Ticagrelor: A New Chapter Openssummitmd.com/pdf/pdf/Ticagrelor final.pdf · Ticagrelor (n=9,333) Clopidogrel (n=9,291) Start of randomised treatment Time after start of chest pain,

SCRIPPS CLINIC

Ticagrelor: A New Chapter Opens

Matthew J. Price MDDirector, Cardiac Catheterization Laboratory, Scripps Clinic, La Jolla, California, USA

SCRIPPS CLINIC

Ticagrelor: Pharmacology

• Class: Cyclopentyl-triazolo-pyrimidine (CPTP)

• Mechanism: Direct inhibition of the P2Y12 receptor (no metabolic activation required).

• Onset of action: Rapid, maxreached at < 2 hrs

• Administration: Oral

• Plasma t½ ≈10-12 hours (bid drug)

O’Donoghue M, Wiviott SD. Circulation. 2006;114:e600-e606; Angiolillo DJ et al. Am J Cardiov Drugs. 2007.Teng, Eur J Clin Pharmacol 2010;66:487-496

SCRIPPS CLINIC

Ticagrelor Antagonizes the P2Y12 Receptor Non-Competitively With ADPReceptor binding and concentration-response studies

Effect of Different Ligands on ADP-binding to the human P2Y12 receptor

Concentration-response curve for ADP in the presence of increasing [ticagrelor]

van Giezen JJ et al, J Thromb Haemost 2009; 7:1556-65

SCRIPPS CLINIC

C T C T0

100

200

300

400

500

Trough Peak

**** ****

235PRU

PLA

TELE

T R

EAC

TIO

N U

NIT

S (P

RU

)

PLATO PLATELET – VerifyNow P2Y12 Assay Results on Maintenance therapy with clopidogrel (C) vs ticagrelor (T)

Storey RF, Angiolillo DJ, et al. Presented at American Heart Association Nov 2009

SCRIPPS CLINICSCRIPPS CLINIC

N=34N=34

Subjects with CAD on aspirin

Gurbel et al, Circulation. 2010;121:1188-1199

*P< 0.0001‡ P

//

LastMaintenance

Dose

Loading Dose

Time (hours)Onset Maintenance Offset

100

90

80

70

60

50

40

30

20

10

0

IPA

%Ticagrelor (n=54)

Clopidogrel (n=50)

Placebo (n=12)

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

*

*

* **

**

*

*

‡

†

†

//

//

//20 µM ADP- Final Extent

ONSET/OFFSET Study: Platelet Recovery after Ticagrelor vs. Clopidogrel

Gurbel PA et al. Circulation 2010

PLATO – NSTE-ACS and STEMI (conservative/invasive)

PLATO Invasive

PLATO CABG – study drug d/c’d

PLATO study design

Primary endpoint: CV death + MI + Stroke Primary safety endpint: Total major bleeding

6–12-month exposure

ClopidogrelIf pre-treated, no additional loading dose;if naive, standard 300 mg loading dose,

then 75 mg qd maintenance;(additional 300 mg allowed pre PCI)

Ticagrelor180 mg loading dose, then

90 mg bid maintenance;(additional 90 mg pre-PCI)

NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)Clopidogrel-treated or -naive;

randomised within 24 hours of index event (N=18,624)

PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack

Baseline and index event characteristics

CharacteristicTicagrelor(n=9,333)

Clopidogrel(n=9,291)

Median age, years 62.0 62.0 Women, % 28.4 28.3

CV risk factors, %Habitual smokerHypertensionDyslipidaemiaDiabetes mellitus

36.065.846.624.9

35.765.146.725.1

History, %Myocardial Infarction Percutaneous coronary interventionCoronary-artery bypass grafting

20.413.65.7

20.713.16.2

ECG at entry, %Persistent ST-segment elevationST-segment depression

37.550.7

37.851.2

Troponin-I positive,* % 85.3 86.0

Study medication

MedicationTicagrelor(n=9,333)


Start of randomised treatment Time after start of chest pain, h, median 11.3 11.3

Randomised treatment compliance, %Premature discontinuation of study drug 23.4 21.5

Clopidogrel start-up, %Clopidogrel in hospital before randomisation 46.0 46.1

Invasive procedures at index hospitalisation, %Planned invasive treatment Coronary angiographyPCI during index hospitalisationCardiac surgery

72.181.460.94.3

71.9 81.561.14.7

K-M estimate of 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

Days after randomisation

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

K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

No. at risk

Clopidogrel

Ticagrelor

9,291

9,333

8,560

8,678

8,405

8,520

8,177


6,703

6,796

5,136

5,210

4,109

4,191

0 60 120 180 240 300 360

6

5

4

3

2

1

0

7

Cum

ulat

ive

inci

denc

e (%

)

Clopidogrel

Ticagrelor

5.8

6.9

8,279

HR 0.84 (95% CI 0.75–0.95), p=0.005

0 60 120 180 240 300 360

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

9,291

9,333

8,865

8,294

8,780

8,822

8,589


7079

7119

5,441

5,482

4,364

4,4198,626

Myocardial infarction Cardiovascular death

Cum

ulat

ive

inci

denc

e (%

)

Secondary efficacy endpoints over time

Time to major bleeding – primary safety event

No. at risk


9,1869,235

7,3057,246

6,9306,826

6,670

Days from first IP dose

5,2095,129

3,8413,783

3,4793,433

0 60 120 180 240 300 360

10

5

0

15

Clopidogrel

Ticagrelor11.2011.58

6,545

HR 1.04 (95% CI 0.95–1.13), p=0.434

K-M

est

imat

ed ra

te (%

per

yea

r)

Non-CABG and CABG-related major bleeding

p=0.026

p=0.025

NS

NS

9

K-M

est

imat

ed ra

te (

% p

er y

ear)

Non-CABGPLATO majorbleeding

8

7

6

5

4

3

2

1

0Non-CABGTIMI major bleeding

CABGPLATO major bleeding

CABG TIMI major bleeding

4.5

3.8

2.8

2.2

7.4

7.9

5.3

5.8

TicagrelorClopidogrel

Holter monitoring & Bradycardia related events

Holter monitoring at first weekTicagrelor(n=1,451)

Clopidogrel(n=1,415) p value

Ventricular pauses ≥3 seconds, % Ventricular pauses ≥5 seconds, %

5.82.0

3.61.2

0.010.10

Holter monitoring at 30 daysTicagrelor(n= 985)


Ventricular pauses ≥3 seconds, %Ventricular pauses ≥5 seconds, %

2.10.8

1.70.6

0.520.60

Bradycardia-related event, %Ticagrelor(n=9,235)


Pacemaker InsertionSyncopeBradycardiaHeart block

0.91.14.40.7

0.90.84.00.7

0.870.080.211.00

Other findings

All patientsTicagrelor(n=9,235)

Clopidogrel(n=9,186) p value*

Dyspnoea, %

Any

With discontinuation of study treatment

13.8

0.9

7.8

0.1

Other findings – laboratory parameters

All patientsTicagrelor(n=9,235)

Clopidogrel(n=9,186) p value*

% increase in creatinine from baselineAt 1 month At 12 months Follow-up visit

10 ± 2211 ± 2210 ± 22

8 ± 219 ± 22

10 ± 22


PLATO Invasive


InvasivePLATO INVASIVE: Procedures and timing*

ProcedureTicagrelor(n=6,732)


Invasive procedures at index hospitalization, % (n)Coronary angiography

Median (IQR), hours

PCI during index hospitalization % (n)Median (IQR), hours

UA/NSTEMI – PCI % (n)Median (IQR), hours

STEMI - Primary PCI % (n)Median (IQR), hours

Coronary by-pass surgery pre-discharge % (n)Median (IQR), hours

96.8 (6514)0.62 (0.10, 3.70)

76.7 (5166)0.77 (0.30, 2.75)

63.8 (1882)2.63 (0.78, 21.10)

83.2 (3138)0.47 (0.23, 0.95)

5.5 (372)117 (47, 216)

96.9 (6471)0.62 (0.12, 3.65)

77.1 (5148)0.78 (0.32, 2.65)

64.8 (1854)2.60 (0.87, 21.30)

82.7 (3149)0.48 (0.23, 0.95)

6.1 (410)121 (48, 218)

* Time between randomization and first procedure

InvasivePrimary endpoint: CV death, MI or stroke

00

5

10

15

60 120 180 240 300 360Days after randomization

K-M

est

imat

ed ra

te (%

per

yea

r)

HR: 0.84 (95% CI = 0.75–0.94), p=0.0025

9.02

10.65Clopidogrel

Ticagrelor

No. at risk


6,6766,732

6,1296,236

6,0346,134

5,881 4,8154,889

3,6803,735

2,9653,0485,972

K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

InvasivePrimary efficacy endpoint by clopidogrel loading dose

Ticagrelor better Clopidogrel better

0.5 1.0 2.00.2

Ti. Cl.TotalPatients

KM % atMonth 12

HR (95% CI)

Hazard Ratio(95% CI)

Clopidogrel loading dose (Pre-rand. + Study drug)

Characteristic

4091 8.0 9.5 0.83 (0.67, 1.03)600 mg9.5 11.2 0.85 (0.74, 0.96)300 mg

p value(Interaction)

0.917

9314

Invasive

No. at risk

Clopidogrel

Ticagrelor

6,676

6,732

6,157

6,268

6,062

6,173

5,917

Days after randomization

4,849

4,924

3,706

3,766

2,987

3,078

0 60 120 180 240 300 360

8

6

4

2

0

Cum

ulat

ive

inci

denc

e (%

)

Clopidogrel

Ticagrelor5.3

6.6

6,010

0 60 120 180 240 300 360

8

4

2

0

Clopidogrel

Ticagrelor3.4

4.3

6

6,676

6,732

6,376

6,439

6,332

6,375

6,209


5,114

5,141

3,917

3,591

3,164

3,2336,241

Myocardial infarction Cardiovascular death

Cum

ulat

ive

inci

denc

e (%

)

HR 0.80 (95% CI = 0.69–0.92), p=0.002 HR 0.82 (95% CI = 0.68–0.98), p=0.025

InvasiveAll-cause mortality

6

4

2

00 60 120 180 240 300 360

Clopidogrel

Ticagrelor


K-M

est

imat

ed ra

te (%

per

yea

r)

5.08

3.94

HR 0.81 (95% CI = 0.68–0.95), p=0.01

No. at risk

Clopidogrel

Ticagrelor

6,676

6,732

6,376

6,439

6,331

6,375

6,209 5,114

5,141

3,917

3,951

3,164

3,2336,241

InvasiveStent thrombosis

Ticagrelor(n=6,732)


HR for ticagrelor(95% CI)

p value*

Stent thrombosis, %

Definite

Probable or definite

Possible, probable, or definite

1.0

1.7

2.2

1.6

2.3

3.1

0.62 (0.45–0.85)

0.72 (0.56–0.93)

0.72 (0.58–0.90)

0.003

0.01

0.003

¶ Evaluated in patients with any stent during the studyTime-at-risk is calculated from the date of first stent insertion in the study or date of randomization* By univariate Cox model

Invasive

TicagrelorClopidogrel

NS

NS

NS

0K-M

est

imat

ed ra

te (%

per

yea

r)

PLATO major bleeding

1

2

3

4

5

6

7

8

9

10

12

11

13

TIMI major bleeding

11.5 11.6

8.0 8.0

2.93.2

GUSTO severe bleeding*

4.7

4.1

2.8 2.3

1.91.7

Non-CABG and CABG-related major bleeding

Non

-CAB

GC

ABG

*Preliminary – from eCRF


PLATO Invasive


Study drug ≤7 days before CABG

Patient disposition18,758 patients

enrolled in PLATO

134 patients not randomized

18,624 patients randomized

Non-CABG:16,725 patients

CABG: 1,899 patients

Last intake of study drug ≤7 days prior to

surgery: 1,261 patients

629 patients treated with clopidogrel

632 patients treated with ticagrelor


Primary endpoint: CV death, MI or stroke

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

14

13

12

11

10

9

8

7

6

5

4

3

2

1

0

Months from CABG procedure

HR: 0.84 (95% CI = 0.60–1.16), p=0.29

No. at risk


629629

541543

516519

448 386386

255268

125108458

13.1

10.6

Clopidogrel

Ticagrelor

K-M

est

imat

ed ra

te (%

)


CV death post-CABG

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

8

7

6

5

4

3

2

1

0

Months from CABG procedure

HR: 0.52 (95% CI = 0.32–0.85), p=0.009

No. at risk


629629

565583

539557

472 404415

269291

130119491

7.9

4.1

Clopidogrel

Ticagrelor

K-M

est

imat

ed ra

te (%

)


All cause mortality post-CABG

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

10

9

8

7

6

5

4

3

2

1

0629 583 557 491 415 291 119629 565 539 472 404 269 130

MonthsNo. at riskTicagrelorClopidogrel

Clopidogrel

Ticagrelor4.7

9.7

HR: 0.49 (95% CI 0.32–0.77), p


Safety: bleeding post-CABG


0.5 1.0 2.00.2

CABG-related bleeding

Characteristic

1.04 (0.83, 1.31)Life-threatening/fatal bleeding

1.07 (0.80, 1.43)Major bleeding

All intracranial bleeding post-CABG*

Fatal bleeding0.83 (0.20, 3.28)

1.01 (0.06, 16.09)

0.67

0.97 (0.73, 1.28)TIMI minor bleeding

1.08 (0.85, 1.36)TIMI major bleeding

GUSTO severe bleeding

43.7 42.6

81.2 80.1

0.8 1.0

0.2 0.2

21.0 21.6

59.3 57.6

10.6 12.2 0.85 (0.59, 1.22)

1.00

All event rates are number of events divided by n

*Hazard ratio Kaplan-Meier estimates. Both CABG-related and non-related

0.73

0.77

0.53

0.84

0.38

p-valueOdds Ratio (95% CI)Ticagrelor(n=631)

Clopidogrel(n=629)


Safety: bleeding post-CABG (cont’d)

Characteristic p value

Hemoglobin decrease*

1.12 (0.87, 1.43)>30 g/L

1.08 (0.86, 1.37)>50 g/L

Major/life-threatening CABG-related bleeding resulting in death within 7 days of CABG†

0.44 (0.19, 1.01)

Re-operation due to bleeding*

0.651.19 (0.63, 2.27)

0.52

0.40

0.05


0.5 1.0 2.00.2

*Odds ratio and p-value from Fisher’s exact test†Hazard ratioEvent rate is number of events divided by n

Hazard/Odds Ratio (95% CI)Ticagrelor(n=631)

Clopidogrel(n=629)

69.9 67.6

38.1 36.2

1.3 2.9

4.0 3.3


Summary

• Ticagrelor, a non-thienoypridine, is a non-competitive, reversible, P2Y12 receptor antagonist.

• In PLATO, ticagrelor significantly reduced CV death, MI, and stroke compared with clopidogrel in patients presenting with NSTE-ACS and STEMI.

• While non-CABG related bleeding was increased with ticagrelor, there was no increase in fatal bleeding or CABG-related bleeding.


Summary (2)

• Furthermore, in patients treated with a planned invasive strategy, ticagrelor provided significant ischemic benefit without an increase in all-cause major bleeding.

• The observed reduction in mortality in the overall trial, invasively-managed patients, and in patients undergoing CABG is provocative and requires further mechanistic evaluation.


A new chapter in antiplatelettherapy is on the horizon….

…thank you!

Ticagrelor: A New Chapter Openssummitmd.com/pdf/pdf/Ticagrelor final.pdf · Ticagrelor (n=9,333) Clopidogrel (n=9,291) Start of randomised treatment Time after start of chest pain,

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