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PLATO: Study Population. Only STEMI patients intended for primary PCI included. Adapted from James S, et al. Am Heart J. 2009;157:599–605. PLATO: Study Design. Primary efficacy endpoint: Composite of CV death, MI (excluding silent MI), or stroke. BRILIQUE (n=9,333). 180-mg loading dose.

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Plato study population

PLATO: Study Population

Only STEMI patients intended for primary PCI included

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


Plato study design

PLATO: Study Design

Primary efficacy endpoint:

Composite of CV death, MI (excluding silent MI), or stroke

BRILIQUE (n=9,333)

180-mg loading dose

90 mg bid + ASA maintenance dose

• All patients were hospitalised with symptom onset <24 hours

• Patients could be taking clopidogrel at time of randomisation

N=18,624

Patients with ACS(UA, NSTEMI, or STEMI*)

Primary safety endpoint:

Total PLATO major bleeding‡

300-mg loading dose†

75 mg qd + ASA maintenance dose

Clopidogrel (n=9,291)

Randomisation

Visit 2

Visit 3

Visit 4

Visit 5

Visit 6

Screening

<24h

Month 1

Month 3

Month 6

Month 9

Month 12

*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.

  • 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.


Plato main inclusion criteria

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

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

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.


Plato study population

Efficacy Results


Plato primary efficacy endpoint composite of cv death mi or stroke

PLATO: Primary Efficacy Endpoint(Composite of CV Death, MI, or Stroke)

8,628

8,460

8,219

6,743

5,161

4,147

8,521

8,362

8,124

6,650

5,096

4,047

0–30 Days

0–12 Months

13

12

11.7

Clopidogrel

11

10

BRILIQUE

9.8

9

Clopidogrel

8

5.4

7

Cumulative Incidence (%)

6

5

ARR=1.9%

RRR=16%

NNT=54*

P<0.001

HR: 0.84 (95% CI, 0.77–0.92)

ARR=0.6%

RRR=12%

P=0.045

HR: 0.88 (95% CI, 0.77−1.00)

4

4.8

3

BRILIQUE

2

1

0

0

2

4

6

8

10

12

No. at risk

Months After Randomization

9,333

BRILIQUE

Clopidogrel

9,291

Both groups included aspirin.

*NNT at one year.

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


Plato predefined testing of primary and major secondary efficacy endpoints

PLATO: Predefined Testing of Primary and Major Secondary Efficacy Endpoints

*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.

Both groups included aspirin.

The percentages presented are Kaplan-Meier estimates of the rate of the endpoint at 12 months.

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


Plato secondary efficacy endpoints

PLATO: Secondary Efficacy Endpoints

Cardiovascular Death

Myocardial Infarction

6.9

7

7

Clopidogrel

6

6

5.8

Clopidogrel

5.1

BRILIQUE

5

5

4.0

4

4

Cumulative Incidence (%)

Cumulative Incidence (%)

BRILIQUE

3

3

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)

2

2

1

1

0

0

0

2

4

6

8

10

12

0

2

4

6

8

10

12

Months After Randomisation

Months After Randomisation

Rate of stroke for BRILIQUE was not different from clopidogrel (1.3% vs 1.1% ), P=0.225.

Both groups included aspirin.

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.


Plato efficacy results

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.


Plato study population

Safety Results


Plato primary safety endpoint

PLATO: Primary Safety Endpoint

No. at risk

9,235

BRILIQUE

7,246

6,826

6,545

5,129

3,783

3,433

Clopidogrel

9,186

7,305

6,930

6,670

5,209

3,841

3,479

15

BRILIQUE

11.6%

P=NS

11.2%

Clopidogrel

10

PLATO-defined Total Major Bleeding (%)

5

P=0.43

HR: 1.04 (95% CI, 0.95–1.13)

0

0

60

120

180

240

300

360

Days From First Dose

Both groups included aspirin.

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


Plato bleeding

PLATO: Bleeding

P = 0.008

NS

NS

K-M Estimated Rate (% Per Year)

NS

P = 0.03

NS

CABG-Major Bleeding

Non-CABG-Major Bleeding

Major and Minor Bleeding

Major Bleeding

Life-threatening/Fatal Bleeding

Fatal Bleeding

All values presented by PLATO criteria. Both groups included aspirin.

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


Plato dyspnoea

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.


Plato bradycardia related events

PLATO: Bradycardia-related Events

  • Ventricular pauses ≥3 seconds occurred in 5.8% of BRILIQUE-treated patients vs3.6% 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

PLATO: Laboratory Parameters

  • 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

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

BRILIQUE: Summary of Product Characteristics, 2010.


Plato safety results

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 BRILIQUEvsclopidogrel

  • 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

Appropriate Use of BRILIQUE


Brilique indication

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)

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

BRILIQUE: Summary of Product Characteristics, 2010.


Contraindications

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

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

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

LOADING

MAINTENANCE

Initial treatment: 180 mg

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

Morning – Take one

BRILIQUE tablet

in the morning (AM)

Take aspirin

Two 90-mg tablets

(either in themorning or night)

Night – Take one

Initiate BRILIQUE with a loading dose of aspirin.

BRILIQUE tablet

in the evening (PM)

BRILIQUE: Summary of Product Characteristics, 2010.


Clinical summary of brilique based on plato

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 BRILIQUEvs clopidogrel

    • Non-CABG-Major bleeding was more common with BRILIQUEvs 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.


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