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.
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.
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.
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.