Jajang Sinardja

The Standard Dual Antiplatelet

Therapy for ACS

� Clopidogrel : loading dose 300 mg, followed

by 75 mg daily

� ASA: 160 mg non-enteric chewed tablet,

followed by 80 mg daily

Trial & population Comparison Primary Endpoint Bleedin g

CURE (2001)NSTE-ACS patientsn = 12,562

Clopidogrel 75 mg(300 mg loading)vs. placebo

CV death, MI, CVAClopidogrel 9.3%Placebo 11.4%(P < 0.001)ARR 2.1%;RRR 20%; NNT 48

Major bleeding*Clopidogrel 3.7%Placebo 2.7%(P = 0.001)NNH: 100

PCI Cure (2001)NSTE-ACS undergoing PCIn = 2,658

Like CURE (after PCIclopidogrel in both groups for 1 month)

CV death, MI, orurgent TVR in30 daysClopidogrel 4.5%Placebo 6.4%ARR 1.9%;RRR 30%; NNT 53

Major bleeding*Clopidogrel 2.7%Placebo 2.5%(P = 0.69

CURRENT OASIS 7 (2010)NSTE-ACS - 63%STEMI - 37%n = 25,086

Clopidogrel double dose(600 mg loading, 150 mg day 2–7, then 75 mg) vs. standard dose75 mg (150 mg loading)

CV death, MI, CVA(at 30 days)Double 4.2%Standard 4.4%(P = 0.30)

Major bleedingDouble 2.5%Standard 2.0%(P = 0.01)NNH: 200

Clopidogrel Trials

Hamm CW et al. Eur Heart J 2011;32:2999 – 3054

* CURE Definition

Potential Limitations of

Clopidogrel

� Moderate overall levels of platelet inhibition

� Average IPA ~50%

� High variability response within a population

� 4-34% with very low levels of platelet inhibition

� Slow onset of antiplatelet effect

� Requiring 300 – 600 mg loading doses in acute

phase

Gurbel et al. Circulation 2009;120:2577-2585

O’ Donoghue M. Wiviott SD . Circulation 2006;114:e600-e606

Inhibition of ADP-Induced Platelet Function Following 600mg Clopidogrel in 1,001 patients

Hochholzer W. Circulation 2005;111: 2560-2564

Variability in Clopidogrel

Responsiveness

Angiolillo DJ & Ueno M. JACC: Cardiology Interventions 2011;4 (4):411–414

Trial & population Comparison Primary Endpoint Bleedin g

TRITON (2007)Undergoing PCINSTE-ACS 74%STEMI 26%n = 13 608

Prasugrel 10 mg(60 mg loading)vs. clopidogrel75 mg(300 loading)

CV death, MI, CVAPrasugrel 9.9%Clopidogrel 12.1%(P < 0.001)ARR 2.2%;RRR 27%;NNT 45

Non–CABG-relatedmajor bleeding:#Prasugrel 2.4%Clopidogrel 1.8%(P = 0.03)NNH: 167CABG-related majorbleeding Prasugrel13.4%Clopidogrel 3.2%(P < 0.001)NNH: 10 (CABG

Prasugrel Trial

Hamm CW et al. Eur Heart J 2011;32:2999 – 3054

* TIMI Criteria

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

OH

OH

O

OH

N

F

S

NH

NN

NN

F

• Direct-acting

– Not a pro drug: does not require metabolic activation

– Rapid onset of inhibitory effect on the P2Y12 receptor than clopidogrel

• Reversibly bound

– Faster offset than clopidogrel

– Functional recovery of circulating platelets within ~ 48 hours

Ticagrelor

Deeks ED. Drugs 2011;71(7):909-933Husted S. Van Giezen JJJ. Cardiovascular Therapeutics 2009;27:259-274

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-dependentoxidationCYP1A2CYP2B6

CYP2C19

CYP-dependentoxidationCYP2C19 CYP3A4/5 CYP2B6

Active compound

Intermediate metabolite

Prodrug

Ticagrelor

Clopidogrel

Binding

P2Y12

Ticagrelor: Does Not Require Hepatic Metabolism for Activation

Platelet

Ticagrelor P2Y12 receptor

binding

ADP, adenosine diphosphateAdapted from Husted S. Van Giezen JJJ. Cardiovascular Therapeutics 2009;27:259-274

ADP

P2Y12 receptor ADP binds and activates the receptor

Conformational change and signalling

Ticagrelor binds away from ADP pocket

ADP can bind reversibly but no conformational change or signalling

Receptor remains intact upon dissociation

ONSET/OFFSET: Pharmacodynamics in

Stable CAD Patients

Onset

100

90

80

70

60

50

40

30

20

10

0

IPA

%

//

Ticagrelor (n=54)

Clopidogrel (n=50)

0 0.5 1 2 4 8 24 6 weeks 0 2 4 8 24 48 72 120 168 240

Maintenance Offset

Time (Hours)

Loading Dose

180 mg

600 mg

*

*

* * *

‡

†

** †

LastMaintenance

Dose90 mg bid75 mg qd

//*

*

//

* P<0.0001† P<0.005‡ P<0.05

Time (Hours)

Gurbel PA et al. Circulation 2009;120:2577-2585

PLATO Study

PLATO Study2: • 43 countries• 862 sites• 18,624 patients

43 countries862 sites

PLATO study tested the hypothesis that…ticagrelor will result in a lower risk of recurrent thrombotic events in a broad patient population with ACS as compared to clopidog rel and this would be

achieved with a clinically acceptable bleeding rate and overall safety profile 1

18,624 patients

1. James S et al. Am Heart J 2009;157: 599 – 6052. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

PLATO: Study Population

ACS Patient

STEMI

Primary PCI

No Reperf

Fibrinolytic Rx

UA/NSTEMI

Initial Invasive Management

PCI

No revascularisation

CABG

Initial Non-Invasive Management

PCI

CABG

No revascularisationOnly STEMI patients

intended for primary PCI included

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

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

PLATO 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

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

PLATO Main: Inclusion Criteria

• 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 Main: Key Exclusion Criteria

• Contraindication to clopidogrel

• Fibrinolytic therapy within 24 hours

• Oral anticoagulation therapy that cannot be stopped

• ACS event was a complication of previous PCI

• PCI after index event (initial clinical signs and symptoms) and before first study dose

• Increased risk for bradycardic events

• Concomitant therapy with strong CYP3A inhibitors/inducers

• Patients requiring dialysis

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

Efficacy Results

PLATO: Baseline Characteristics

CharacteristicTicagrelor(n=9,333)

Clopidogrel (n=9,291)

Median age, years 62.0 62.0

Age ≥75 years, n (%) 1,396 (15.0) 1,482 (16.0)

Women, n (%) 2,655 (28.4) 2,633 (28.3)

CV risk factors, n (%)

Habitual smoker 3,360 (36.0) 3,318 (35.7)

Hypertension 6,139 (65.8) 6,044 (65.1)

Dyslipidemia 4,347 (46.6) 4,342 (46.7)

Diabetes mellitus 2,326 (24.9) 2,336 (25.1)

History, n (%)

MI 1,900 (20.4) 1,924 (20.7)

PCI 1,272 (13.6) 1,220 (13.1)

CABG 532 (5.7) 574 (6.2)

ECG at study entry, n (%)

ST-segment elevation, persistent 3,497 (37.5) 3,511 (37.8)

ST-depression 4,730 (50.7) 4,756 (51.2)

T-wave inversion 2,970 (31.8) 2,975 (32.0)

Troponin-I positive, n (%) 7,965 (85.3) 7,999 (86.0)

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 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

13C

umul

ativ

e In

cide

nce

(%)

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 Major Secondary Efficacy Endpoints

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

All Patients*Ticagrelor(n=9,333)

Clopidogrel (n=9,291)

HR for Ticagrelor(95% CI)

P Value **

Primary endpoint, n (%/year)

Death from vascular cause + MI† + stroke 864 (9.8) 1,014 (11.7) 0.84 (0.77–0.92) <0.001

Secondary endpoints, n (%/yr)

Death from any cause + MI† + stroke 901 (10.2) 1,065 (12.3) 0.84 (0.77–0.92) <0.001

Death from vascular causes + MI† + stroke + severe recurrent ischemia + recurrent ischemia + TIA + arterial thrombus

1,290 (14.6) 1,456 (16.7) 0.88 (0.81–0.95) <0.001

MI† 504 (5.8) 593 (6.9) 0.84 (0.75–0.95) 0.005

Death from vascular causes 353 (4.0) 442 (5.1) 0.79 (0.69–0.91) 0.001

Stroke 125 (1.5) 106 (1.3) 1.17 (0.91–1.52) 0.22

Death from any cause 399 (4.5) 506 (5.9) 0.78 (0.69–0.89) <0.001‡

Nominal Significance

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 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 fro m 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.

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.

PLATO Primary Endpoint: Initial Invasive vsInitial Non-Invasive Management

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

Stent Thrombosis ticagrelor vs clopidogrel

0,6%ARR

33%RRR

P = 0.009

Ticagrelorn= 5640

Clopidogreln = 5649

Wallentin L, et al. N Engl J Med 2009;361:1045-57

* Definition by Academic Research Consortium criteria

PLATO Efficacy Results

Summary

� Ticagrelor significantly reduced the composite of

CV death, MI or stroke vs clopidogrel at 1 year

(1.9% ARR, 16% RRR, P<0.001, NNT=54)

� Ticagrelor significantly reduced CV mortality vs

clopidogrel

(1.1% ARR, 21% RRR, P=0.001)� Risk of CV death and MI were both significantly reduced

� Risk of stroke was not significantly different

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

PLATO Efficacy Results

Summary

� The absolute risk reduction with ticagrelor vs

clopidogrel starts early and continues to build

over the full 1 year treatment period

� For every 91 ACS patients treated with

ticagrelor for 1 year, instead of clopidogrel, 1

CV death was prevented (NNT=91)

� The effect of ticagrelor over clopidogrel

appears consistent across many subgroups

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

Safety Results

P=0.43

HR: 1.04 (95% CI, 0.95–1.13)

PLATO: Primary Safety Endpoint

PLA

TO-d

efin

ed T

otal

M

ajor

Ble

edin

g (%

)

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: Safety Endpoints - bleeding

*Both groups included aspirin; **Proportion of patients (%)

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

PLATO: 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

imat

ed R

ate

(% P

er Y

ear)

NS

P = 0.03

P = 0.008

NS

NS

NS

PLATO: Dyspnoea

• Ticagrelor-associated dyspnoea 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

BRILINTA. Indonesia Prescribing Information 2012.Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.Storey R, et al. Eur Heart J 2011;32:2945-2953

Dyspnoea in the PLATO trial Ticagrelor Clopidogrel P Value

Incidence of dyspnoea adverse events (%) 13.8 7.8 <0.001

Patients who discontinued treatment due to dyspnoea (%)

0.9 0.1 <0.001

PLATO: Bradycardia-related Events

All PatientsTicagrelor(n=9,235)

Clopidogrel (n=9,186) P Value

Bradycardia-related event, n (%)

Pacemaker insertion 82 (0.9) 79 (0.9) 0.87

Syncope 100 (1.1) 76 (0.8) 0.08

Bradycardia 409 (4.4) 372 (4.0) 0.21

Heart Block 67 (0.7) 66 (0.7) 1.00

• 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)

1. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.2. Scirica BM et al. J Am Coll Cardiol 2011;57:1908-19163. BRILINTA Indonesia Prescribing Information 2012.

PLATO: Laboratory Parameters

All PatientsTicagrelor(n=9,235)

Clopidogrel (n=9,186) P Value

Mean % increase ( ± SD) in serum creatinine from baseline

At 1 month 10 ± 22 8 ± 21 <0.001

At 12 months 11 ± 22 9 ± 22 <0.001

1 month after end of treatment 10 ± 22 10 ± 22 0.59

Mean % increase ( ± SD) in serum uric acid from baseline

At 1 month 14 ± 46 7 ± 44 <0.001

At 12 months 15 ± 52 7 ± 31 <0.001

1 month after end of treatment 7 ± 43 8 ± 48 0.56

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

CI, confidence interval; CrCl, creatinine clearance; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction.James S, et al. Circulation 2010;122:1056–1067.

Renal function and outcomes in PLATO : Primary composite endpoint by CrCl

Ticagrelor better

Clopidogrel better

Risk of CV death, stroke or MIHR (95% CI)

30

40

50

60

70

80

90

100

CrCl(mL/min)

0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.20.4

Incr

easi

ng r

enal

impa

irmen

t

PLATO Safety Results

Summary

� No increase in overall major bleeding with

Ticagrelor vs clopidogrel

� Non-CABG major bleeding and major + minor

bleeding were more frequent with Ticagrelor

vs clopidogrel

� No increase in overall fatal/life-threatening

bleeding with Ticagrelor vs clopidogrel

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

PLATO Safety Results

Summary

� There are more dyspnoea-related events

associated with Ticagrelor vs clopidogrel,

however most events were mild to moderate

in intensity and often resolved without a need

for treatment

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

Implicating New Guidelines into ACS Management

ESC Guidelines for the management of ACS in patient s presenting without persistent ST-segment elevation

Hamm CW et al. Eur Heart J 2011;32:2999 – 3054

LevelClass

Steg PG, et al. European Heart Journal. 2012;33:2569-2619

Oral antiplatelet in ESC

2012 STEMI Guideline

ACCF/AHA 2013 STEMI

Guideline

Anderson JL, et al. Circulation. 2007;116:e148-e304.

Summary

� Ticagrelor is an active drug with reversible

binding to P2Y12 receptor

� Ticagrelor provide fast onset and fast offset

� Ticagrelor significantly reduces the combined

risk of CV death, MI, or stroke as compared to

clopidogrel in patients with ACS

Summary

� Ticagrelor is effective in a broad spectrum of

ACS patients

� There is no increase of overall major bleeding

with Ticagrelor as compared to clopidogrel

� Ticagrelor has been recommended in ACS

guidelines both in initial management ,

before PCI procedure and at discharge