Online Supplementary Data
Ticagrelor Versus Clopidogrel in Patients With Non-ST-elevation Acute
Coronary Syndrome With or Without Revascularization: Results From the
PLATO Trial
Daniel Lindholm1, Christoph Varenhorst1, Christopher P Cannon2, Robert A Harrington3, Anders Himmelmann4,
Juan Maya5, Steen Husted6, Philippe Gabriel Steg7, Jan H Cornel8, Robert F Storey9, Susanna R Stevens10, Lars
Wallentin1, Stefan K James1
1.
Department of Medical Sciences, Cardiology and Uppsala Clinical Research Center, Uppsala University,
Uppsala, Sweden
2.
TIMI Study Group, Brigham and Women’s Hospital, Boston, Massachusetts
3.
Department of Medicine, Stanford University, Stanford, CA, USA
4.
AstraZeneca Research and Development, Mölndal, Sweden
5.
AstraZeneca Research and Development, Wilmington, DE, USA
6.
Medical Department, Hospital Unit West, Herning/Holstbro, Denmark
7.
INSERM-Unité 698, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris, France;
Université Paris-Diderot, Sorbonne-Paris Cité, Paris, France
8.
Department of Cardiology, Medisch Centrum Alkmaar, Alkmaar, The Netherlands
9.
Department of Cardiovascular Science, University of Sheffield, Sheffield, UK
10. Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA
Table S1: Interaction of ticagrelor treatment and revascularization within 30 days (adjusting for region). Kaplan-Meier (KM) rates 330
days after day 30 post-randomization.
NSTE-ACS with revascularization
NSTE-ACS without revascularization
N
Ticagrelor
KM rate
Clopidogrel
KM rate
HR (95% CI)
N
Ticagrelor
KM rate
Clopidogrel
KM rate
HR (95% CI)
Interaction p
CV death / MI (excluding silent) / Stroke
5906
4.17
5.02
0.84 (0.65, 1.08)
4466
7.91
10.01
0.83 (0.68, 1.02)
0.9619
All Cause Death / MI (excl. silent) / Stroke
5906
4.50
5.61
0.81 (0.64, 1.03)
4466
8.38
10.70
0.83 (0.68, 1.02)
0.8934
CV Death / MI (all) / Stroke / Severe Recurrent Ischemia / Recurrent
Ischemia / TIA / Arterial Thrombotic Event
5699
6.95
8.48
0.82 (0.68, 1.00)
4363
11.15
12.67
0.94 (0.78, 1.12)
0.3543
Myocardial infarction (excluding silent)
5934
2.84
3.25
0.86 (0.63, 1.16)
4479
4.77
5.62
0.89 (0.68, 1.17)
0.8343
Cardiovascular Death (includes vascular and unknown deaths)
6218
1.18
1.88
0.67 (0.43, 1.02)
4514
3.67
4.55
0.84 (0.62, 1.14)
0.3929
Stroke
6188
0.53
0.47
1.14 (0.54, 2.40)
4503
1.25
1.62
0.84 (0.50, 1.40)
0.5015
All Cause Death
6218
1.59
2.64
0.64 (0.44, 0.92)
4514
4.30
5.39
0.84 (0.63, 1.11)
0.2442
Major Bleeding (Study Criteria)
4958
4.05
3.49
1.14 (0.84, 1.56)
3964
6.80
6.12
1.18 (0.91, 1.54)
0.8705
Major or Minor Bleeding (Study Criteria)
4797
6.02
5.03
1.20 (0.92, 1.56)
3899
9.00
8.23
1.16 (0.92, 1.46)
0.8437
Non-CABG Major Bleeding (Study Criteria)
5424
2.53
1.73
1.53 (1.02, 2.30)
3964
2.20
2.03
1.25 (0.77, 2.02)
0.5214
Fatal or Life-Threatening Major Bleeding (Study Criteria)
5256
1.74
1.55
1.22 (0.78, 1.91)
3985
3.17
3.30
0.98 (0.67, 1.43)
0.4643
Other Major Bleeding (Study Criteria)
5232
2.39
2.00
1.14 (0.76, 1.70)
3973
4.03
2.98
1.46 (1.01, 2.12)
0.3661
Major Bleeding (TIMI Criteria)
5137
2.60
2.27
1.13 (0.78, 1.65)
3980
4.52
4.45
1.08 (0.78, 1.48)
0.8385
Major or Minor Bleeding (TIMI Criteria)
4961
3.96
3.34
1.16 (0.85, 1.59)
3965
6.66
5.95
1.20 (0.92, 1.58)
0.8697
GUSTO Severe Bleeding
5422
0.82
1.08
0.73 (0.40, 1.33)
3980
2.00
1.56
1.37 (0.81, 2.32)
0.1209
GUSTO Moderate or Severe Bleeding
5214
3.19
2.59
1.14 (0.81, 1.61)
3976
4.20
3.32
1.29 (0.91, 1.83)
0.6319
Efficacy endpoints
Safety endpoints
Table S2: Interaction of ticagrelor treatment and revascularization within 10 days (adjusting for region) for the full study population.
Kaplan-Meier (KM) rates 350 days after day 10 post-randomization.
Full study population with revascularization
N
Ticagrelor
KM rate
Clopidogrel
KM rate
HR (95% CI)
CV death / MI (excluding silent) / Stroke
11459
5.15
5.96
All Cause Death / MI (excl. silent) / Stroke
11459
5.48
CV Death / MI (all) / Stroke / Severe Recurrent Ischemia /
Recurrent Ischemia / TIA / Arterial Thrombotic Event
11261
Myocardial infarction (excluding silent)
Full study population without revascularization
N
Ticagrelor
KM rate
Clopidogrel
KM rate
HR (95% CI)
Interaction
p
0.87 (0.74, 1.02)
6358
9.69
12.32
0.80 (0.69, 0.94)
0.47
6.41
0.86 (0.73, 1.00)
6358
10.24
13.22
0.79 (0.68, 0.92)
0.49
8.45
9.56
0.87 (0.77, 0.99)
6260
13.86
15.94
0.90 (0.79, 1.03)
0.74
11501
3.20
3.76
0.85 (0.69, 1.04)
6378
5.76
6.88
0.86 (0.70, 1.06)
0.90
Cardiovascular Death (includes vascular and unknown deaths)
11811
1.90
2.41
0.81 (0.62, 1.04)
6396
4.27
6.16
0.70 (0.55, 0.87)
0.40
Stroke
11779
0.78
0.53
1.45 (0.91, 2.33)
6383
1.65
1.66
1.02 (0.68, 1.53)
0.27
All Cause Death
11811
2.30
2.98
0.79 (0.63, 1.00)
6396
4.96
7.29
0.69 (0.56, 0.85)
0.40
Major Bleeding (Study Criteria)
10833
4.98
4.56
1.08 (0.90, 1.30)
5998
11.54
11.53
1.02 (0.87, 1.20)
0.64
Major or Minor Bleeding (Study Criteria)
10572
7.27
6.08
1.19 (1.02, 1.40)
5897
14.40
14.13
1.03 (0.89, 1.19)
0.19
Non-CABG Major Bleeding (Study Criteria)
11206
2.45
1.75
1.38 (1.04, 1.83)
6000
2.78
2.93
1.00 (0.71, 1.39)
0.14
Fatal or Life-Threatening Major Bleeding (Study Criteria)
11118
2.24
2.10
1.11 (0.85, 1.45)
6033
5.41
6.18
0.89 (0.71, 1.12)
0.23
Other Major Bleeding (Study Criteria)
11141
2.82
2.61
1.04 (0.81, 1.32)
6021
6.60
5.76
1.16 (0.93, 1.45)
0.49
Major Bleeding (TIMI Criteria)
11025
3.29
2.98
1.10 (0.88, 1.38)
6023
7.75
8.54
0.92 (0.76, 1.11)
0.23
Major or Minor Bleeding (TIMI Criteria)
10850
4.93
4.48
1.09 (0.90, 1.31)
6001
11.51
11.24
1.05 (0.89, 1.23)
0.77
Non-CABG Major Bleeding (TIMI Criteria)
11310
1.52
0.97
1.53 (1.06, 2.22)
6023
1.91
1.95
1.01 (0.67, 1.52)
0.14
GUSTO Severe Bleeding
11271
1.24
1.27
0.94 (0.66, 1.34)
6014
2.69
2.82
0.96 (0.69, 1.35)
0.92
GUSTO Moderate or Severe Bleeding
11060
3.62
3.12
1.15 (0.93, 1.44)
6012
6.84
6.29
1.09 (0.88, 1.35)
0.73
Efficacy endpoints
Safety endpoints
Table S3: Interaction of ticagrelor treatment and significant CAD among 8092 patients with disease severity
assessed by angiography within 10 days (adjusting for region). Kaplan-Meier (KM rates) at 350 days after day 10
post-randomization.
Significant disease
CV death / MI (excluding silent) / Stroke
All cause death
Major bleeding (study criteria)
No significant disease
N
Ticagrelor
KM rate
Clopidogrel
KM rate
HR (95% CI)
6911
7153
6419
6.34
2.59
10.32
7.46
3.41
9.33
0.87 (0.73, 1.05)
0.80 (0.61, 1.06)
1.11 (0.94, 1.31)
N
Ticagrelor
KM rate
Clopidogrel
KM rate
HR (95% CI)
Interaction
p
810
816
700
1.78
0.74
2.37
4.10
3.11
3.73
0.46 (0.18, 1.16)
0.26 (0.07, 0.93)
0.78 (0.28, 2.14)
0.1843
0.0906
0.4963
Figure S1: Efficacy end points – Kaplan-Meier estimates of time to first occurrence of efficacy endpoints: A)
Primary endpoint, B) All-cause death; in the overall NSTE-ACS subgroup.
A.
CV death, MI (excluding silent), or
stroke (%)
14
12
10
8
6
Clopidogrel
Ticagrelor
4
2
0
0
60
120
180
240
300
360
Days from randomization
Clopidogrel
5499
5019
4924
4768
3924
2999
2395
Ticagrelor
5581
5152
5036
4888
4056
3112
2471
B.
7
All-cause death (%)
6
5
4
3
2
Clopidogrel
1
Ticagrelor
0
0
60
120
180
240
300
360
Days from randomization
Clopidogrel
5499
5250
5200
5078
4207
3225
2591
Ticagrelor
5581
5343
5283
5165
4307
3328
2651
Figure S2: Safety end points – Kaplan-Meier estimate of time to bleeding events: A) Major bleeding according to
PLATO criteria, and B) Non-CABG major bleeding; in the overall NSTE-ACS subgroup.
A.
16
Major bleeding (%)
14
12
10
8
6
Clopidogrel
4
Ticagrelor
2
0
0
60
120
180
240
300
360
Days from randomization
Clopidogrel
5434
4211
3956
3811
3006
2212
2000
Ticagrelor
5516
4166
3904
3725
2943
2183
1965
B.
Non-CABG major bleeding (%)
6
5
4
3
2
Clopidogrel
1
Ticagrelor
0
0
60
120
180
240
300
360
Days from randomization
Clopidogrel
5434
4470
4230
4086
3232
2389
2164
Ticagrelor
5516
4413
4161
3987
3152
2347
2119
Figure S3: Forest plot of the primary endpoint in subgroups of the NSTE-ACS population undergoing
revascularization within 10 days after randomization.
Figure S4: Forest plot of the primary endpoint in subgroups of the NSTE-ACS population managed without
revascularization during the initial 10 days after randomization.