Transcript Slide 1

A Trial of
PLATelet inhibition and Patient Outcomes
Naotsugu Oyama, MD, PhD, MBA
Presentation Objectives
• To share the scientific evidence in the PLATO
trial, related to the efficacy of ticagrelor, in the
treatment of a broad spectrum of ACS patients
• To review the safety profile of ticagrelor to
facilitate effective management of your ACS
patients
PLATO Study
PLATO study tested the hypothesis that…
ticagrelor will result in a lower risk of recurrent thrombotic events in a broad
patient population with ACS as compared to clopidogrel and this would be
achieved with a clinically acceptable bleeding rate and overall safety profile
PLATO Study:
• 43 countries
• 862 sites
• 18,624 patients
• 78 Filipino participants
18,624
43
patients
862countries
sites
•Philippine Heart Center
•Philippine General Hospital
•The Medical City
•St. Lukes Medical Center
•Perpetual Succour Hospital
•Cebu Doctors University Hospital
•Davao Doctors Hospital
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
PLATO: Study Population
ACS Patient
STEMI
Primary PCI
UA/NSTEMI
Initial Invasive Management
Initial Non-Invasive
Management
No Reperf
PCI
PCI
Fibrinolytic Rx
No revascularization
CABG
Only STEMI patients
intended for primary
PCI included
CABG
No revascularization
Adapted from James S, et al. Am Heart J. 2009;157:599–605.
PLATO: Study Design
Ticagrelor (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 hospitalized with symptom onset <24 hours
• Patients could be taking clopidogrel at time of randomization
300-mg loading dose†
75 mg qd + ASA maintenance dose
Clopidogrel (n=9,291)
Primary safety
endpoint:
Total PLATO
major bleeding‡
Randomization
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 Study: Summary
• PLATO (N Engl J Med. 2009;361:1045–1057)
was a pivotal clinical study, comparing ticagrelor
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.
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: Summary
• 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
PLATO: Baseline Characteristics
Ticagrelor
(n=9,333)
Clopidogrel
(n=9,291)
62.0
62.0
Age ≥75 years, n (%)
1,396 (15.0)
1,482 (16.0)
Women, n (%)
2,655 (28.4)
2,633 (28.3)
Habitual smoker
3,360 (36.0)
3,318 (35.7)
Hypertension
6,139 (65.8)
6,044 (65.1)
Dyslipidemia
4,347 (46.6)
4,342 (46.7)
Diabetes mellitus
2,326 (24.9)
2,336 (25.1)
MI
1,900 (20.4)
1,924 (20.7)
PCI
1,272 (13.6)
1,220 (13.1)
532 (5.7)
574 (6.2)
ST-segment elevation, persistent
3,497 (37.5)
3,511 (37.8)
ST-depression
4,730 (50.7)
4,756 (51.2)
T-wave inversion
2,970 (31.8)
2,975 (32.0)
7,965 (85.3)
7,999 (86.0)
Characteristic
Median age, years
CV risk factors, n (%)
History, n (%)
CABG
ECG at study entry, n (%)
Troponin-I positive, n (%)
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
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 Ticagrelor
Clopidogrel
5.4
4.8
Ticagrelor
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
Ticagrelor
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: Secondary Efficacy Endpoints
Cardiovascular Death
Myocardial Infarction
Clopidogrel
6
Ticagrelor
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
Ticagrelor
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 Ticagrelor 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.
TICAGRELOR: Summary of Product Characteristics, 2010.
5.1
5
0
0
0
6.9
Cumulative Incidence (%)
Cumulative Incidence (%)
7
12
PLATO: Invasive and Non-invasive management
Patient presents with ACS
(n=18,624)
Initial investigator intent
(as per clinical practice)
Intent for
non-invasive management
(n=5216)
Intent for invasive treatment
(n=13,408)
Change in
circumstances
(n=2183)
Invasive treatment
(n=15,991)
James S, et al. BMJ 2011;342:d3527.
Non-invasive management
(n=3033)
CV death, MI or stroke (%)
Primary Outcome: Invasive and Non-Invasive
Number at risk:
Invasive
Ticagrelor
Clopidogrel
Non-invasive
Ticagrelor
Clopidogrel
Non-invasive
HR, 0.85, 95% CI: (0.73–1.0)
Invasive
HR, 0.84, 95% CI: (0.75–0.94)
Days after randomization
6732
6676
6236
6129
6134
6034
5972
5881
4889
4815
3735
3680
3048
2965
2601
2615
2392
2392
2326
2328
2247
2243
1854
1835
1426
1416
1099
1109
James S, et al. BMJ 2011;342:d3527.
PLATO Efficacy Results
Summary
• In PLATO, Ticagrelor 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)
• Ticagrelor 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
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
TICAGRELOR: Summary of Product Characteristics, 2010.
Supplement to: Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
PLATO Efficacy Results
Summary
• The absolute risk reduction with Ticagrelor vs clopidogrel
starts early and continues to build over the full 1 year
treatment period.
• In PLATO, for every 91 ACS patients treated with Ticagrelor
for 1 year, instead of clopidogrel, 1 CV death was prevented
(NNT=91).
• The effect of Ticagrelor over clopidogrel appears
consistent across many subgroups.
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
TICAGRELOR: 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
Ticagrelor
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
Ticagrelor
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
K-M Estimated Rate (% Per Year)
P = 0.008
NS
NS
NS
P = 0.03
NS
Major Bleeding Life-threatening/
Fatal Bleeding
All values presented by PLATO criteria.
Both groups included aspirin.
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
Fatal Bleeding
Major and
Minor Bleeding
Non-CABGMajor Bleeding
CABG-Major
Bleeding
PLATO Safety Results
Summary
• No increase in overall PLATO-defined major bleeding
with ticagrelor vs clopidogrel.
• Non-CABG major bleeding and major + minor bleeding
were more frequent with ticagrelor vs clopidogrel.
• No increase in overall fatal/life-threatening bleeding with
ticagrelor vs clopidogrel.
• There are more dyspnea-related events associated with
Ticagrelor vs clopidogrel, however most events were
mild to moderate in intensity and often resolved without
a need for treatment.
Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
TICAGRELOR: Summary of Product Characteristics, 2010.
PLATO Safety Results
Summary
• Ticagrelor should be used with caution in patients at risk
of bradycardic events.
• Creatinine levels may increase during treatment with
ticagrelor; 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.
TICAGRELOR: Summary of Product Characteristics, 2010.
Clinical Summary of Ticagrelor Based on PLATO
• Ticagrelor significantly reduces the combined risk of CV
death, MI, or stroke vs clopidogrel in patients with ACS.
• Ticagrelor significantly reduced CV mortality vs
clopidogrel.
• The absolute risk reduction with ticagrelor vs clopidogrel
starts early and continues to build over the full 1 year of
treatment.
• Ticagrelor is effective in a broad spectrum of ACS
patients.
TICAGRELOR: Summary of Product Characteristics, 2010.
Clinical Summary of Ticagrelor Based on PLATO
• There is no increase of overall major bleeding with
ticagrelor vs clopidogrel:
– No increase in life-threatening/fatal bleeding with ticagrelor vs
clopidogrel
– Major and minor bleeding was more common with ticagrelor vs
clopidogrel
– Non-CABG-Major bleeding was more common with ticagrelor vs
clopidogrel
• There are more dyspnea-related events associated with
ticagrelor vs clopidogrel, however most events were mild to
moderate in intensity and often resolved without a need for
treatment.
TICAGRELOR: Summary of Product Characteristics, 2010.
Thank You