Naotsugu Oyama, MD, PhD, MBA

A Trial of

PLATelet inhibition and Patient Outcomes

Presentation Objectives

• To share the scientific evidence in the PLATO trial, related to the efficacy of ticagrelor, in the treatment of a broad spectrum of ACS patients

• To review the safety profile of ticagrelor to

facilitate effective management of your ACS patients

PLATO Study

PLATO Study: • 43 countries• 862 sites• 18,624 patients• 78 Filipino participants

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 clopidogrel and this would be achieved with a clinically acceptable bleeding rate and overall safety profile

18,624 patients

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

• Philippine Heart Center• Philippine General Hospital• The Medical City• St. Lukes Medical Center• Perpetual Succour Hospital• Cebu Doctors University

Hospital• Davao Doctors Hospital

PLATO: Study Population

ACS Patient

STEMI

Primary PCI

No Reperf

Fibrinolytic Rx

UA/NSTEMI

Initial Invasive Management

PCI

No revascularization

CABG

Initial Non-Invasive Management

PCI

CABG

No revascularizationOnly 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.

Randomization

• All patients were hospitalized with symptom onset <24 hours• Patients could be taking clopidogrel at time of randomization

PLATO: Study Design

PLATO Study: Summary

• PLATO (N Engl J Med. 2009;361:1045–1057) was a pivotal clinical study, comparing ticagrelor to the current standard of care, clopidogrel.

• A total of 18,624 patients with ACS were randomised early after admission to the hospital─within 24 hours of symptom onset and generally prior to angiography.

Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.James S, et al. Am Heart J. 2009;157:599–605.Cannon CP, et al. Lancet. 2010;375:283–293.

PLATO Study: Summary

• The study was designed to reflect clinical practice:– Allowed prior clopidogrel use– Included both intent for invasive management (72%)

and intent for medical management (28%)– PLATO allowed up to 600-mg clopidogrel loading dose

pre-PCI

• PLATO enrolled a broad spectrum of patients with ACS (UA, NSTEMI, or STEMI).

Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.James S, et al. Am Heart J. 2009;157:599–605.Cannon CP, et al. Lancet. 2010;375:283–293.

Efficacy Results

PLATO: Baseline CharacteristicsCharacteristic Ticagrelor

(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

13

Cum

ulat

ive

Inci

denc

e (%

) 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

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 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.TICAGRELOR: Summary of Product Characteristics, 2010.

ARR=1.1%RRR=16%

Calculated NNT=91P=0.005

HR: 0.84 (95% CI, 0.75–0.95)

ARR=1.1%RRR=21%NNT=91P=0.001

HR: 0.79 (95% CI, 0.69–0.91)

Both groups included aspirin.

PLATO: Invasive and Non-invasive management

Patient presents with ACS(n=18,624)

Invasive treatment(n=15,991)

Intent for invasive treatment(n=13,408)

Non-invasive management(n=3033)

Intent for non-invasive management

(n=5216)

Initial investigator intent (as per clinical practice)

James S, et al. BMJ 2011;342:d3527.

Change in circumstances

(n=2183)

CV

deat

h, M

I or s

trok

e (%

)Non-invasive

HR, 0.85, 95% CI: (0.73–1.0)

InvasiveHR, 0.84, 95% CI: (0.75–0.94)

Number at risk:Invasive

Ticagrelor 6732 6236 6134 5972 4889 3735 3048Clopidogrel 6676 6129 6034 5881 4815 3680 2965

Non-invasiveTicagrelor 2601 2392 2326 2247 1854 1426 1099Clopidogrel 2615 2392 2328 2243 1835 1416 1109

Days after randomization

Primary Outcome: Invasive and Non-Invasive

James S, et al. BMJ 2011;342:d3527.

PLATO Efficacy Results

Summary• In PLATO, 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.TICAGRELOR: Summary of Product Characteristics, 2010.Supplement to: 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.

• In PLATO, 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.TICAGRELOR: Summary of Product Characteristics, 2010.Supplement to: Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

Safety Results

P=0.43HR: 1.04 (95% CI, 0.95–1.13)

PLATO: Primary Safety EndpointPL

ATO

-def

ined

Tot

al

Maj

or 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: Bleeding

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 Safety Results

Summary• No increase in overall PLATO-defined 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.• There are more dyspnea-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.TICAGRELOR: Summary of Product Characteristics, 2010.

PLATO Safety Results

Summary• Ticagrelor should be used with caution in patients at risk

of bradycardic events.

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

• Please reference the label for all precautions and warnings.

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

Clinical Summary of Ticagrelor Based on PLATO

• Ticagrelor significantly reduces the combined risk of CV death, MI, or stroke vs clopidogrel in patients with ACS.

• Ticagrelor significantly reduced CV mortality vs clopidogrel.

• The absolute risk reduction with ticagrelor vs clopidogrel starts early and continues to build over the full 1 year of treatment.

• Ticagrelor is effective in a broad spectrum of ACS patients.

TICAGRELOR: Summary of Product Characteristics, 2010.

Clinical Summary of Ticagrelor Based on PLATO

• There is no increase of overall major bleeding with ticagrelor vs clopidogrel:– No increase in life-threatening/fatal bleeding with ticagrelor vs

clopidogrel– Major and minor bleeding was more common with ticagrelor vs

clopidogrel– Non-CABG-Major bleeding was more common with ticagrelor vs

clopidogrel

• There are more dyspnea-related events associated with ticagrelor vs clopidogrel, however most events were mild to moderate in intensity and often resolved without a need for treatment.

TICAGRELOR: Summary of Product Characteristics, 2010.

Thank You