1. Title:
PLATO
Key Points:
This slide is a transition between the previous “Unmet Need and BRILINTA Clinical Pharmacology” section and the upcoming “PLATO: Trial Design, Efficacy and Safety Results” section
Additional Information:
N/A
References:

2. 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
Title:
PLATO: Study Population
Key Points:
PLATO was designed to reflect current clinical practice
PLATO randomized
A broad spectrum of patients with ACS, based on initial presentation, and ECG within 24 hours
Unstable Angina, NSTEMI or STEMI
Both invasive or non-invasively managed patients at the time treatment was planned, regardless of whether or not it was performed
Among STEMI patients, only those intended for primary PCI were included
In PLATO, patients randomised prior to angiography and elucidation of coronary anatomy
Additional Information:
For patients who had ACS without ST-segment elevation, at least 2 of the following 3 criteria had to be met: ST-segment changes on ECG, indicating ischaemia; a positive test of a biomarker, indicating myocardial necrosis; or one of several risk factors (age ≥60 years; previous MI or CABG; coronary artery disease with stenosis of ≥50% in at least 2 vessels; previous ischaemic stroke, TIA, carotid stenosis of at least 50%, or cerebral revascularisation; DM; PAD; or chronic renal dysfunction, defined as a creatinine clearance of <60 mL per minute per 1.73 m2 of body surface area)
For patients who had ACS with ST-segment elevation, the following 2 inclusion criteria had to be met: persistent ST-segment elevation of at least 0.1 mV in at least 2 contiguous leads or a new left bundle-branch block, and the intention to perform primary PCI
Major exclusion criteria were any contraindication against the use of clopidogrel, fibrinolytic therapy within 24 hours before randomisation, a need for oral anticoagulation therapy, an increased risk of bradycardia, and concomitant therapy with a strong cytochrome P-450 3A inhibitor or inducer
References:
James S, Akerblom A, Cannon CP, et al. Comparison of ticagrelor, the first reversible oral P2Y12 receptor antagonist, with clopidogrel in patients with acute coronary syndromes: rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial. Am Heart J. 2009;157:599–605.
Wallentin L, Becker RC, Bujah A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057.
Only STEMI patients intended for primary PCI included
Adapted from James S, et al. Am Heart J. 2009;157:599–605. 2

3. Patients with ACS (UA, NSTEMI, or STEMI*)
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
N=18,624
Patients with ACS (UA, NSTEMI, or STEMI*)
• All patients were hospitalised with symptom onset <24 hours
• Patients could be taking clopidogrel at time of randomisation
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
Title:
PLATO: Study Design
Key Points:
BRILIQUE was investigated in the landmark PLATO study that recruited 18,624 patients from 862 centers in 43 countries from October 2006 through July 20081
PLATO was designed to reflect clinical practice in ACS by2
Including a broad spectrum of ACS patients and treatment plans and following them for up to 1 year
Allowing prior clopidogrel use1
Including both intent for invasive management (72%) and intent for medical management (28%)3
Allowing up to a 600-mg clopidogrel loading dose pre-PCI3
The primary efficacy endpoint was a composite of CV death, MI (excluding silent MI), and stroke
The primary safety endpoint was Total PLATO major bleeding
The PLATO study expanded the definition of major bleeding to be more inclusive compared with previous studies in ACS patients
Additional Information:
A total of 18,624 patients were included who presented within 24 hours of onset of UA, NSTEMI, or STEMI symptoms and were randomised prior to available laboratory or coronary anatomy results1
Patients could be treated non-invasively or invasively with PCI or CABG, and were randomised at the time of treatment planning1
Patients treated with clopidogrel prior to enrollment were included, and a clopidogrel loading dose of 300 mg was permitted in patients not previously treated with clopidogrel, with an additional 300 mg permitted at the discretion of the investigator3
References:
Wallentin L, Becker RC, Bujah A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057.
James S, Akerblom A, Cannon CP, et al. Comparison of ticagrelor, the first reversible oral P2Y12 receptor antagonist, with clopidogrel in patients with acute coronary syndromes: rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial. Am Heart J. 2009;157:599–605.
Cannon CP, Harrington RA, James S, et al. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study. Lancet. 2010;375:283–293.
Screening
<24h
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%)
*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.
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
James S, et al. Am Heart J. 2009;157:599–605.

4. 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)
Title:
PLATO Main: Inclusion Criteria
Key Points:
The inclusion criteria were chosen to be reflective of clinical practice and similar to the CURE study
The short time window for inclusion (within 24 hours) and the requirement of additional risk factors for inclusion if a patient did not have both ST-segment deviation and cardiac biomarker elevation excluded patients with the lowest risk of recurrent events from the population. Therefore, the study included those patients most likely to benefit from antiplatelet therapy
Additional Information:
N/A
Reference:
James S, Akerblom A, Cannon CP, et al. Comparison of ticagrelor, the first reversible oral P2Y12 receptor antagonist, with clopidogrel in patients with acute coronary syndromes: rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial. Am Heart J. 2009;157:599–605.
James S, et al. Am Heart J. 2009;157:599–605.

5. 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
Title:
PLATO Main: Key Exclusion Criteria
Key Points:
The PLATO study exclusion criteria sought to enroll a typical ACS population
Patients with ST-segment elevation ACS treated with fibrinolysis were excluded because of the lack of safety data with this combination of treatments
As a result of data seen in a phase II trial (DISPERSE2), patients with increased risk for bradycardic events due to sinus pauses were excluded
Due to drug-drug interaction (DDI) data from clinical pharmacology studies, patients requiring concomitant therapy with strong CYP3A inhibitors/inducers were excluded
Patients requiring dialysis were excluded because of the lack of clinical data in this patient population
Additional Information:
N/A
Reference:
James S, Akerblom A, Cannon CP, et al. Comparison of ticagrelor, the first reversible oral P2Y12 receptor antagonist, with clopidogrel in patients with acute coronary syndromes: rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial. Am Heart J. 2009;157:599–605.
James S, et al. Am Heart J. 2009;157:599–605.

6. 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)
Title
PLATO Study
Key Points:
To summarize the PLATO study design
PLATO (N Engl J Med. 2009;361:1045–1057) was a pivotal clinical study, comparing BRILIQUE 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
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)
Additional Information:
N/A
References:
Wallentin L, Becker RC, Bujah A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057.
James S, Akerblom A, Cannon CP, et al. Comparison of ticagrelor, the first reversible oral P2Y12 receptor antagonist, with clopidogrel in patients with acute coronary syndromes: rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial. Am Heart J. 2009;157:599–605.
Cannon CP, Harrington RA, James S, et al. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study. Lancet. 2010;375:283–293.
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.

7. Efficacy Results Title: PLATO Efficacy Results Key Points:
The following section of the presentation will consist of the baseline characteristics of the PLATO study population and the primary and secondary efficacy endpoints
Additional Information:
N/A
References:

8. Cumulative Incidence (%) Months After Randomization
PLATO: Primary Efficacy Endpoint (Composite of CV Death, MI, or Stroke)
0–30 Days
0–12 Months 13 12
11.7
Clopidogrel 11 10
9.8
BRILIQUE 9
Clopidogrel 8
5.4 7
Cumulative Incidence (%) 6 5
ARR=0.6%
RRR=12%
P=0.045
HR: 0.88 (95% CI, 0.77−1.00)
ARR=1.9%
RRR=16%
NNT=54*
P<0.001
HR: 0.84 (95% CI, 0.77–0.92) 4
4.8 3
BRILIQUE 2
Title:
PLATO: Primary Efficacy Endpoint (Composite of CV Death, MI, or Stroke)
Key Points:
BRILIQUE significantly reduces the combined risk of CV death, MI, or stroke vs clopidogrel in patients with ACS
The absolute risk reduction of BRILIQUE over clopidogrel starts early and continues to build over the full 1-year treatment regimen
BRILIQUE provided benefits in the critical early period of risk. Importantly, the benefits were consistent over time
The Kaplan-Meier curves continued to diverge up to 12 months, demonstrating a benefit beyond the acute phase
Additional Information:
In the PLATO study, BRILIQUE significantly decreased the rate of the combined endpoint of CV death, MI, and stroke in ACS patients with UA, NSTEMI, or STEMI who were medically or invasively managed1,2
The difference in treatments was driven by reduced risk of CV death and MI, with no significant difference in the rate of stroke3
In the first 30 days, an absolute risk reduction of 0.6% (P=0.045) was seen with BRILIQUE as compared to clopidogrel, with a hazard ratio of 0.88 (95% CI, 0.77–1.00)
Improvement in the absolute risk reduction continued over the full 12 months (ARR: 1.9%, P<0.001) and was seen with BRILIQUE as compared to clopidogrel (HR: 0.84 [95% CI, 0.77–0.92])
In the PLATO trial, for every 54 ACS patients treated with BRILIQUE instead of clopidogrel one atherothrombotic event (NNT=54) was prevented
References:
Wallentin L, Becker RC, Bujah A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057.
Supplement to: Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057.
BRILIQUE: Summary of Product Characteristics, 2010. 1 2 4 6 8 10 12
Months After Randomization
No. at risk
Clopidogrel
BRILIQUE
9,291
9,333
8,521
8,628
8,362
8,460
8,124
6,650
6,743
5,096
5,161
4,047
4,147
8,219
Both groups included aspirin.
*NNT at one year.
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

9. <0.001‡ Nominal Significance
PLATO: Predefined Testing of Primary and Major Secondary Efficacy Endpoints
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)
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)
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
Title:
PLATO: Predefined Testing of Primary and Major Secondary Efficacy Endpoints
Key Points:
BRILIQUE significantly decreased the rate of the primary efficacy endpoint of CV death, MI, and stroke in ACS patients with UA, NSTEMI, or STEMI who were medically or invasively managed1,2
The difference in treatments was driven by reduced risk of CV death and MI, with no significant difference in the rate of stroke1
Similar to the primary efficacy endpoint, BRILIQUE also significantly decreased the rate of the following secondary efficacy endpoints1:
Death from any cause + MI (excluding silent MI) + stroke
Death from vascular causes + MI (excluding silent MI) + stroke + severe recurrent ischaemia + recurrent ischaemia + TIA + arterial thrombus
MI (excluding silent MI)
Death from vascular causes
There was no significant difference in the rate of stroke between BRILIQUE and clopidogrel1
Due to statistical hierarchical testing, which is defined as, formal statistical testing performed in sequence until first nonsignificant result was observed; the P-value for the secondary endpoint of “Death from any cause” has only nominal significance1
Additional Information:
To address the issue of multiple testing, a hierarchical test sequence was conducted in which the secondary composite efficacy endpoints were tested individually, in the order in which they are listed on the slide, until the first nonsignificant difference was found between the 2 treatment groups1
References:
Wallentin L, Becker RC, Bujah A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057.
BRILIQUE: Summary of Product Characteristics, 2010.
Plavix® (clopidogrel bisulfate) Prescribing Information. Sanofi-aventis U.S. LLC. Revised March 2010.
* 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.

10. PLATO: Secondary Efficacy Endpoints
Myocardial Infarction
Cardiovascular Death 7
6.9
Clopidogrel 7 6
5.8 6
Clopidogrel
5.1 5
BRILIQUE 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
Title:
PLATO: Secondary Efficacy Endpoints
Key Points:
BRILIQUE significantly reduced the risk of MI (excluding silent MI) vs clopidogrel1
BRILIQUE is the first oral antiplatelet to reduce CV death vs clopidogrel in a broad ACS patient population (UA, NSTEMI, STEMI) for up to 52 weeks1
Rate of stroke for BRILIQUE was not different from clopidogrel (1.3% vs 1.1% ), P=0.225
Additional Information:
In the PLATO trial, for every 91 ACS patients treated with BRILIQUE instead of clopidogrel, 1 CV death was prevented; NNT=913
In the PLATO trial, for every 91 ACS patients treated with BRILIQUE instead of clopidogrel, 1 MI was prevented; calculated NNT=91
NNT = 1/ARR
References:
Wallentin L, Becker RC, Bujah A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057.
Plavix® (clopidogrel bisulfate) Prescribing Information. Sanofi-aventis U.S. LLC. Revised March 2010.
BRILIQUE: Summary of Product Characteristics, 2010. 2 4 6 8 10 12 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.

11. 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
Title:
PLATO Efficacy Results
Key Points:
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)1,2
BRILIQUE significantly reduced CV mortality vs clopidogrel (1.1% ARR, 21% RRR, P=0.001)1
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 period1
In PLATO, for every 91 ACS patients treated with BRILIQUE for 1 year, instead of clopidogrel, 1 CV death was prevented (NNT=91)2
The effect of BRILIQUE over clopidogrel appears consistent across many subgroups1,3
Additional Information:
N/A
References:
Wallentin L, Becker RC, Bujah A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057.
BRILIQUE: Summary of Product Characteristics, 2010.
Supplement to: Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057.
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.

12. Safety Results Title: PLATO Safety Results Key Points:
The following section of the presentation will consist of the primary and secondary safety endpoints of the PLATO trial
Additional Information:
N/A
References:

13. PLATO: Primary Safety Endpoint15
BRILIQUE
11.6%
P=NS
11.2% 10
Clopidogrel
PLATO-defined Total Major Bleeding (%) 5
P=0.43
HR: 1.04 (95% CI, 0.95–1.13)
Title:
PLATO: Primary Safety Endpoint
Key Points:
There was no significant difference in the rates of PLATO-defined Total Major Bleeding, despite the increased efficacy of BRILIQUE vs clopidogrel1
Additional Information:
The PLATO study expanded bleeding definitions from previous trials in patients with ACS. In the PLATO study, total major bleeding was more inclusive than in previous studies of ACS patients because it included bleeding that led to clinically significant disability (eg, intraocular bleeding with permanent vision loss) or bleeding either associated with a drop in hemoglobin levels of ≥3 g/dL or requiring transfusion of 2 to 3 units of red cells1,2
References:
Wallentin L, Becker RC, Bujah A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057.
James S, Akerblom A, Cannon CP, et al. Comparison of ticagrelor, the first reversible oral P2Y12 receptor antagonist, with clopidogrel in patients with acute coronary syndromes: rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial. Am Heart J. 2009;157:599–605. 60
120
180
240
300
360
Days From First Dose
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
3,433
6,545
Both groups included aspirin.
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

14. PLATO: Bleeding P = 0.008 NS K-M Estimated Rate (% Per Year) NS NS
Title:
PLATO: Bleeding
Key Points:
There were no significant differences in Major Bleeding, Life-threatening/Fatal bleeding, Fatal Bleeding or CABG-Major Bleeding events with BRILIQUE vs clopidogrel in the PLATO trial1
However, there was a significant increase in risk of non-CABG Major bleeding with BRILIQUE vs clopidogrel1
There was also a significant increase in Major and Minor Bleeding with BRILIQUE vs clopidogrel1
Minor bleeding was defined as: requires medical intervention to stop or treat bleeding
Additional Information:
The PLATO study expanded bleeding definitions from previous trials in patients with ACS. In the PLATO study, total major bleeding was more inclusive than in previous studies of ACS patients because it included bleeding that led to clinically significant disability (eg, intraocular bleeding with permanent vision loss) or bleeding either associated with a drop in hemoglobin levels of
≥3 g/dL or requiring transfusion of 2 to 3 units of red cells2
References:
Wallentin L, Becker RC, Bujah A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057.
BRILIQUE: Summary of Product Characteristics, 2010. NS
Major Bleeding
Life-threatening/ Fatal Bleeding
Fatal Bleeding
Major and Minor Bleeding
Non-CABG-Major Bleeding
CABG-Major Bleeding
All values presented by PLATO criteria. Both groups included aspirin.
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

15. 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
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
Title:
PLATO: Dyspnoea
Key Points:
The PLATO trial showed more dyspnoea-related adverse events associated with BRILIQUE compared with clopidogrel1,2
There were more dyspnoea-related drug discontinuations in patients taking BRILIQUE (0.9%) than in those taking clopidogrel (0.1%)1,2
Most of the dyspnoea-related adverse events (AEs) were mild to moderate in intensity and resolved without a need for treatment1,2
Most events were reported as a single episode occurring early after starting treatment1
The data from PLATO do not suggest that the higher frequency of dyspnoea with BRILIQUE is due to new or worsening heart or lung disease1
Additional Information:
In 2.2% of patients taking ticagrelor and in 0.6% taking clopidogrel, investigators considered the dyspnoea causally related to treatment in the PLATO study and few were serious (0.14% ticagrelor; 0.02% clopidogrel)1
The mechanism for the increased incidence of dyspnoea has not yet been determined1
References:
BRILIQUE: Summary of Product Characteristics, 2010.
Wallentin L, Becker RC, Bujah A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057.
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.

16. PLATO: Bradycardia-related Events
All Patients
BRILIQUE (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
Title:
PLATO: Bradycardia-related Events
Key Points:
There were no differences in adverse clinical consequences, ie, pacemaker insertion, syncope, bradycardia and heart block between BRILIQUE and clopidogrel in the PLATO trial1
Additional Information:
Due to observations of mostly asymptomatic ventricular pauses in an earlier clinical study, patients with an increased risk of bradycardic events (eg, patients without a pacemaker who have sick sinus syndrome, 2nd or 3rd degree AV block or bradycardic-related syncope) were excluded from the main PLATO study evaluating the safety and efficacy of BRILIQUE. Therefore, due to the limited clinical experience, BRILIQUE should be used with caution in these patients2
References:
Wallentin L, Becker RC, Bujah A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057.
BRILIQUE: Summary of Product Characteristics, 2010.
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.

17. PLATO: Laboratory Parameters
All Patients
BRILIQUE (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
1 month after end of treatment
0.59
Mean % increase (± SD) in serum uric acid from baseline
14 ± 46
7 ± 44
15 ± 52
7 ± 31
7 ± 43
8 ± 48
0.56
Title:
PLATO: Laboratory Parameters
Key Points:
Serum creatinine increases reversed after treatment was stopped and there was no difference in frequency of AEs and clinical sequelae1,2
The same was true with the serum uric acid increases, as they reversed after treatment was stopped and there was no difference in frequency of AEs and clinical sequelae1,2
Renal function should be checked after 1 month and thereafter according to medical practice2
Additional Information:
Creatinine levels may increase during treatment with BRILIQUE. The mechanism has not been elucidated. Renal function should be checked after 1 month and thereafter according to routine medical practice, paying special attention to patients ≥75 years, patients with moderate/severe renal impairment and those receiving concomitant treatment with an ARB2
In the PLATO study, patients on ticagrelor had a higher risk of hyperuricaemia than those patients receiving clopidogrel. Caution should be exercised when administering ticagrelor to patients with history of hyperuricaemia or gouty arthritis. As a precautionary measure, the use of ticagrelor in patients with uric acid nephropathy is discouraged2
References:
Wallentin L, Becker RC, Bujah A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. 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
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
BRILIQUE: Summary of Product Characteristics, 2010.

18. 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
Title:
PLATO Safety Results
Key Points:
To summarize the PLATO safety data presented1,2
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
Additional Information:
N/A
References:
Wallentin L, Becker RC, Bujah A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057.
BRILIQUE: Summary of Product Characteristics, 2010.
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
BRILIQUE: Summary of Product Characteristics, 2010.

19. Appropriate Use of BRILIQUE
Title:
Appropriate Use of BRILIQUE
Key Points:
The following section of the presentation will cover the appropriate use of BRILIQUE
Additional Information:
N/A
References:

20. 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)
Title:
BRILIQUE Indication
Key Points:
BRILIQUE is indicated for the prevention of atherothrombotic events (CV death, MI, and stroke) in adult ACS patients
BRILIQUE can be taken by a broad range of ACS patients, including those managed medically or those managed with PCI and/or CABG
Additional Information:
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
Reference:
BRILIQUE: Summary of Product Characteristics, 2010.
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.

21. 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
Title:
Contraindications
Key Points:
The following are contraindications for 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
Additional Information:
N/A
References:
BRILIQUE: Summary of Product Characteristics, 2010.
BRILIQUE: Summary of Product Characteristics, 2010.

22. 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
Title:
Special Warnings and Precautions
Key Points:
The following are 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
Additional Information:
N/A
Reference:
BRILIQUE: Summary of Product Characteristics, 2010.
BRILIQUE: Summary of Product Characteristics, 2010.

23. Dosing and Administration
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
in the evening (PM)
Take aspirin
(either in the morning or night)
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
Title:
Dosing and Administration
Key Points:
BRILIQUE can be used in patients with ACS irrespective of diagnosis (UA, NSTEMI, or STEMI), and without regard to management strategy, medical history, age, or body weight
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
Additional Information:
BRILIQUE should be used with low-dose aspirin (75–150 mg); coadministration of BRILIQUE and high maintenance-dose aspirin (>300 mg) is not recommended
Reference:
BRILIQUE: Summary of Product Characteristics, 2010.
BRILIQUE: Summary of Product Characteristics, 2010.

24. 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
Title:
Clinical Summary of BRILIQUE Based on PLATO
Key Points:
Here is a 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 reduced 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
Additional Information:
N/A
Reference:
BRILIQUE: Summary of Product Characteristics, 2010.
BRILIQUE: Summary of Product Characteristics, 2010.