ticagrelor (brilique®), - uzleuven.be desmet.pdf · ticagrelor (brilique®), the new kid on the...

Ticagrelor (Brilique ®),

the new kid on the block

W. Desmet, MD PhDHead of Interventional Radiological and Cardiovascular CentreUniversity Hospitals LeuvenBelgium

Class Level

P2Y12 inhibitor recommendations

Class Level

ESC NSTE-ACS guidelines 2011

GP = glycoprotein; PAR = protease-activated recepto r; TP = thromboxane A 2 / prostaglandin H 2.Storey RF. Curr Pharm Des. 2006;12:1255-1259.

Mechanisms of Platelet Inhibition

ThromboxaneA2

5HT

P2Y12

ADP ADPADP

5HT

PLATELETACTIVATION

P2Y15HT2A

PAR-1

PAR-4

Densegranule

Thrombingeneration

Shapechange

ααααIIb ββββ3

ααααIIb ββββ3

FibrinogenααααIIb ββββ3

Aggregation

AmplificationAlpha

granule

Coagulation factorsInflammatory mediators

TPαααα

Coagulation

GPVI

Collagen

ATPATP

P2X1

ASPIRIN

xCLOPIDOGRELPRASUGREL

ACTIVE METABOLITE

x CANGRELORTICAGRELOR

GP IIb/IIIa ANTAGONISTS

xx

Thrombin

Possible reasons for therapeutic gap: limitations of clopidogrel

• The current standard oral antiplatelet used in ACS,

clopidogrel, is a prodrug requiring metabolic activation

• Suboptimal onset and delayed peak of antiplatelet activity

• Irreversible P2Y12 receptor binding

• Individual patient response highly variable

• Has not demonstrated a CV mortality benefit in randomized

clinical trials

Angiolillo DF, et al. Am Heart J. 2008a;156:S3-S9; Gurbel PA et al . Circulation. 2009;120:2577-2585; Yusuf S, et al. NEJM. 2001;345:494-502.

Clinically important attributes of an oral antiplatelet agent

– Rapid onset of effect• Direct acting

– Does not require metabolic activation

– Rapid offset of effect• Reversible binding

– Does not require production of new platelets to restore platelet function

– Consistent and sustained inhibition of platelet aggregation

• No nonresponders

• Few drug-drug interactions

Mehta SR, et al. J Am Coll Cardiol. 2003;41:79S-88S; Angiolillo DJ, et al . Am Heart J. 2008a;156:S3-S9.

Time (hours)Onset Maintenance Offset

100

90

80

70

60

50

40

30

20

10

0

IPA

%Ticagrelor 180mg LD / 90 mg bd (n=54)

Clopidogrel 600mg LD / 75 mg od(n=50)

0 .5 1 2 4 8 24 6 weeks 0 2 4 8 24 48 72 120 168 240

*

*

* * *

**

*

*

‡

†

†

////////

////////

////////

ONSET/OFFSET Study IPA with ADP 5uM (final extent)

Gurbel PA et al. Circulation 2009

0 24 48 72 96 120 144 168 192 216 2400

20

40

60

80

100

Ticagrelor

Clopidogrel*

**

**

*****

* p<0.05, ** p<0.01, *** p<0.001

Hours

% IP

A

ONSET/OFFSET high responder subanalysisIPA with ADP 20 µmol/L (final extent)

Storey RF et al. J Thromb Haemost 2011

PLATO: primary endpoint:K-M estimate of time to major CV event (composite of CV death, MI or stroke)

No. at risk

Clopidogrel

Ticagrelor

9291

9333

8521

8628

8362

8460

8124

Months after randomization

6650

6743

5096

5161

4047

4147

0 2 4 6 8 10 12

121110

9876543210

13

Cum

ulat

ive

inci

denc

e (%

)9.8

11.7

8219

HR 0.84;

95% CI 0.77-0.92; P<0.001

Clopidogrel

Ticagrelor

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

8688

8763

0 10 20 30

8

6

4

2

0

Cum

ulat

ive

inci

denc

e (%

)

Clopidogrel

Ticagrelor4.85.4

(HR, 0.88; 95% CI, 0.77-1.00; P=0.045)

No. at risk

Clopidogrel

Ticagrelor

9291

9333

8875

8942

8763

8827

Days after randomization31 90 150 210 270 330

8

6

4

2

0

Clopidogrel

Ticagrelor

5.3

6.6

8688

8673

8286

8397

6379

6480

Days after randomization *

(HR, 0.80; 95% CI, 0.70-0.91; P<0.001)

8437

8543

6945

7028

4751

4822

*Excludes patients with any primary event during th e first 30 days

Wallentin L. Presented at the European Society of C ardiology Congress 2009, Barcelona, Spain. August 2 9-September 2: 179. http://spo.escardio.org/eslides/view.aspx?eevt id=33&id=179 -2.

PLATO: primary efficacy endpoint over time (composite of CV death, MI or stroke)

0-30 days 31-360 days

Cum

ulat

ive

inci

denc

e (%

)

No. at risk

Clopidogrel

Ticagrelor

9291

9333

8560

8678

8405

8520

8177


6703

6796

5136

5210

4109

4191

0 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

8279

HR 0.84 (95% CI, 0.75-0.95)

P=0.005

0 2 4 6 8 10 12

6

4

3

2

1

0

Clopidogrel

Ticagrelor

4.0

5.1

HR 0.79 (95% CI, 0.69-0.91) P=0.001

7

5

9291

9333

8865

8294

8780

8822

8589


7079

7119

5441

5482

4364

44198626

Myocardial infarction Cardiovascular death

Cum

ulat

ive

inci

denc

e (%

)

Wallentin L. Presented at European Society of Cardio logy Congress 2009, Barcelona Spain: 179. Available at http://spo.escardio.org/eslides/view.a spx?eevtid=33&id=179

PLATO: K-M estimates of time to secondary efficacy endpoints*

*The rate of stroke did not differ significantly be tween the 2 treatment groups

Which price to pay for these nice results ?

PLATO: time to major bleeding: primary safety endpoint

K-M

est

imat

ed r

ate

(% p

er y

ear)

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

Months from first dose of drug

10

5

0

15

0 2 4 6 8 10 12

Clopidogrel*

Ticagrelor*11.2%11.6%

HR 1.04 (95% CI 0.95-1.13), P=0.43

*Both groups included aspirin; NS, not significant

No. at risk

Ticagrelor 9235 7246 6826 6545 5129 3783 3433

Clopidogrel 9186 7305 6930 6670 5209 3841 3479

Ticagrelor better Clopidogrel better

Ti. Cl.Total

Patients

KM % atMonth 12

HR (95% CI)Hazard Ratio

(95% CI)

First Troponin I

N ST elevation/LBBB at randomization

Overall Treatment Effect

Planned Treatment Approach

TIMI Risk Score: UA/NSTEMI

Time from Index Event to first IP

Characteristic

0.5 1.0 2.0

4849 14.4 15.6 0.92 (0.79, 1.07)5-75488 8.2 10.9 0.77 (0.64, 0.92)3-4

730 4.2 4.1 1.11 (0.53, 2.31)0-2

5216 12.0 14.3 0.85 (0.73, 1.00)Medically managed13,408 8.9 10.6 0.84 (0.75, 0.94)Invasive

8854 11.4 12.9 0.90 (0.79, 1.01)≥12 hours9556 8.2 10.4 0.79 (0.69, 0.90)<12 hours

2968 7.0 7.0 1.00 (0.75, 1.32)Negative15,089 10.3 12.3 0.85 (0.77, 0.94)Positive

7544 9.4 10.8 0.87 (0.75, 1.01)Yes11,074 10.1 12.3 0.83 (0.74, 0.93)No

18,624 9.8 11.7 0.84 (0.77, 0.92)Primary Endpoint

Medical History of MI

Revascularization History of PCI

TIMI Risk Score: STEMI

Yes 2492 14.1 14.6 0.98 (0.79, 1.22)No 16,312 9.1 11.2 0.82 (0.74, 0.90)

Yes 3824 14.6 17.2 0.84 (0.71, 0.99)No 14,800 8.6 10.2 0.85 (0.76, 0.94)

≥3 3137 13.1 15.2 0.86 (0.71, 1.04)0-2 3889 4.7 6.2 0.76 (0.58, 1.01)

0.2

P value(Interaction)

0.68

0.29

0.17

0.88

0.27

0.32

0.94

0.13

Primary endpoint in predefined subgroups (1)

[Wallentin 2009-3:A]

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


Ti. Cl.Total

Patients

KM % atMonth 12


(95% CI)

Yes

Yes

Revascularization History of CABG

Sex

Weight Group

≥65 Years

Characteristic

0.5 1.0 2.0

17,256 9.5 11.2 0.86 (0.78, 0.94)<80 kg

1312 13.1 17.3 0.75 (0.60, 0.99)≥60 kg

5288 11.2 13.2 0.83 (0.71, 0.97)

<60 kg

13,336 9.2 11.1 0.85 (0.76, 0.95)Female

2878 16.8 18.3 0.94 (0.78, 1.12)

Male

15,744 8.6 10.4 0.82 (0.74, 0.91)≥75 Years

7979 13.2 16.0 0.83 (0.74, 0.94)<75 Years

10,643 7.2 8.5 0.85 (0.74, 0.97)<65 Years

1152 19.0 20.8 0.87 (0.66, 1.13)Age Group

17,462 9.2 11.1 0.84 (0.76, 0.93)No

1106 19.5 21.7 0.88 (0.67, 1.15)Previous TIA/Non-hemorrhagic Stroke

17,518 9.2 11.0 0.84 (0.77, 0.93)No

Yes

Central/South America

≥80 kg

North America

1237 15.2 17.9 0.86 (0.65, 1.13)Europe/Middle East/Africa

1714 11.4 14.8 0.80 (0.61, 1.04)Asia/Australia

4662 14.1 16.2 0.88 (0.76, 1.03)Region

13,962 8.4 10.2 0.83 (0.74, 0.92)No

9513 8.3 10.5 0.79 (0.69, 0.90)Medical History of DM

9055 11.4 12.8 0.90 (0.79, 1.01)

0.2


0.76

0.84

0.86

0.22

0.82

0.36

0.17

0.05

1814 11.9 9.6 1.25 (0.93, 1.67)13,859 8.8 11.0 0.80 (0.72, 0.90)

0.49


DM=diabetes mellitus[Wallentin 2009-3:A]



Ti. Cl.Total

Patients

KM % atMonth 12


(95% CI)

No

ASA

Antiplatelet Therapy Prior to Index Event

Caucasian

Other

No

Characteristic

0.5 1.0 2.0

9001 11.4 12.5 0.93 (0.82, 1.05)Males ≥82 kg/females ≥71 kg

221 14.4 21.4 0.63 (0.33, 1.21)

Males <82 kg/females <71 kg

1096 12.5 14.8 0.87 (0.62, 1.21)

Weight by Gender-specific Median

229 13.0 19.6 0.63 (0.32, 1.23)Oriental

17,077 9.5 11.2 0.85 (0.77, 0.94)Black

5062 10.0 11.1 0.90 (0.76, 1.07)Race

13,562 9.7 11.9 0.82 (0.74, 0.92)Yes

17,697 9.7 11.6 0.84 (0.77, 0.93)GPIIb/IIIa (IE to End of Index Hosp.)

927 11.6 13.8 0.87 (0.60, 1.27)Yes

12,147 8.2 10.0 0.82 (0.73, 0.93)ASA on Day of Rand.

5024 11.8 14.0 0.84 (0.71, 0.98)None

1397 15.8 17.8 0.95 (0.73, 1.24)Clopidogrel ± ASA

Unknown

≥30 kg/m 2

Waist Circumference Group

5178 8.9 10.8 0.83 (0.69, 0.99)13,354 10.1 11.9 0.86 (0.77, 0.95)<30 kg/m 2

1019 12.6 13.4 0.95 (0.66, 1.35)BMI Group

7978 9.7 12.1 0.79 (0.69, 0.91)≥100 cm9627 9.6 11.1 0.88 (0.77, 1.00)<100 cm

9567 8.2 10.8 0.76 (0.67, 0.87)

0.2


0.43

0.86

0.41

0.66

0.04

0.44

0.73

BMI=body mass index





Ti. Cl.Total

Patients

KM % atMonth 12


(95% CI)

Mod. Isoenzyme 3A (Rand.)

NSTEMI

Final Diagnosis

Lipid-Lowering Drugs (Rand.)

Beta Blockers (Rand.)

Heparin Use (IE to end of Index Hosp.)

Characteristic

0.5 1.0 2.0

8102 9.4 10.6 0.90 (0.78, 1.03)ACE Inhibitors (Rand.)

14,060 10.1 11.7 0.86 (0.78, 0.96)Yes4564 9.0 11.6 0.79 (0.65, 0.95)No

14,856 9.5 11.8 0.80 (0.73, 0.89)Yes3768 11.0 11.2 1.02 (0.83, 1.24)No

11,928 9.5 11.1 0.85 (0.75, 0.95)Yes6696 10.4 12.6 0.84 (0.73, 0.98)No

1907 10.4 12.1 0.85 (0.65, 1.12)Yes

489 9.1 14.7 0.58 (0.34, 1.00)

No

7026 8.5 10.1 0.84 (0.72, 0.98)Other

7955 11.4 13.9 0.83 (0.73, 0.94)STEMI

3112 8.6 9.1 0.96 (0.75, 1.22)Unstable angina

No

No

No

Proton Pump Inhibitors (Rand.)2736 10.8 13.8 0.76 (0.61, 0.95)Yes

15,888 9.6 11.3 0.86 (0.78, 0.95)Calcium Channel Blockers (Rand.)

Yes 1643 11.8 12.8 0.96 (0.72, 1.28)

Angiotensin II Receptor Blockers (Rand.)16,981 9.6 11.6 0.83 (0.76, 0.92)

Yes 10,522 10.1 12.5 0.81 (0.72, 0.91)

0.2


0.41

0.93

0.98

0.04

0.40

0.27

0.37

0.33

NoYes 6375 11.0 12.9 0.86 (0.75, 1.00)

12,249 9.2 11.0 0.83 (0.74, 0.93)

16,717 9.7 11.6 0.84 (0.77, 0.93)

0.69




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 CP, et al. Lancet. 2010;375:283–293.

10.7%

9%

Clopidogrel

BRILIQUE

6,676

6,732

6,129

6,236

6,034

6,134

5,881 4,815

4,889

3,680

3,735

2,965

3,0485,972BRILIQUE

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

1,0992,247BRILIQUE

Clopidogrel

P<0.045

HR: 0.85 (95% CI, 0.73–1.00)

14.3%

12%Clopidogrel

BRILIQUE

K-M

Est

imat

ed R

ate

Prim

ary

Com

posi

te o

f CV

Dea

th/M

I/Str

oke

(%)

No. at risk

Days After Randomisation

K-M

Est

imat

ed R

ate

Prim

ary

Com

posi

te o

f CV

Dea

th/M

I/Str

oke

(%)

PLATO intent for non-invasive management: All-cause mortality

Days after randomisation

10

8

6

4

2

0

All-

caus

e m

orta

lity

(%)

Initially intended for non-invasive managementTicagrelor (n=2601)Clopidogrel (n=2615)HR (95% CI) = 0.75(0.61–0.93); p=0.010

Initially intended for invasive managementTicagrelor (n=6732)Clopidogrel (n=6676)HR (95% CI) = 0.80(0.61–0.93)

0 60 120 180 240 300 360

CI, confidence interval; HR, hazard ratio; NSTEMI, non-ST-segment elevated myocardial infarction; UA, unstable angina.James S, et al. BMJ 2011;342:d3527.

6.1%

8.2%

3.9%

5.3%

p for interaction = 0.64

All-cause mortality benefit with ticagrelor was cons istent with the overall PLATO trial results

17.3%

22.0%

Renal function and outcomes in PLATO : Primary composite endpoint

CI, confidence interval; CKD, chronic kidney disease; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction.James S, et al. Circulation 2010;122:1056–1067;Wallentin L, et al. N Engl J Med 2009;361:1045–1057.


Normal renal functionTicagrelorClopidogrelHR (95% CI) = 0.90(0.79–1.02)

7.9%8.9%

0 60 120 180 240 300 360

25

20

15

10

5

0

CV

dea

th, M

I or

stro

ke (%

)CKDTicagrelorClopidogrelHR (95% CI) = 0.77(0.65–0.90)

p for interaction = 0.13

Primary endpoint benefit with ticagrelor was consist ent with the overall PLATO trial results

No interaction between treatment and renal function (p=0.13)

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

Ticagrelorbetter

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 re

nal i

mpa

irmen

t

Ticagrelor

Class Level


Prasugrel

Class Level


In practice : dosing

• Loading dose 180 mg; thereafter 90 mg b.i.d.• On top of A.S.A. 75-150 mg/d.• Duration 1 year

Statement of EMA

“ The claimed faster offset of platelet aggregation of ticagrelor in comparison to clopidogrel by %IPA offset (higher within 24 hours) after discontinuati on of the drug seems only to be theoretical . Other markers of bleeding risk such as Hb concentration and chest tube drainage showed that bleeding risks were similar between ticagrelor and clopidogrel. This means that ticagrelor should also be discontinued 7 days prior to CABG.”

Assessment report for Briliquehttp://www.ema.europa.eu/ema/index.jsp?curl=pages/m edicines/human/medicines/001241/human_med_001398.jsp&murl=menus /medicin

es/medicines.jsp&mid=WC0b01ac058001d125

ADP=Adenosine Diphosphate; CABG=coronary artery bypass graft; Hb=hemoglobin; IPA=Inhibition of Platelet Aggregation; PCI=percutaneous coronary intervention;

STEMI=ST-Segment Elevation Myocardial Infarction; NSTEMI=Non-ST-Segment Elevation Myocardial Infarction

+ 2 pills/day needed→ higher chance of non-compliance→ higher chance of eventsTrial patients ↔ daily life patients !!!

In practice : particular patient subsets

• No dose adjustement needed in

– Elderly

– Chronic kidney dysfunction (no data for

dialysis)

– Slightly decreased hepatic function

• < 18 year: no data

Index Hospitalization Procedures

61

6

34

0

20

40

60

80

100

PCI CABG MedicalManagement

Only

99

1 00

20

40

60

80

100

PCI CABG MedicalManagement

Only

% %

PLATO TRITON-TIMI 38

PLATO: time to first primary efficacy event (composite of CV death, MI or stroke)

No. at risk

ClopidogrelTicagrelor

9,2919,333

8,5218,628

8,3628,460

8,124


6,7436,743

5,0965,161

4,0474,147

0 60 120 180 240 300 360

1211109876543210

13

Cum

ulat

ive

inci

denc

e (%

)9.8

11.7

8,219

HR 0.84 (95% CI 0.77–0.92), p=0.0003

Clopidogrel

Ticagrelor

Curves are Kaplan-Meier rates, HR = hazard ratio; CI = confidence interval

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

End

poin

t (%

)

12.1

9.9

HR 1.32(1.03-1.68)P=0.03

Prasugrel

Clopidogrel1.82.4

138events

35events

TRITON-TIMI study Balance of Efficacy and Safety

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

NNT = 46

NNH = 167

Faster action of prasugrel?

Prasugrel Ticagrelor

TRITON TIMI-38: STEMI Cohort (N= 3534)

0

5

10

15

0 30 60 90 180 270 360 450

End

poin

t (%

)

Days

9.5%

6.5%

HR 0.68(0.54 - 0.87)

P = 0.002

12.4%

10.0%

HR 0.79(0.65 - 0.97)

P = 0.02

Clopidogrel

Prasugrel

NNT = 42

CV death / MI / stroke

TIMI major non-CABG bleeds

Clopidogrel

Prasugrel 2.4%

2.1%

N = 3534

Montalescot G, et al. Lancet 2009;373:723-731

No increase in bleeding

PLATO: STEMI Subgroup Analyses (N = 7544 Patients)

Number at RiskTicagrelor

Clopidogrel34763501

34243438

33313356

26872726

20492097

16751679

37523792

Steg G, et al. Circulation 2010;122:2131-2141

PLATO=PLATelet Inhibition and Patient Outcomes; STEMI=ST-Segment Elevation Myocardial Infarction

p = 0.07HR = 0.87 (0.75-1.01)

PLATO: STEMI Subgroup Analysis:Secondary End Point

Steg G, et al. Circulation 2010;122:2131-2141

4.5 4.7

1.7

5.5 5.8

1.0

0,0%

2,0%

4,0%

6,0%

8,0%

Cardiovascular Death Myocardial Infarction Stroke

Kap

lan-

Mei

er E

stim

ate

(%) Ticagrelor

Clopidogrelp = 0.07 p = 0.03

p = 0.02

*

* MI excludes silent infarctions

PLATO=PLATelet Inhibition and Patient Outcomes; STEMI=ST-Segment Elevation Myocardial Infarction

Primary End Point* Diabetes Subgroup:PLATO and PLATO Invasive

No

Yes

Characteristic

Medical history of diabetes mellitus

KM% at Month 12

Total Patients Ticagrelor Clopidogrelp value

(Interaction)

0.4913962 8.4 10.2

4662 14.1 16.2

Ticagrelor Better Clopidogrel Better

No

Yes

Characteristic

Medical history of diabetes mellitus

KM% at Month 12

Total Patients Ticagrelor Clopidogrelp value

(Interaction)

0.64410289 8.0 9.6

3109 12.4 14.2

Ticagrelor Better Clopidogrel Better

PLATO1

PLATO Invasive 2

*Cardiovascular Death/Myocardial Infarction/Stroke1. Wallentin L, et al. N Engl J Med 2009;361:1045-1057

2. Cannon CP, et al. Lancet 2010;375:283-293 PLATO=PLATelet Inhibition and Patient Outcomes

TRITON-TIMI 38:Diabetes Subgroup (n = 3146)

0

2

4

6

8

10

12

14

16

18

0 30 60 90 180 270 360 450

HR 0.70p < 0.001

Time (Days)

End

Poi

nt (

%)

NNT = 21

17.0

12.2

2.62.5

Prasugrel

Clopidogrel CV Death, NF MI or NF Stroke

Non-CABG TIMI Major Bleeding

CABG=Coronary Artery Bypass Graft; CV=Cardiovascular; HR=Hazard Ratio; MI=Myocardial Infarction; NF=nonfatal; NNT=Number Needed to Treat; TIMI=Thrombolysis In Myocardial Infarction

Wiviott SD, et al. Circulation 2008;118:1626-1636

HR 1.06 p = 0.81

TRITON-TIMI 38: Reduction in Primary End Pointby Diabetes (DM) Status and Treatment

Wiviott SD, et al. Circulation 2008 ;118:1626-1636

No DM

DM No Insulin

DM on Insulin

Prasugrel Better Clopidogrel Better

PrasugrelClopido

grelReduction

in Risk

9.2% 10.6% 14%

11.5% 15.3% 26%

14.3% 22.2% 37%

DM=Diabetes Mellitus; TRITON-TIMI=TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel Thrombolysis In Myocardial Infarction

Definite/Probable Stent Thrombosis at 360 Days

3.0

2.2

0

1

2

3

4

5

4928 4949

HR = 0.73p = 0.014

Eve

nt R

ate

(%)

HR=Hazard Ratio; PLATO=PLATelet Inhibition and Patient Outcomes

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

N=

Clopidogrel Ticagrelor

2.2

1.1

0

1

2

3

4

5

6422 6422N=

HR = 0.48p < 0.0001

Eve

nt R

ate

(%)

Clopidogrel Prasugrel

Wiviott SD, et al. Lancet 2008;371:1353-1363

PLATO TRITON

Drug -Eluting Stent Thrombosisat 360 Days

Effe

ctiv

e R

ate

(%)

2.52.3

HR = 0.90

p = 0.66

Clopidogrel Ticagrelor0

1

2

3

4

5

Effe

ctiv

e R

ate

(%) HR = 0.35

p < 0.0001

Clopidogrel Prasugrel

2.0

0.7

0

1

2

3

4

5

HR = 0.53

P=0.001

PLATO TRITON

PLATO: Time from CABG to Any Death (CABG Population)

0 1 2 3 4 5 6 7 8 9 10 11 12

10

9

8

7

6

5

4

3

2

1

0

Months

Clopidogrel

Ticagrelor4.7

9.7

HR: 0.49 (95% CI 0.32-0.77), p < 0.01

K-M

Est

imat

ed R

ate

(%)

629 583 557 491 415 291 119629 565 539 472 404 269 130

No. at riskTicagrelor

Clopidogrel

CABG=Coronary Artery Bypass Graft; CI=Confidence Interval; HR=Hazard Ratio; K-M=Kaplan MeierHeld C, et al. JACC 2011;57(6):672-684.

TRITON-TIMI 38: Isolated CABG All Cause Death

HR = 0.26 (0.085-0.77), p = 0.016

Adjusted Odds Ratio: 0.26 (0.079-0.85)p = 0.025

N = 346

Days from CABG

K-M

Est

imat

edA

ll C

ause

Dea

th R

ate

(%)

0

2

4

6

8

0 30 90 180 270 360 450

Clopidogrel

Prasugrel

8.7%

2.3%

10

Smith PK et al. American Heart Association Scientific Sessions, 2010, Nov 16, Chicago, IL

CABG=Coronary Artery Bypass Graft; HR=Hazard Ratio; K-M=Kaplan-Meier; TRITON-TIMI= TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet

InhibitioN with Prasugrel Thrombolysis In Myocardial Infarction

The mortality risk at 30-days adjusted for possible imbalances at CABG baseline when analyzed by logistic regression per EURO

scoring

Considerations

With prasugrel :

• Bleeding risk

With ticagrelor :

• Bleeding risk

• Dyspnea

• Lab values

• Contra-indications

• Drug interactions

Ticagrelor: Dyspnea

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

All PatientsClopidogrel (n = 9186)

Ticagrelor(n = 9235) p value*

Dyspnea,%

Any 7.8 13.8 <0.001

With discontinuation of study treatment

0.1 0.9 <0.001

*p values were calculated using Fischer’s exact test

Trial ↔ real lifeDiagnostic dilemma

Total death 31-360 days in patients with dyspnoea A E in first 30 days

Storey et al. Eur Heart J 2011 July 30

Differences in mortality outcome amongst dyspnoeicpatients treated with ticagrelor or clopidogrel

Conclusion


Ticagrelor-related dyspnoea:

• Tends to occur early during ticagrelor treatment

• Is usually mild or moderate in intensity

• Resolves spontaneously or upon discontinuation of

medication in the majority of patients

• Does not appear to be associated with any differences in

any efficacy or other safety outcomes compared with

clopidogrel therapy in ACS patients.

And the problem doesn’t stop….


TRITON-TIMI 38: Primary End Point in Patients With CKDand With Normal Renal Function (NRF)

Data on File, Daiichi Sankyo, Inc. and Eli Lilly and CompanyCABG=Coronary Artery Bypass Graft; CKD=Chronic Kidney Disease; CI=Confidence Interval; HR=Hazard Ratio; RF=Renal Function; TRITON-TIMI= TRial to Assess Improvement in

Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel Thrombolysis In Myocardial Infarction

Days of Randomization

5

0

10

15

20

25

0 30 90 180 270 360 450

HR= 0.861(95% CI, 0.664-1.117), p = 0.518

Prim

ary

End

Poi

nt (

% F

ailu

re)

Clopidogrel CKDPrasugrel CKDClopidogrel Normal RFPrasugrel Normal RF

Primary End Point: Composite of CV Death, Nonfatal MI, or Nonfatal Stroke

PLATO: Primary End Point in CKD Patients and Patien ts With Normal Renal Function (NRF)

James S, et al. Circulation 2010;122:1056-1067

5

0

10

15

20

25

Prim

ary

End

Poi

nt (

% F

ailu

re)

0 60 120 180 240 300 360

HR = 0.77 (95% CI, 0.65-0.90)

HR = 0.90 (95% CI, 0.79-1.02)

p interaction = 0.13

Clopidogrel CKDTicagrelor CKDClopidogrel Normal RFTicagrelor Normal RF

Days of Randomization

C-G=Cockcroft-Gault Equation; CKD=Chronic Kidney Disease; CV=Cardiovascular; CI=Confidence Interval; HR=Hazard Ratio; MI=Myocardial Infarction; PLATO=PLATelet

Inhibition and Patient Outcomes; RF=Renal Function

In practice : interactions

• Substrate for CYP3A4• Weak to moderate inhibitor of CYP3A4

• Substrate for P-gp• Weak inhibitor of P-gp

In practice : interactions with CYP3A4 inhibitors

• Ketoconazol– Cmax ticagrelor x 2.4– AUC ticagrelor x 7.3– Cmax primary metabolite ticagrelor -89%– AUC primary metabolite ticagrelor -56%– Comparable effect expected with other strong CYP3A4

inhibitors, like clarithromycin, nefazodon, ritonavir, atanazavir

• Diltiazem– Cmax ticagrelor +69%– AUC ticagrelor x 2.7– Plasma concentration diltiazem unchanged– Comparable effect expected with erythromycin, fluconazol…

Co-administrationContra-indicated

Can beCo-administered

In practice : interactions with CYP3A4 inductors

• Rifampicine– Cmax ticagrelor -73%– AUC ticagrelor -86%– Cmax primary metabolite ticagrelor unchanged– AUC primary metabolite ticagrelor -46%– Efficacy of ticagrelor possibly lowered by concomitant use of

strong inductors

Co-administrationDiscouraged

In Practice: interactions with CYP3A4 substrates

• Simvastatin

– Cmax simvastatin +81%

– AUC simvastatin +56%

– No effect of simvastatin on plasma levels of ticagrelor

• Atorvastatine

– Cmax atorvastatine +23%

– AUC atorvastatine +36%

• Careful with CYP3A4 substrates with narrow

therapeutic band width (cisapride, ergot alkaloids)

Co-administrationwith > 40 mg simvastatin/lovastatin

not recommended

Can beCo-administered

In Practice: with P-glycoprotein substrates

• Digoxin

– Cmax digoxin +75%

– AUC digoxin +28%

– No effect of digoxin on plasma levels ticagrelor

• Cyclosporin

– No data

Monitor plasma levels !

PLATO: bradycardia-related events and Holter monitoring program

All PatientsTicagrelor (n=9235)

Clopidogrel (n=9186)

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

Holter monitor first week, n (%) Ticagrelor (n=1451)


P value

Ventricular pauses ≥3 seconds 84 (5.8) 51 (3.6) 0.01


Holter monitor at 30 days, n (%) Ticagrelor (n=985)


P value



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

Laboratory parameters

All patientsTicagrelor(n=9,235)

Clopidogrel(n=9,186) p value *

% increase in creatinine from baseline

At 1 month

At 12 months

Follow-up visit

10 ±±±± 22

11 ±±±± 22

10 ±±±± 22

8 ±±±± 21

9 ±±±± 22

10 ±±±± 22

<0.001

<0.001

0.59

% increase in uric acid from baseline

At 1 month

At 12 months

Follow-up visit

14 ±±±± 46

15 ±±±± 52

7 ±±±± 43

7 ±±±± 44

7 ±±±± 31

8 ±±±± 48

<0.001

<0.001

0.56

Values are mean % ±±±± SD; *p values were calculated using Fisher’s exact test

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

Conclusion

• Slight increase in serum uric acid and creatininecompared to clopidogrel

• Serum levels return to normal 1 month after treatmenttermination

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

The adenosine-like properties of ticagrelor may provide a (partial) explanation for some of these effects

Serebruany et al. Eur Heart J 2010;31:764-67

Contraindications and warnings of clopidogrel/prasugrel/ticagrelor

Ticagrelor- Active pathological bleeding- History of intracranial haemorrhage

- Moderate to severe hepatic impairment

- Co-administration with strong CYP3A4 inhibitors

Bradycardic events - History of asthma and/or COPD- Moderate/severe renal impairment

- Concomitant use of ARBs- History of hyperuricaemia orgouty arthritis

- Uric acid nephropathy- Co-administration of simvastatinor lovastatin >40 mg

- Co-administration of digoxin

Prasugrel- Active pathological bleeding- History of stroke or TIA- Child Pugh class C

- For Age >75 only use of 5 mg- For Body weight <60 kg use 5 mg

- TTP- Galactose intolerance

Clopidogrel- Active pathological bleeding- Severe hepatic impairment

- TTP- Recent (<7 days) ischemic stroke

- Poor CYP2C19 metabolizers- Renal impairement- Galactose intolerance- Concomitant use of omeprazole and esomeprazole

CO

NT

RA

IND

ICAT

ION

SW

AR

NIN

GS

Venn diagram: which drug for which patientJukema JW et al. Adapted from: Cur Med Res Opin 2012

TICAGRELOR PRASUGREL

CLOPIDOGRELCost –restricted1

Prior stroke2

Low body weight

3 Asthma/COPD, Bradycardia,

dyspnea

4

ElderlyElderly5

Modest hepatic Impairment

4

CYP3A4 interactions1,4

STEMI PCI 6-8

Diabetics9Clopidogrel non-

responders

11,12

Renal impairment1,4-6

ACS Med Man3,10

Stent thrombosis

6,7

DES 7,13

CABG3

Non CV surgery

3,6

Stable CAD

6,14

BRILIQUETM qualitative & quantitative composition

BRILIQUETM qualitative & quantitative composition

Film-coated tablets, each containing 90 mg ticagrel or

Round, biconvex, yellow tablets marked with ‘90’ ab ove ‘T’ on one side and plain on the other.

List of excipients:CoreMannitol (E421), Dibasic calcium phosphate, Magnesi um stearate (E470b), Sodium starch glycolate, Hydroxypropyl-cellulose (E 463)

CoatingTalc, Titanium dioxide (E171), Ferric oxide yellow (E172), Polyethylene-glycol 400, Hypromellose (E464)

BRILIQUETM Summary of Product Characteristics, 2010.

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