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 revascularisation

Only STEMI patients intended for primary PCI

included

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

180-mg loading dose

BRILIQUE (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

• 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.

PLATO Study

Summary• PLATO (N Engl J Med. 2009;361:1045–1057) was a pivotal clinical

study, comparing BRILIQUE to 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

• 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

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

BRILIQUE

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 BRILIQUE

ARR=0.6%

RRR=12%

P=0.045

HR: 0.88 (95% CI, 0.77−1.00)

0–30 Days

4.8

5.4Clopidogrel

BRILIQUE

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*BRILIQUE (n=9,333)

Clopidogrel (n=9,291)

HR for BRILIQUE (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

Cu

mu

lati

ve I

nci

de

nce

(%

)

Clopidogrel

BRILIQUE

5.8

6.9

0 2 4 6 8 10 12

6

4

3

2

1

0

Clopidogrel

BRILIQUE

4.0

5.1

7

5

Months After Randomisation

Myocardial Infarction Cardiovascular Death

Cu

mu

lati

ve I

nci

de

nce

(%

)

PLATO: Secondary Efficacy Endpoints

Rate of stroke for BRILIQUE 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.

PLATO Efficacy Results

Summary• In PLATO, BRILIQUE 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)

• BRILIQUE 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

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

• In PLATO, for every 91 ACS patients treated with BRILIQUE for 1 year, instead of clopidogrel, 1 CV death was prevented (NNT=91)

• The effect of BRILIQUE over clopidogrel appears consistent across many subgroups

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

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

BRILIQUE

11.2%11.6%

P=NS

No. at risk

Clopidogrel

BRILIQUE

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.

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

18BRILIQUE (n=9,235)

Clopidogrel (n=9,186)

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

ima

ted

Rat

e (%

Per

Yea

r)

NS

P = 0.03

P = 0.008

NS

NS

NS

PLATO: Dyspnoea

• BRILIQUE-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• In 2.2% of patients, investigators considered dyspnoea causally related to treatment

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

and COPD

BRILIQUE: 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.

Dyspnoea in the PLATO trial BRILIQUE 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 PatientsBRILIQUE (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 BRILIQUE-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: BRILIQUE should be used with caution in patients at risk of bradycardic events

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

PLATO: Laboratory Parameters

All PatientsBRILIQUE (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.BRILIQUE: Summary of Product Characteristics, 2010.

• Creatinine levels may increase during treatment with BRILIQUE; 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 BRILIQUE in patients with uric acid nephropathy is discouraged

PLATO Safety Results

Summary• No increase in overall major bleeding with BRILIQUE vs clopidogrel• Non-CABG major bleeding and major + minor bleeding were more frequent

with BRILIQUE vs clopidogrel• No increase in overall fatal/life-threatening bleeding with BRILIQUE vs

clopidogrel• There are more dyspnoea-related events associated with BRILIQUE vs

clopidogrel, however most events were mild to moderate in intensity and often resolved without a need for treatment

• BRILIQUE should be used with caution in patients at risk of bradycardic events

• Creatinine levels may increase during treatment with BRILIQUE; 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.BRILIQUE: Summary of Product Characteristics, 2010.

Appropriate Use of BRILIQUE

BRILIQUE Indication

• BRILIQUE, 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)

BRILIQUE: Summary of Product Characteristics, 2010.

By Diagnosis By Treatment

UA/NSTEMI STEMI Medicalmanagement PCI CABG

If clinically indicated, BRILIQUE 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 BRILIQUE dosing

Contraindications

• Contraindications specific to BRILIQUE– Hypersensitivity to the active substance (BRILIQUE) or to any of

the excipients– Active pathological bleeding– History of intracranial haemorrhage– Moderate-to-severe hepatic impairment– Combination with strong CYP3A4 inhibitors such as

ketoconazole, clarithromycin, nefazodone, ritonavir and atazanavir is contraindicated, as co-administration may lead to substantial increases in exposure to BRILIQUE

BRILIQUE: Summary of Product Characteristics, 2010.

Special Warnings and Precautions

• Precautions specific to BRILIQUE– The use of BRILIQUE in patients at known increased risk for bleeding should be

balanced against the benefits– BRILIQUE should be discontinued 7 days prior to elective surgery– BRILIQUE should be used with caution in patients with a history of asthma

and/or COPD– BRILIQUE should be used with caution in patients at risk of bradycardic events– BRILIQUE 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 BRILIQUE dosing

– As a precautionary measure, the use of BRILIQUE in patients with uric acid nephropathy is discouraged

– Creatinine levels may increase during treatment with BRILIQUE – Renal function should be checked after 1 month and thereafter according to

routine medical practice– High maintenance dose of ASA (>300 mg) is not recommended– The concomitant use of BRILIQUE with doses of simvastatin >40 mg is not

recommended

BRILIQUE: Summary of Product Characteristics, 2010.

Dosing and Administration

• BRILIQUE treatment should be initiated with a single 180-mg loading dose (two 90-mg tablets) and then continued at 90 mg twice daily with concomitant low dose ASA

• Treatment with BRILIQUE is recommended for up to 12 months unless discontinuation is clinically indicated

• BRILIQUE can be administered with or without food

Initial treatment: 180 mg

Morning – Take one

LOADING

Continue treatment: 90 mg twice daily + Aspirin: 75–150 mg once daily

MAINTENANCE

Two 90-mg tablets

Initiate BRILIQUE with a loading dose of aspirin.

BRILIQUE tablet in the morning (AM)

Night – Take one

BRILIQUE tablet in the evening (PM)

Take aspirin(either in themorning or night)

BRILIQUE: Summary of Product Characteristics, 2010.

Clinical Summary of BRILIQUE Based on PLATO

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

• BRILIQUE significantly reduces CV mortality vs clopidogrel• The absolute risk reduction with BRILIQUE vs clopidogrel starts early and

continues to build over the full 1 year of treatment• BRILIQUE is effective in a broad spectrum of ACS patients• There is no increase of overall major bleeding with BRILIQUE vs clopidogrel

– No increase in life-threatening/fatal bleeding with BRILIQUE vs clopidogrel– Major and minor bleeding was more common with BRILIQUE vs clopidogrel– Non-CABG-Major bleeding was more common with BRILIQUE vs clopidogrel

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

BRILIQUE: Summary of Product Characteristics, 2010.