PLATO: Study Population
ACS Patient
STEMI
Primary PCI
UA/NSTEMI
Initial Invasive
Management
Initial Non-Invasive
Management
No Reperf
PCI
PCI
Fibrinolytic Rx
No revascularisation
CABG
Only STEMI patients
intended for primary PCI
included
CABG
No revascularisation
Adapted from James S, et al. Am Heart J. 2009;157:599–605.
PLATO: Study Design
BRILIQUE (n=9,333)
180-mg loading dose
N=18,624
Patients with ACS
(UA, NSTEMI, or
STEMI*)
90 mg bid + ASA maintenance dose
Primary efficacy
endpoint:
Composite of CV
death, MI (excluding
silent MI), or stroke
• All patients were hospitalised with symptom onset <24 hours
• Patients could be taking clopidogrel at time of randomisation
300-mg loading dose†
75 mg qd + ASA maintenance dose
Primary safety
endpoint:
Total PLATO major
bleeding‡
Clopidogrel (n=9,291)
Randomisation
Screening
<24h
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Month 1
Month 3
Month 6
Month 9
Month 12
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.
*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.
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
Cumulative Incidence (%)
PLATO: Primary Efficacy Endpoint
(Composite of CV Death, MI, or Stroke)
13
12
11
10
9
8
7
6
5
4
3
2
1
0
0–30 Days
0–12 Months
11.7 Clopidogrel
9.8 BRILIQUE
Clopidogrel
5.4
4.8
BRILIQUE
ARR=0.6%
ARR=1.9%
RRR=12%
RRR=16%
P=0.045
NNT=54*
HR: 0.88 (95% CI, 0.77−1.00)
P<0.001
HR: 0.84 (95% CI, 0.77–0.92)
0
2
4
6
8
10
12
Months After Randomization
No. at risk
BRILIQUE
9,333
8,628
8,460
8,219
6,743
5,161
4,147
Clopidogrel
9,291
8,521
8,362
8,124
6,650
5,096
4,047
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
BRILIQUE
(n=9,333)
Clopidogrel
(n=9,291)
HR for BRILIQUE
(95% CI)
P Value**
864 (9.8)
1,014 (11.7)
0.84 (0.77–0.92)
<0.001
901 (10.2)
1,065 (12.3)
0.84 (0.77–0.92)
<0.001
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‡
All Patients*
Primary endpoint, n (%/year)
Death from vascular cause + MI† + stroke
Secondary endpoints, n (%/yr)
Death from any cause + MI† + stroke
Death from vascular causes + MI† + stroke
+ severe recurrent ischemia + recurrent
ischemia + TIA + arterial thrombus
Nominal
Significance
* 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
Cardiovascular Death
Myocardial Infarction
Clopidogrel
6
BRILIQUE
5
4
3
ARR=1.1%
2
RRR=16%
Calculated NNT=91
1
P=0.005
HR: 0.84 (95% CI, 0.75–0.95)
2
4
6
8
10
Months After Randomisation
7
5.8
6
Clopidogrel
12
4.0
4
BRILIQUE
3
ARR=1.1%
2
RRR=21%
NNT=91
1
P=0.001
HR: 0.79 (95% CI, 0.69–0.91)
0
2
4
6
8
10
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.
5.1
5
0
0
0
6.9
Cumulative Incidence (%)
Cumulative Incidence (%)
7
12
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
PLATO: Primary Safety Endpoint
PLATO-defined Total
Major Bleeding (%)
15
BRILIQUE
Clopidogrel
10
11.6%
11.2%
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
No. at risk
BRILIQUE
9,235
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
Both groups included aspirin.
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
P=NS
PLATO: Bleeding
P = 0.008
BRILIQUE (n=9,235)
K-M Estimated Rate (% Per Year)
18
Clopidogrel (n=9,186)
16.1
16
14
12
14.6
NS
11.6
11.2
NS
10
NS
8
P = 0.03
5.8
6
7.9
5.8
4.5
4
7.4
3.8
NS
2
0.3
0
Major Bleeding
0.3
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.
Major and
Minor Bleeding
Non-CABGMajor Bleeding
CABG-Major
Bleeding
PLATO: Dyspnoea
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
•
•
•
•
•
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
BRILIQUE
(n=9,235)
Clopidogrel
(n=9,186)
P Value
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
All Patients
Bradycardia-related event, n (%)
• 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
BRILIQUE
(n=9,235)
Clopidogrel
(n=9,186)
P Value
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
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
All Patients
Mean % increase (± SD) in serum creatinine from
baseline
Mean % increase (± SD) in serum uric acid from
baseline
• 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
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
By Diagnosis
•
By Treatment
UA/NSTEMI
STEMI
Medical
management
PCI
CABG





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 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
LOADING
Initial treatment: 180 mg
MAINTENANCE
Continue treatment: 90 mg twice daily
+
Aspirin: 75–150 mg once daily
Morning – Take one
Two 90-mg tablets
Initiate BRILIQUE with a
loading dose of aspirin.
•
•
•
BRILIQUE tablet
in the morning (AM)
Night – Take one
Take aspirin
(either in the
morning or night)
BRILIQUE tablet
in the evening (PM)
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
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.