-labelclopidogrelper MD in

both groups

ClopidogrelClopidogrel in STEMI in STEMI

PlaceboPlaceboClopidogrelClopidogrel

36% P<0.0001

36% P<0.0001

Sabatine MS et al. NEJM 2005; 352: 1179

days

CV

Dea

th, M

I, o

r U

rg R

evas

c (%

)C

V D

eath

, MI,

or

Urg

Rev

asc

(%)

05

1015

0 5 10 15 20 25 30

PlaceboPlacebo

ClopidogrelClopidogrel

Odds Ratio 0.80Odds Ratio 0.80(95% CI 0.65-0.97)(95% CI 0.65-0.97)

P=0.026P=0.026

20%20%

PCI-CLARITY DesignPCI-CLARITY Design

30-day clinical follow-up

933 underwent PCI during index hosp.

930 underwent PCIduring index hosp.

3491 Patients Randomized into CLARITY-TIMI 28

1752 assigned clopidogrel300 mg 75 mg/d

1739 assigned placebo

Open-label clopidogrel w/ loading dose

recommended

(CLOPIDOGREL PRETREATMENT) (NO PRETREATMENT)

A n g i o g r a p h y

CV Death, MI, or StrokeCV Death, MI, or Strokefollowingfollowing PCIPCI

02

46

8

0 10 20 30Days post PCI

Pe

rce

nta

ge

wit

h o

utc

om

e (

%)

No Pretreatment – 6.2%No Pretreatment – 6.2%

Clopidogrel – 3.6%Clopidogrel – 3.6%Pretreatment Pretreatment

46%46%

Odds Ratio 0.54(95% CI 0.35-0.85)

P=0.008

Odds Ratio 0.54(95% CI 0.35-0.85)

P=0.008

Sabatine MS et al. JAMA 2005;294:1224-32

Clopidogrel NoTrial Pretreatment Pretreatment

PCI-CURE 3.6 5.1

CREDO n/a n/a

PCI-CLARITY 4.0 6.1

Overall 3.7 5.5

Clopidogrel NoTrial Pretreatment Pretreatment

PCI-CURE 2.9 4.4

CREDO 6.0 7.1

PCI-CLARITY 3.3 5.4

Overall 3.9 5.5

Meta-Analysis of Clopidogrel PretreatmentMeta-Analysis of Clopidogrel Pretreatment

1.00.25 2.00.5

1.00.25 2.00.5OR (95% CI)

OR (95% CI)

CV Death or MI after PCI (%)CV Death or MI after PCI (%)

MI before PCI (%)MI before PCI (%)

OR 0.67OR 0.67P=0.005P=0.005OR 0.67OR 0.67P=0.005P=0.005

FavorsPretreatment

FavorsNo Pretreatment

OR 0.71OR 0.71P=0.004P=0.004OR 0.71OR 0.71P=0.004P=0.004

Sabatine MS et al. JAMA 2005;294:1224-32

20Variable and Unpredictable Variable and Unpredictable Response to ClopidogrelResponse to Clopidogrel

24 hrs after 300 mg Clopidogrel24 hrs after 300 mg Clopidogrel

Gurbel PA et al. Circulation 2003; 107: 2908-2913

10

2020

≤ ≤ -30-30(-30,-20)(-30,-20)

(-20,-10)(-20,-10)(-10,0)(-10,0)

(0,10)(0,10)(10,20)(10,20)

(20,30)(20,30)(30,40)(30,40)

(40,50)(40,50)(50,60)(50,60)

>60>60

Platelet aggregation before and after Clopidogrel (%)Platelet aggregation before and after Clopidogrel (%)

Pat

ien

ts (

%)

Pat

ien

ts (

%)

““ResistanceResistance”” = 31% = 31% N = 96N = 96, Elective PCI

““ResistanceResistance”” = ≤ 10% = ≤ 10% platelet aggregation platelet aggregation2015.01

21Clopidogrel Response Variability andClopidogrel Response Variability andIncreased Risk of Ischemic EventsIncreased Risk of Ischemic Events Primary PCI for STEMI (N = 60)Primary PCI for STEMI (N = 60)

3116.01

0

20

40

60

80

100

120

0

10

20

30

40

5 µM ADP induced plt agg Death/ACS/CVA by 6 m

Days1 2 3 4 5 6

Bas

elin

e (%

)

Quartiles of response

Q1

Q2

Q3

Q4

Clop resist 40

6.7

0 0P

erce

nt

P = 0.007

Q1 Q2 Q3 Q4

Matetzky S, et al. Circulation. 2004;109:3171-3175.Wiviott SD, Antman EM. Circulation. 2004 109:3064-3067.

Evolution of ACS TherapiesEvolution of ACS Therapies

Adapted from White HD et al. Lancet 2008; 372: 570–84

AspirinAspirin

HeparinHeparin

1990 19961996 19971997 20002000 20012001 20052005 20072007 20082008

YearYear

Low molecularLow molecularweight heparinweight heparin

IIb/IIIa receptorIIb/IIIa receptorantagonistantagonist

Early invasive managementEarly invasive management

CLOPIDOGRELCLOPIDOGRELAtorvastatin

FondaparinuxFondaparinux

BivalirudinBivalirudin

IntegratedIntegratedstrategystrategy

PRASUGRELPRASUGREL

More Efficient and Less Variable Activation of Prasugrel More Efficient and Less Variable Activation of Prasugrel Compared to ClopidogrelCompared to Clopidogrel

Clopidogrel

CYP1A2, 2B6, 2C19

IntermediateIntermediate

Active MetaboliteActive Metabolite

CYP3A, 2B6,CYP3A, 2B6,2C9, 2C192C9, 2C19Liver

CYP2C19 variants and inhibitors affect the PK and PD of clopidogrel

Liver

85% Inactive

Metabolite

hCE1hCE1

Prasugrel has no clinically relevant interactions with CYP2C19 variants or inhibitors

Prasugrel

Gut hCE2

IntermediateIntermediate

Active MetaboliteActive Metabolite

Liver

Gut

and CYP3A, 2B6,CYP3A, 2B6,2C9, 2C192C9, 2C19

Time (Hrs)0 2 4 6 8

0

100

300

400

500

600

Ac

tive

Me

tab

olit

e C

on

ce

ntr

atio

n

(ng

/mL

)

Clopidogrel 300 mg LD

Clopidogrel 600 mg LD

Prasugrel 60 mg LD

Higher Active Metabolite Concentrations of Prasugrel After Loading Dose

Cmax and Tmax influence onset of platelet inhibition• Relevant for loading dose but not maintenance dose

AUC influences extent of platelet inhibition• Relevant for loading and maintenance dose

Day 28 (0 hr)

-N

on

Res

po

nd

ers

(%)

0

10

20

30

40

50

60

Pras60 mg

Clop300 mg

Loading dose Maintenance dose

3% 3%

52%

36%

21%

0% 0%

45%

Day 1 (4 hr)

-

Pras40 mg

Pras5 mg

Pras7.5 mg

Pras10 mg

Pras15 mg

Clop75 mg

Prasugrel 60 mg LD with 10 mg MD Demonstrates Prasugrel 60 mg LD with 10 mg MD Demonstrates Superior Response Compared to Clopidogrel Superior Response Compared to Clopidogrel

Jernberg et al., Eur Heart J 2006; 27:1166-1173

TRITON-TIMI 38 Study DesignTRITON-TIMI 38 Study Design

Double-blind

ACS (STEMI or UA/NSTEMI) & Planned PCI

ASA

PRASUGREL60 mg LD/ 10 mg MD

CLOPIDOGREL300 mg LD/ 75 mg MD

1o endpoint: CV death, MI, stroke2o endpoints: CV death, MI, stroke, rehosp-Rec Isch

CV death, MI, UTVR Stent thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, life-threatening bleedsKey substudies: Pharmacokinetic, genomic

Median duration of therapy - 12 months

N = 13,608

Balance of Efficacy and Safety: All ACSBalance of Efficacy and Safety: All ACS

Wiviott SD et al. Wiviott SD et al. NEJMNEJM 2007; 357: 2001-2015 2007; 357: 2001-2015

HR 1.32(1.03 - 1.68)

P = 0.03

35 events

0

5

10

15

0 30 60 90 180 270 360 450

HR 0.81(0.73 - 0.90)P = 0.0004

Prasugrel

Clopidogrel

Days

En

dp

oin

t (%

)

12.1%

9.9%

Prasugrel

Clopidogrel1.8%2.4%

138 events

CV death / MI / stroke

NNT = 46

NNH = 167

TIMI major Non-CABG bleeds

Antiplatelet Therapy in ACSAntiplatelet Therapy in ACS

Single Antiplatelet Rx

Dual Antiplatelet Rx

Higher IPA

ASAASA + Clopidogrel

ASA + Prasugrel

- 22%

- 20%

- 19%

+ 60% + 38% + 32%

Reduction in

IschemicEvents

Increase in

Major Bleeds

0

100

Placebo APTC CURE TRITON-TIMI 38

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

Isch

emic

eve

nts

Net Clinical Benefit in Subgroups: Net Clinical Benefit in Subgroups: Death / MI / CVA / Major BleedDeath / MI / CVA / Major BleedPost-Hoc AnalysisPost-Hoc Analysis

OVERALL

≥ 60 kg

< 60 kg

< 75 yrs

≥ 75 yrs

No

Yes

0.5 1 2

PriorTIA / stroke

Age

Weight

Risk (%)

+ 54

-16

-1

-16

+3

-14

-13

HR

Pint = 0.006

Pint = 0.18

Pint = 0.36

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

Favors Prasugrel

Favors Clopidogrel

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

Balance of Efficacy and Safety in Patients Balance of Efficacy and Safety in Patients < 75 Yrs, ≥ 60 kg, and without Prior TIA/Stroke < 75 Yrs, ≥ 60 kg, and without Prior TIA/Stroke

0

2

4

6

8

10

12

14

16

0 30 90 180 270 360 450

En

dp

oin

t (%

)

Hazard Ratio, 1.240(95% CI, 0.91 - 1.69)

P = 0.17

Hazard Ratio, 0.75(95% CI, 0.66 - 0.84)

P < 0.001

Clopidogrel 11.0%

Prasugrel 8.3%

Clopidogrel 1.50%

Prasugrel 2.0%

Days

CV death, NF MI, or NF stroke

TIMI major bleeding

Kaplan-Meier estimates of the incidence of the primary Kaplan-Meier estimates of the incidence of the primary composite endpoint and of non-CABG related TIMI Major composite endpoint and of non-CABG related TIMI Major bleeding for All ACS patients with diabetes. bleeding for All ACS patients with diabetes.

30 900 180 270 360 450

Hazard Ratio, 1.06(95% CI, 0.66-1.69)

p=0.81

All ACSPatients with Diabetes

12.2%

17.0%

2.5%

2.6%

Hazard Ratio, 0.705(95% CI, 0.58-0.85)

p<0.001

Prasugrel

Clopidogrel

Clopidogrel

TIMI Major Bleeding Prasugrel

CV Death, NF MI , or NF Stroke

Days From Randomization or First Dose

KM

Est

imat

es o

f E

ven

t R

ate

(%)

0

5

10

15

20

Therapeutic ConsiderationsTherapeutic Considerations

Significant Net Clinical Benefit

with Prasugrel80%

MD MD 10 mg10 mg

Recommend

Reduced MD

Guided PK

Wt < 60 kg

Age > 75 y

16%

Avo

id

Prasu

grel

Prio

r

CV

A/T

IA4%

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

August 30, 2009

TICAGRELOR: TICAGRELOR: First and Only Approved CPTPFirst and Only Approved CPTP TICAGRELOR, a new chemical class,

is a cyclo-pentyl-triazolo-pyrimidine (CPTP)

Ticagrelor is direct acting (not a pro-drug 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.

0

20

40

60

80

100

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

Inhibition of Platelet Aggregation: OnsetInhibition of Platelet Aggregation: Onset

Ticagrelor (n=54)

Clopidogrel (n=50)

Placebo (n=12)

Time (Hours)

Inh

ibit

ion

of

Pla

tele

t A

gg

reg

atio

n

*P<0.0001Ticgrelor vs Clopidogrel

Loading Dose

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

* * **

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

*

*

PLATO: Study DesignPLATO: Study Design

Initial treatment approaches18,624 patients with ACS (UA, NSTEMI, or STEMI*)

randomized within 24 hours of symptom onset

180-mg loading dose90 mg bid + ASA Maintenance dose

Patients could be taking clopidogrel at time of randomization

• Medically managed (n=5,216 — 28.0%)• Invasively managed (n=13,408 — 72.0%)

Ticagrelor (n=9,333) Clopidogrel (n=9,293)

6–12 months of double-blind treatment

300-mg loading dose†

75 mg qd + ASA Maintenance dose

Primary efficacy endpoint:Composite of CV death, MI

(excluding silent MI), or stroke

Primary safety endpoint:Total PLATO major bleeding‡

*STEMI patients scheduled for primary PCI were randomized; 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.

1. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.2. James S, et al. Am Heart J. 2009;157:599–605.

PLATO Main: Inclusion CriteriaPLATO Main: Inclusion Criteria

Hospitalisation for STEMI or NSTEMI/UA ACS, with onset during previous 24 hours

With STEMI, the following 2 inclusion criteria were required• Persistent ST elevation of at least 0.1 mV in ≥2 contiguous leads or new

LBBB• Primary PCI planned

With NSTEMI, at least 2 of the following 3 were required• ST changes on ECG indicating ischaemia• Positive biomarker indicating myocardial necrosis• One of the following risk indicators

≥60 years of age Previous MI or CABG CAD with ≥50% stenosis in ≥2 vessels Previous ischaemic stroke, TIA, carotid stenosis (≥50%), or cerebral

revascularisation Diabetes mellitus Peripheral artery disease Chronic renal dysfunction (creatinine clearance <60 mL/min)

James S, et al. Am Heart J. 2009;157:599–605.

PLATO: Baseline CharacteristicsPLATO: Baseline Characteristics

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

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

Both groups included aspirin.*NNT at one year.

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

12111098765432

10

13

Cu

mu

lati

ve In

cid

ence

(%

) 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

TICAGRELOR

ARR=1.9%

RRR=16%

NNT=54*

P<0.001

HR: 0.84 (95% CI, 0.77–0.92)

0–12 Months

PLATO: Predefined Testing of Primary and PLATO: Predefined Testing of Primary and Major Secondary Efficacy EndpointsMajor Secondary Efficacy Endpoints

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

Both groups included aspirin. The percentages presented are Kaplan-Meier estimates of the rate of the endpoint at 12 months.

* Patients could have had more than one type of endpoint. Death from CV causes and fatal bleeding, as only traumatic fatal bleeds were excluded from the CV death category. ** By Cox regression analysis using treatment as factor; †Excluding silent MI; ‡Death from any cause was tested after stroke, which

was non-significant, so the results should be considered nominally significant.

Months After Randomisation

0 2 4 6 8 10 12

6

5

4

3

2

1

0

7

Cu

mu

lati

ve I

nci

de

nce

(%

)

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

Cu

mu

lati

ve I

nci

de

nce

(%

)

PLATO: Secondary Efficacy EndpointsPLATO: Secondary Efficacy Endpoints

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

BRILIQUE: Summary of Product Characteristics, 2010.

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 EndpointPLATO: Primary Safety Endpoint

PL

AT

O-d

efin

ed T

ota

l M

ajo

r B

leed

ing

(%

)

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

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: BleedingPLATO: Bleeding

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

18BRILINTA (n=9,235)

Clopidogrel (n=9,186)

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

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

ima

ted

Rat

e (%

Per

Yea

r)

NS

P = 0.03

P = 0.008

NS

NS

NS

PLATO: DyspneaPLATO: Dyspnea

Ticagrelor-associated dyspnea was mostly mild to moderate in severity and did not reduce efficacy

Most events were reported as single episode occurring early after starting treatment

Not associated with new or worsening heart or lung disease

In 2.2% of patients, investigators considered dyspnoea causally related to treatment with Ticagrelor

Label precautions and warnings: use with caution in patients with history of asthma and COPD

Ticagrelor: Summary of Product Characteristics, 2010.; Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.Storey R, et al. J Am Coll Cardio. 2010;55(Suppl 1):A108.E1007.

PLATO: Bradycardia-related EventsPLATO: Bradycardia-related Events

• Ventricular pauses ≥3 seconds occurred in 5.8% of ticagrelor-treated patients vs 3.6% of clopidogrel-treated patients in the acute phase, and 2.1% and 1.7% after 1 month, respectively

• There were no differences in adverse clinical consequences (ie, pacemaker insertion, syncope, bradycardia, and heart block)

• Label precautions and warnings: Ticagrelor should be used with caution in patients at risk of bradycardic events

Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.; Ticagrelor: Summary of Product Characteristics, 2010.

PLATO: Laboratory ParametersPLATO: Laboratory Parameters

Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.; Ticagrelor: Summary of Product Characteristics, 2010.

• Creatinine levels may increase during treatment with ticagrelor; renal function should be checked after 1 month and thereafter according to medical practice

• Label precautions and warnings: as a precautionary measure, the use of ticagrelor in patients with uric acid nephropathy is discouraged

Presented at ESC 2009 as an oral presentation

Subsequently published in Lancet, January 2010

A pre-specified objective of PLATO was to compare outcomes of Ticagrelol versus clopidogrel in patients with planned invasive strategy at randomization

For all patients, the intention for early invasive management had to be indicated by the investigator before patients were randomized

Cannon CP, et al. Lancet. 2010;375:283−293.

Comparison of ticagrelor with clopidogrel in Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for patients with a planned invasive strategy for acute coronary syndromes (PLATO): a acute coronary syndromes (PLATO): a randomised double-blind studyrandomised double-blind study

Christopher P. Cannon, Robert A. Harrington, Stefan James, et al.Christopher P. Cannon, Robert A. Harrington, Stefan James, et al. for the for the PLATelet inhibition and patient Outcomes (PLATO) investigatoPLATelet inhibition and patient Outcomes (PLATO) investigators rs

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

6,676

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 Invasive72% of patients in PLATO

P<0.0025

HR: 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<0.045

HR: 0.85 (95% CI, 0.73–1.00)

14.3%

12%Clopidogrel

Ticagrelor

K-M

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ed R

ate

Pri

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CV

Dea

th/M

I/Str

oke

(%

)No. at risk

Days After Randomisation

K-M

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Pri

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Clinical ImplicationsClinical Implications In ACS patients with planned invasive management at randomisation in

PLATO, compared with clopidogrel, ticagrelor significantly reduced the incidence of• CV death/MI/stroke (primary efficacy endpoint)

Ticagrelol: 9.0% vs clopidogrel: 10.7%

• CV death Ticagrelol: 3.4% vs clopidogrel: 4.3%

Consistent with the overall study, ticaggrelor had an increase in dyspnea in this patient population compared to clopidogrel

In PLATO, in ACS patients with a planned invasive management strategy, Ticagrelol was shown to be more effective than clopidogrel for the prevention of CV and total death without any significant increase in major bleeding*

Invasive study was consistent with the overall results from PLATO

European Association for Percutaneous Cardiovascular Intervention, et al. Eur Heart J. 2010;31:2501–2555.Canadian Cardiovascular Society Anti Platelet Guidelines published online at http://www.ccs.ca. Accessed February 12, 2011.Adapted form Cannon CP, et al. Lancet. 2010;375:283−293.

* No overall increase in major bleeding in this sub-study, however there was an increase in the PLATO main non-CABG bleeding (Ticagrelor: 4.5% vs. clopidogrel 3.8%); and major and minor bleeding (Ticagrelor16.1% vs. clopidogrel 14.6%).

TICAGRELOR IndicationTICAGRELOR Indication

Ticagrelor, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic 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: Summary of Product Characteristics, 2010.

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

1. The availability, of new treatment alternatives for stroke prevention in patients with nonvalvular atrial fibrillation is a great step forward to further improve outcomes and quality of life.

2. Compared with warfarin, these new alternatives have important advantages, with their lower risk of intracranial bleeding, no clear interactions with food, fewer interactions with medications, and no need for frequent laboratory monitoring and dose adjustments.

3. Dabigatran etexilate is a synthetic low molecular weight peptidomimetic that binds directly and reversibly to the catalytic site of thrombin.

4. Rivaroxaban, apixaban, and endoxaban are selective direct factor Xa inhibitors.

5. Based on the currently available results from the individual trials, it is clear that both the oral direct thrombin inhibitor dabigatran etexilate and the oral factor Xa inhibitors apixaban and rivaroxaban are attractive alternatives to warfarin or aspirin in patients with nonvalvular atrial fibrillation and an increased risk of stroke.

1. The availability, of new treatment alternatives for stroke prevention in patients with nonvalvular atrial fibrillation is a great step forward to further improve outcomes and quality of life.

2. Compared with warfarin, these new alternatives have important advantages, with their lower risk of intracranial bleeding, no clear interactions with food, fewer interactions with medications, and no need for frequent laboratory monitoring and dose adjustments.

3. Dabigatran etexilate is a synthetic low molecular weight peptidomimetic that binds directly and reversibly to the catalytic site of thrombin.

4. Rivaroxaban, apixaban, and endoxaban are selective direct factor Xa inhibitors.

5. Based on the currently available results from the individual trials, it is clear that both the oral direct thrombin inhibitor dabigatran etexilate and the oral factor Xa inhibitors apixaban and rivaroxaban are attractive alternatives to warfarin or aspirin in patients with nonvalvular atrial fibrillation and an increased risk of stroke.

New Anticoagulants in AF and ACSPerspective:

6.6. Apixaban 5 mg (with dose reduction to 2.5 mg in specific cases) BID is currently Apixaban 5 mg (with dose reduction to 2.5 mg in specific cases) BID is currently the best documented alternative to both warfarin and aspirin for stroke the best documented alternative to both warfarin and aspirin for stroke prevention in a broad population with atrial fibrillation and increased risk of prevention in a broad population with atrial fibrillation and increased risk of stroke, based on two independent large-scale trials. Apixaban is awaiting Food stroke, based on two independent large-scale trials. Apixaban is awaiting Food and Drug Administration approval in the United States for atrial fibrillation. and Drug Administration approval in the United States for atrial fibrillation.

7.7. Patients already on long-term vitamin K antagonist (VKA) treatment, with well-Patients already on long-term vitamin K antagonist (VKA) treatment, with well-controlled international normalized ratio and handling VKA treatment and controlled international normalized ratio and handling VKA treatment and laboratory monitoring without problems, derive uncertain overall advantages laboratory monitoring without problems, derive uncertain overall advantages from switching to the new oral anticoagulants, and the arguments for changing from switching to the new oral anticoagulants, and the arguments for changing treatment in such patients appear weak. treatment in such patients appear weak.

8.8. There is also a need for more information on how to manage patients with There is also a need for more information on how to manage patients with bleeding because there are no specific antidotes for any of the new agents. bleeding because there are no specific antidotes for any of the new agents.

9.9. The cost of the drug at the patient level might be an obstacle to their use, The cost of the drug at the patient level might be an obstacle to their use, although the cost-effectiveness at a societal level might be tolerable in although the cost-effectiveness at a societal level might be tolerable in comparison with other recently accepted novel treatments. comparison with other recently accepted novel treatments.

10.10. Additional trials are indicated to determine the utility of these agents in Additional trials are indicated to determine the utility of these agents in combination with antiplatelet treatments after myocardial infarction and combination with antiplatelet treatments after myocardial infarction and percutaneous coronary intervention.percutaneous coronary intervention.

6.6. Apixaban 5 mg (with dose reduction to 2.5 mg in specific cases) BID is currently Apixaban 5 mg (with dose reduction to 2.5 mg in specific cases) BID is currently the best documented alternative to both warfarin and aspirin for stroke the best documented alternative to both warfarin and aspirin for stroke prevention in a broad population with atrial fibrillation and increased risk of prevention in a broad population with atrial fibrillation and increased risk of stroke, based on two independent large-scale trials. Apixaban is awaiting Food stroke, based on two independent large-scale trials. Apixaban is awaiting Food and Drug Administration approval in the United States for atrial fibrillation. and Drug Administration approval in the United States for atrial fibrillation.

7.7. Patients already on long-term vitamin K antagonist (VKA) treatment, with well-Patients already on long-term vitamin K antagonist (VKA) treatment, with well-controlled international normalized ratio and handling VKA treatment and controlled international normalized ratio and handling VKA treatment and laboratory monitoring without problems, derive uncertain overall advantages laboratory monitoring without problems, derive uncertain overall advantages from switching to the new oral anticoagulants, and the arguments for changing from switching to the new oral anticoagulants, and the arguments for changing treatment in such patients appear weak. treatment in such patients appear weak.

8.8. There is also a need for more information on how to manage patients with There is also a need for more information on how to manage patients with bleeding because there are no specific antidotes for any of the new agents. bleeding because there are no specific antidotes for any of the new agents.

9.9. The cost of the drug at the patient level might be an obstacle to their use, The cost of the drug at the patient level might be an obstacle to their use, although the cost-effectiveness at a societal level might be tolerable in although the cost-effectiveness at a societal level might be tolerable in comparison with other recently accepted novel treatments. comparison with other recently accepted novel treatments.

10.10. Additional trials are indicated to determine the utility of these agents in Additional trials are indicated to determine the utility of these agents in combination with antiplatelet treatments after myocardial infarction and combination with antiplatelet treatments after myocardial infarction and percutaneous coronary intervention.percutaneous coronary intervention.

New Anticoagulants in AF and ACSPerspective:

Thank you for your attention!Thank you for your attention!