Transcript Document

Invasive
Ticagrelor compared with clopidogrel
in patients with acute coronary
syndromes – the PLATelet Inhibition
and patient Outcomes trial
Outcomes in patients with a Planned Invasive Strategy
The PLATO trial was funded by AstraZeneca
PLATO background
Invasive
• In STEMI and UA/NSTEMI, current guidelines
recommend 12 months of aspirin and clopidogrel
• Efficacy of clopidogrel is hampered by
– slow and variable transformation to the active
metabolite (e.g. 2C19)
– modest and variable platelet inhibition
–  risk stent thrombosis and MI in poor responders
– Irreversible effect – and increased risk of bleeding if
urgent CABG is required
PLATO = PLATelet inhibition and patient Outcomes; NSTEMI = non-ST segment elevation;
STEMI = ST segment elevation; ACS = acute coronary syndromes; MI = myocardial infarction
Ticagrelor (AZD 6140):
an oral reversible P2Y12 antagonist
HO
N
N
N
H
N
HO
O
F
N
N
S
Ticagrelor is a cyclo-pentyltriazolo-pyrimidine (CPTP)
F
OH
• Direct acting
– Not a prodrug; does not require metabolic activation
– Rapid onset of inhibitory effect on the P2Y12 receptor
– Greater inhibition of platelet aggregation than clopidogrel
• Reversibly bound
– Degree of inhibition reflects plasma concentration
– Faster offset of effect than clopidogrel
– Functional recovery of all circulating platelets 2-3 days
PLATO study design
NSTEMI ACS (moderate-to-high risk) STEMI (if primary PCI) (N=18,624)
Clopidogrel-treated or -naive; randomized <24 hours of index event
At randomization, 13,408 (72%) of patients were
specified by the Investigator: intent for invasive strategy
Clopidogrel (n=6,676)
If pre-treated, no additional loading dose;
if naive, standard 300 mg loading dose,
then 75 mg qd maintenance;
(additional 300 mg allowed pre-PCI)
Ticagrelor (n=6,732)
180 mg loading dose, then
90 mg bid maintenance;
(additional 90 mg pre-PCI)
6–12 months treatment
Primary endpoint: CV death + MI + Stroke
Primary safety endpoint: Total major bleeding
PCI = percutaneous coronary intervention; CV = cardiovascular; PI = principal investigator
Wallentin L, et al. N Engl J Med. 2009;361:1045-1057.
PLATO: Overall trial efficacy endpoints
All patients*
Ticagrelor Clopidogrel
(n=9,333) (n=9,291)
HR for
(95% CI)
p value†
Primary objective, n (%)
CV death + MI + stroke
864 (9.8)
1,014 (11.7) 0.84 (0.77–0.92)
<0.001
Secondary objectives, n (%)
Total death + MI + stroke
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
CV death + MI + stroke +
ischaemia + TIA + arterial
thrombotic events
Myocardial infarction
504 (5.8)
593 (6.9)
0.84 (0.75–0.95)
0.005
CV death
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
399 (4.5)
506 (5.9)
0.78 (0.69–0.89)
<0.001
Total death
The percentages are K-M estimates of the rate of the endpoint at 12 months.
Wallentin L, et al. N Engl J Med. 2009;361:1045-1057.
Figure 1: Trial profile
Invasive
18758 patients enrolled
134 not randomly assigned
18624 randomly assigned
5216 non-invasive strategy
planned
13408 invasive strategy
planned
6732 randomly assigned to
ticagrelor (efficacy
population)
81 no intake of study drug
6651 safety population
6676 randomly assigned to
clopidogrel (efficacy
population)
91 no intake of study drug
6585 safety population
Cannon CP, et al. Lancet 2010;375:283–293
Table 1: Baseline characteristics, treatments and interventions
Invasive
Ticagrelor
(n=6732)
Clopidogrel
(n=6676)
Age (years; median, IQR)
61.0 (53–69)
61.0 (53–70)
Age ≥75 years
843 (12.5%)
927 (13.9%)
Women
1694 (25.2%)
1688 (25.3%)
White
6138 (91.2%)
6056 (90.7%)
Black
90 (1.3%)
101 (1.5%)
Oriental
409 (6.1%)
428 (6.4%)
Other
94 (1.4%)
91 (1.4%)
Myocardial infarction
1148 (17.1%)
1131 (16.9%)
PCI
947 (14.1%)
885 (13.3%)
Coronary artery bypass graft
357 (5.3%)
380 (5.7%)
Transient ischaemic attack
145 (2.2%)
143 (2.1%)
Non-haemorrhagic stroke
209 (3.1%)
218 (3.3%)
1530 (22.7%)
1579 (23.7%)
Ethnic origin
History
Diabetes mellitus
Data are number (%), unless otherwise indicated. PCI=percutaneous coronary intervention
Cannon CP, et al. Lancet 2010;375:283–293
Table 1: Baseline characteristics, treatments and interventions (cont’d)
Invasive
Ticagrelor
(n=6732)
Clopidogrel
(n=6676)
ST-elevation myocardial infarction
3278 (48.8%)
3297 (49.5%)
Non-ST-elevation myocardial infarction
2564 (38.2%)
2481 (37.2%)
Unstable angina or other
873 (13.0%)
887 (13.3%)
Aspirin
6584 (97.9%)
6544 (98.2%)
Unfractionated heparin
4440 (66.0%)
4404 (66.1%)
Low-molecular-weight heparin
3185 (47.4%)
3133 (47.0%)
Fondaparinux
124 (1.8%)
129 (1.9%)
Bivalirudin
181 (2.7%)
175 (2.6%)
2368 (35.2%)
2362 (35.4%)
<600 mg
5646 (83.9%)
5638 (84.5%)
≥600 mg
1085 (16.1%)
1037 (15.5%)
Acute coronary syndrome
Antithrombotic drug during initial hospital admission
Glycoprotein IIb/IIIa inhibitor
Clopidogrel (OL before randomisation)
Total clopidogrel (OL+IP) before randomisation to 24 h after first dose of IP
<600 mg
4889 (72.6%)
4882 (73.1%)
≥600 mg
1842 (27.4%)
1792 (26.8%)
Data are number (%), unless otherwise indicated. OL=open label. IP=investigational product
Cannon CP, et al. Lancet 2010;375:283–293
Table 1: Baseline characteristics, treatments and interventions (cont’d)
Invasive
Ticagrelor
(n=6732)
Clopidogrel
(n=6676)
β blocker
5751 (85.5%)
5738 (86.1%)
Angiotensin-converting-enzyme inhibitor
or angiotensin-receptor blocker
5851 (87.0%)
5786 (86.8%)
Cholesterol-lowering (statin)
6416 (95.4%)
6362 (95.5%)
Proton pump inhibitor
3659 (54.4%)
3578 (53.7%)
Coronary angiography
6511 (96.7%)
6476 (97.0%)
Primary PCI* for ST-elevation myocardial
infarction
2986 (44.4%)
2984 (44.7%)
Other PCI† before discharge for first event
2173 (32.3%)
2155 (32.3%)
PCI (total)
5159 (76.6%)
5139 (77.0%)
372 (5.5%)
410 (6.1%)
Other drug from randomisation to end of study
Invasive procedures during initial hospital admission
Coronary bypass surgery before discharge
Data are number (%), unless otherwise indicated. PCI=percutaneous coronary intervention
*Any PCI during the first 24 h after randomisation
†Any PCI after first 24 h following randomisation in patients with ST-elevation myocardial infarction,
or any PCI in patients with non-ST-elevation myocardial infarction
Cannon CP, et al. Lancet 2010;375:283–293
Kaplan-Meier estimated rate (% per year)
Figure 2: Cumulative Kaplan-Meier estimates of time to first primary
efficacy endpoint in patients intended to undergo an invasive strategy
Invasive
Clopidogrel
Ticagrelor
15
10.65
10
8.95
5
0
0
60
120
180
240
300
360
3680
3735
2965
3048
Time after randomisation (days)
Number at risk
Clopidogrel
6676
Ticagrelor
6732
6129
6236
6034
6134
5881
5972
4815
4889
Cannon CP, et al. Lancet 2010;375:283–293
Table 2: Efficacy of ticagrelor versus clopidogrel
Invasive
Ticagrelor
(n=6732)
Clopidogrel
(n=6676)
Hazard ratio
(95% CI)
p value
569 (9.0%)
668 (10.7%)
0.84 (0.75–0.94)
0.0025
All-cause death+myocardial infarction*+stroke
595 (9.4%)
701 (11.2%)
0.84 (0.75–0.94)
0.0016
Cardiovascular death+myocardial infarction+
stroke+severe recurrent cardiac ischaemia+
recurrent cardiac ischaemia+transient
ischaemic attack+other arterial thrombotic
event
830 (13.1%)
964 (15.3%)
0.85 (0.77–0.93)
0.0005
Myocardial infarction*
328 (5.3%)
406 (6.6%)
0.80 (0.69–0.92)
0.0023
Cardiovascular death
221 (3.4%)
269 (4.3%)
0.82 (0.68–0.98)
0.0250
Stroke
75 (1.2%)
69 (1.1%)
1.08 (0.78–1.50)
0.6460
Ischaemic†
59 (0.9%)
59 (0.9%)
..
1.0000
Haemorrhagic†
12 (0.2%)
9 (0.1%)
..
0.6634
Unknown†
5 (0.07%)
1 (0.01%)
..
0.2187
252 (3.9%)
311 (5.0%)
0.81 (0.68–0.95)
0.0103
Primary efficacy endpoint
Cardiovascular death+myocardial
infarction*+stroke
Secondary efficacy endpoint
All-cause death
Data are number (Kaplan-Meier estimated % at 360 days), unless otherwise indicated
p values calculated by use of univariate Cox model, unless otherwise indicated
*Excludes silent myocardial infarction
†Data are number (%), and p values calculated with Fisher’s exact test
Cannon CP, et al. Lancet 2010;375:283–293
Kaplan-Meier estimated rate (% per year)
Figure 3: (A) Cumulative Kaplan-Meier estimates of time to myocardial
infarction in patients intended to undergo an invasive strategy
Invasive
Clopidogrel
Ticagrelor
8
6.59
6
5.26
4
2
0
0
60
120
180
240
300
360
3706
3766
2987
3078
Time after randomisation (days)
Number at risk
Clopidogrel
6676
Ticagrelor
6732
6157
6268
6062
6173
5917
6010
4849
4924
Cannon CP, et al. Lancet 2010;375:283–293
Kaplan-Meier estimated rate (% per year)
Figure 3: (B) Cumulative Kaplan-Meier estimates of time to cardiovascular
death in patients intended to undergo an invasive strategy
Invasive
Clopidogrel
Ticagrelor
8
6
4.33
4
3.44
2
0
0
60
120
180
240
300
360
3917
3591
3164
3233
Time after randomisation (days)
Number at risk
Clopidogrel
6676
Ticagrelor
6732
6376
6439
6332
6375
6209
6241
5114
5141
Cannon CP, et al. Lancet 2010;375:283–293
Kaplan-Meier estimated rate (% per year)
Figure 4: Cumulative Kaplan-Meier estimates of time to all-cause
mortality in patients intended to undergo an invasive strategy
Invasive
Clopidogrel
Ticagrelor
6
5.02
4
3.94
2
0
0
60
120
180
240
300
360
3917
3951
3164
3233
Time after randomisation (days)
Number at risk
Clopidogrel
6676
Ticagrelor
6732
6376
6439
6331
6375
6209
6241
5114
5141
Cannon CP, et al. Lancet 2010;375:283–293
Table 2: Efficacy of ticagrelor versus clopidogrel (cont’d)
Invasive
Ticagrelor
(n=6732)
Clopidogrel
(n=6676)
Hazard ratio
(95% CI)
p value
4949
4928
..
..
62 (1.3%)
97 (2.0%)
0.64 (0.46–0.88)
0.0054
Patients with a drug-eluting stent
17 (1.3%)
25 (1.8%)
0.69 (0.37–1.27)
0.2304
Patients with a bare-metal stent
45 (1.4%)
72 (2.1%)
0.62 (0.43–0.90)
0.0115
104 (2.2%)
142 (3.0%)
0.73 (0.57–0.94)
0.0142
Patients with a drug-eluting stent
32 (2.3%)
36 (2.5%)
0.90 (0.56–1.45)
0.6581
Patients with a bare-metal stent
72 (2.2%)
106 (3.1%)
0.67 (0.50–0.91)
0.0092
Total (definite, probable or possible)
132 (2.8%)
179 (3.8%)
0.73 (0.59–0.92)
0.0068
Patients with a drug-eluting stent
41 (3.1%)
53 (3.8%)
0.78 (0.52–1.17)
0.2349
Patients with a bare-metal stent
91 (2.7%)
126 (3.8%)
0.71 (0.55–0.94)
0.0142
Stent thrombosis (n)
Definite
Definite or probable
Data are number (Kaplan-Meier estimated % at 360 days), unless otherwise indicated
p values calculated by use of univariate Cox model, unless otherwise indicated
Cannon CP, et al. Lancet 2010;375:283–293
Kaplan-Meier estimated failure rate (%)
Figure 6: (A) Kaplan-Meier estimates of definite (angiographically
documented) stent thrombosis during 30 days in patients given
ticagrelor versus clopidogrel
Invasive
Clopidogrel, <600 mg clopidogrel loading dose
Clopidogrel, ≥600 mg clopidogrel loading dose
3
Ticagrelor, <600 mg clopidogrel loading dose
Ticagrelor, ≥600 mg clopidogrel loading dose
2
1.42
1.41
0.96
1
0.87
0
0
5
10
15
20
25
30
Time since percutaneous coronary intervention (days)
Number at risk
Clopidogrel (<600 mg)
Clopidogrel (≥600 mg)
Ticagrelor (<600 mg)
Ticagrelor (≥600 mg)
3432
1494
3382
1565
3375
1470
3320
1545
3344
1456
3294
1532
3333
1452
3284
1525
3325
1448
3279
1524
3322
1445
3275
1523
3316
1444
3270
1521
Cannon CP, et al. Lancet 2010;375:283–293
Kaplan-Meier estimated failure rate (%)
Figure 6: (B) Kaplan-Meier estimates of definite (angiographically
documented) stent thrombosis during 360 days in patients given
ticagrelor versus clopidogrel
4
Invasive
Clopidogrel, <600 mg clopidogrel loading dose
Clopidogrel, ≥600 mg clopidogrel loading dose
Ticagrelor, <600 mg clopidogrel loading dose
Ticagrelor, ≥600 mg clopidogrel loading dose
3
2.29
1.91
2
1.48
1
1.03
0
0
60
120
180
240
300
360
Time since percutaneous coronary intervention (days)
Number at risk
Clopidogrel (<600 mg)
Clopidogrel (≥600 mg)
Ticagrelor (<600 mg)
Ticagrelor (≥600 mg)
3432
1494
3382
1565
3283
1437
3253
1512
3254
1423
3220
1498
3158
1392
3128
1455
2626
1147
2616
1182
1992
879
1956
922
1498
686
1475
740
Cannon CP, et al. Lancet 2010;375:283–293
Kaplan-Meier estimated failure rate (%)
Figure 7: (A) Kaplan-Meier estimates of total stent thrombosis
during 30 days in patients given ticagrelor versus clopidogrel
Invasive
Clopidogrel, <600 mg clopidogrel loading dose
Clopidogrel, ≥600 mg clopidogrel loading dose
3
Ticagrelor, <600 mg clopidogrel loading dose
Ticagrelor, ≥600 mg clopidogrel loading dose
2.23
2.22
2
1.82
1.42
1
0
0
5
10
15
20
25
30
Time since percutaneous coronary intervention (days)
Number at risk
Clopidogrel (<600 mg)
Clopidogrel (≥600 mg)
Ticagrelor (<600 mg)
Ticagrelor (≥600 mg)
3432
1494
3382
1565
3373
1468
3317
1544
3341
1454
3290
1532
3330
1450
3280
1524
3322
1446
3275
1523
3319
1443
3271
1522
3312
1442
3266
1520
Cannon CP, et al. Lancet 2010;375:283–293
Kaplan-Meier estimated failure rate (%)
Figure 7: (B) Kaplan-Meier estimates of total stent thrombosis
during 360 days in patients given ticagrelor versus clopidogrel
Invasive
4
3.81
3.80
3.12
3
2.15
2
Clopidogrel, <600 mg clopidogrel loading dose
Clopidogrel, ≥600 mg clopidogrel loading dose
1
Ticagrelor, <600 mg clopidogrel loading dose
Ticagrelor, ≥600 mg clopidogrel loading dose
0
0
60
120
180
240
300
360
Time since percutaneous coronary intervention (days)
Number at risk
Clopidogrel (<600 mg)
Clopidogrel (≥600 mg)
Ticagrelor (<600 mg)
Ticagrelor (≥600 mg)
3432
1494
3382
1565
3278
1435
3247
1512
3249
1421
3214
1498
3154
1389
3122
1455
2622
1144
2611
1182
1989
877
1951
922
1496
684
1471
740
Cannon CP, et al. Lancet 2010;375:283–293
Kaplan-Meier estimated rate (% per year)
Figure 8: Cumulative Kaplan-Meier estimates of time to total major
bleeding in patients intended to undergo an invasive strategy
Invasive
Clopidogrel
Ticagrelor
15
11.6
11.5
10
5
0
0
60
120
180
240
300
360
2754
2741
2496
2503
Time after randomisation (days)
Number at risk
Clopidogrel
6585
Ticagrelor
6651
5215
5235
4984
4947
4786
4755
3753
3726
Cannon CP, et al. Lancet 2010;375:283–293
Table 3: Safety of ticagrelor versus clopidogrel in patients intended
to undergo an invasive strategy
Invasive
Ticagrelor
(n=6651)
Clopidogrel
(n=6585)
Hazard ratio
(95% CI)
p value*
Total major bleeding
689 (11.5%)
691 (11.6%)
0.99 (0.89–1.10)
0.8803
Life-threatening or fatal bleeding
366 (6.0%)
351 (5.9%)
1.04 (0.90–1.20)
0.6095
Intracranial bleeding
15 (0.3%)
11 (0.2%)
1.36 (0.63–2.97)
0.4364
Other major bleeding
340 (5.9%)
360 (6.2%)
0.94 (0.81–1.09)
0.4030
Non-CABG-related
272 (4.7%)
235 (4.0%)
1.16 (0.97–1.38)
0.1040
CABG-related†
430 (7.1%)
480 (8.0%)
0.89 (0.78–1.01)
0.0745
Coronary-procedure-related
521 (8.5%)
554 (9.2%)
0.93 (0.83–1.05)
0.2573
Non-coronary-procedure-related
26 (0.5%)
30 (0.6%)
0.87 (0.51–1.46)
0.5911
Primary safety endpoint
Major bleeding events
Data are number (Kaplan-Meier estimated % at 360 days), unless otherwise indicated
CABG=coronary artery bypass graft; TIMI=Thrombolysis In Myocardial Infarction
GUSTO=Global Use of Strategies To Open occluded coronary arteries
*Calculated by use of univariate Cox model
†Percentages are of total population of patients with CABG-related bleeding. 906 (67.8%)
of 1335 patients who had a CABG during the study had PLATelet inhibition and patient
Outcomes-defined major bleeding, 673 (50.4%) had TIMI-defined major bleeding, and
165 (12.0%) had severe GUSTO-defined bleeding
Cannon CP, et al. Lancet 2010;375:283–293
Table 3: Safety of ticagrelor versus clopidogrel in patients intended
to undergo an invasive strategy (cont’d)
Invasive
Ticagrelor
(n=6651)
Clopidogrel
(n=6585)
Hazard ratio
(95% CI)
p value*
Total
961 (16.0%)
883 (14.7%)
1.09 (0.99–1.19)
0.0700
Non-CABG-related
523 (8.9%)
416 (7.1%)
1.26 (1.11–1.43)
0.0004
CABG-related†
464 (7.7%)
516 (8.7%)
0.89 (0.79–1.01)
0.0710
Coronary-procedure-related
645 (10.5%)
652 (10.7%)
0.98 (0.88–1.10)
0.7768
42 (0.7%)
50 (0.9%)
0.84 (0.56–1.26)
0.3998
PRBCs or whole blood
531 (8.9%)
525 (8.7%)
1.01 (0.89–1.14)
0.9095
Platelets
98 (1.6%)
114 (1.9%)
0.85 (0.65–1.12)
0.2506
Total
476 (7.9%)
474 (7.9%)
1.00 (0.88–1.14)
1.0000
Non-CABG-related
160 (2.8%)
130 (2.2%)
1.23 (0.98–1.55)
0.0814
CABG-related†
322 (5.3%)
354 (5.9%)
0.90 (0.78–1.05)
0.1914
Major or minor bleeding events
Non-coronary-procedure-related
Transfusion of blood products
TIMI-defined cutoff point for major bleeding
Data are number (Kaplan-Meier estimated % at 360 days), unless otherwise indicated
CABG=coronary artery bypass graft; PRBCs=packed red blood cells
TIMI=Thrombolysis In Myocardial Infarction
GUSTO=Global Use of Strategies To Open occluded coronary arteries
*Calculated by use of univariate Cox model
†Percentages are of total population of patients with CABG-related bleeding. 906 (67.8%)
of 1335 patients who had a CABG during the study had PLATelet inhibition and patient
Outcomes-defined major bleeding, 673 (50.4%) had TIMI-defined major bleeding, and
165 (12.0%) had severe GUSTO-defined bleeding
Cannon CP, et al. Lancet 2010;375:283–293
Table 3: Safety of ticagrelor versus clopidogrel in patients intended
to undergo an invasive strategy (cont’d)
Invasive
Ticagrelor
(n=6651)
Clopidogrel
(n=6585)
Hazard ratio
(95% CI)
p value*
Total
219 (3.8%)
220 (3.7%)
0.99 (0.82–1.19)
0.9218
Non-CABG-related
119 (2.1%)
101 (1.7%)
1.18 (0.90–1.53)
0.2329
CABG-related†
102 (1.8%)
122 (2.1%)
0.83 (0.64–1.08)
0.1665
TIMI-defined cutoff point for minor bleeding
TIMI-defined cutoff point for major or minor bleeding
Total
675 (11.2%)
678 (11.3%)
0.99 (0.89–1.10)
0.8573
Non-CABG-related
270 (4.6%)
227 (3.9%)
1.19 (1.00–1.42)
0.0561
CABG-related†
424 (7.0%)
476 (8.0%)
0.88 (0.78–1.01)
0.0630
All
185 (2.9%)
198 (3.2%)
0.91 (0.74–1.12)
0.3785
Non-CABG-related
120 (2.0%)
103 (1.8%)
1.09 (0.83–1.43)
0.5227
CABG-related†
69 (1.1%)
97 (1.5%)
0.73 (0.53–1.00)
0.0520
GUSTO-defined severe bleeding
Data are number (Kaplan-Meier estimated % at 360 days), unless otherwise indicated
CABG=coronary artery bypass graft; TIMI=Thrombolysis In Myocardial Infarction
GUSTO=Global Use of Strategies To Open occluded coronary arteries
*Calculated by use of univariate Cox model
†Percentages are of total population of patients with CABG-related bleeding. 906 (67.8%)
of 1335 patients who had a CABG during the study had PLATelet inhibition and patient
Outcomes-defined major bleeding, 673 (50.4%) had TIMI-defined major bleeding, and
165 (12.0%) had severe GUSTO-defined bleeding
Cannon CP, et al. Lancet 2010;375:283–293
Figure 9: Rates of bleeding according to different definitions
Invasive
13
12
Non-CABG-related bleeding only
Both non-CABG-related and CABG-related bleeding
CABG-related bleeding only
p=0.8803
11.45
11.56
Kaplan-Meier estimated rate (% per year)
11
10
9
p=1.000
7.91
8
7.93
7
6
5
p=0.3785
4
2.94
3
3.24
2
1
0
Ticagrelor
Clopidogrel
PLATO-defined major bleeding
Ticagrelor
Clopidogrel
TIMI-defined major bleeding
CABG=coronary artery bypass graft; PLATO=PLATelet inhibition and patient Outcomes
TIMI=Thrombolysis In Myocardial Infarction
GUSTO=Global Use of Strategies To Open occluded coronary arteries.
Ticagrelor
Clopidogrel
GUSTO-defined severe bleeding
Cannon CP, et al. Lancet 2010;375:283–293
Figure 5: Hazard ratios of benefit with ticagrelor versus clopidogrel
for primary efficacy endpoint according to patient subgroups, and
clopidogrel dosing before randomisation and percutaneous coronary
intervention
Hazard ratio
(95% CI)
Patients
Ticagrelor
Clopidogrel
Hazard ratio
(95% CI)
13408
569 (9.0%)
668 (10.7%)
0.84 (0.75–0.94)
Characteristic
Overall treatment effect
Primary efficacy endpoint
Age
<65 years
≥65 years
Sex
Male
Female
Weight
<60 kg
≥60 kg
Final diagnosis
STEMI
NSTEMI/UA/other ACS
Time from index event to treatment
<12 h
≥12 h
0.2
Invasive
p value
(interaction)
0.4857
8206
5200
260 (6.7%) 318 (8.3%)
308 (12.6%) 349 (14.4%)
0.81 (0.68–0.95)
0.87 (0.75–1.02)
0.9429
10026
3382
399 (8.3%) 469 (10.0%)
170 (10.8%) 199 (12.5%)
0.84 (0.74–0.96)
0.84 (0.68–1.03)
879
12484
48 (12.0%)
515 (8.7%)
61 (14.2%)
600 (10.3%)
0.84 (0.57–1.22)
0.84 (0.75–0.95)
0.9681
0.7544
6575
6805
250 (8.1%)
316 (9.7%)
293 (9.5%)
372 (11.8%)
0.86 (0.72–1.02)
0.83 (0.71–0.96)
0.5697
7808
5407
295 (8.0%) 350 (9.7%)
264 (10.3%) 306 (11.9%)
0.82 (0.70–0.95)
0.87 (0.74–1.03)
0.5
1.0
2.0
Ticagrelor better
Clopidogrel better
Data are number (Kaplan-Meier estimated % at 360 days), unless otherwise indicated
Vertical dashed line represents the hazard ratio for the overall treatment effect
STEMI=ST-elevation myocardial infarction; NSTEMI=non-ST-elevation myocardial infarction
UA=unstable angina; ACS=acute coronary syndrome
Cannon CP, et al. Lancet 2010;375:283–293
Figure 5: Hazard ratios of benefit with ticagrelor versus clopidogrel
for primary efficacy endpoint according to patient subgroups, and
clopidogrel dosing before randomisation and percutaneous coronary
intervention (cont’d)
Hazard ratio
(95% CI)
Characteristic
Troponin I
Positive
Negative
Diabetes mellitus
No
Yes
Previous myocardial infarction
No
Yes
Previous CABG
No
Yes
Aspirin during first hospital admission
No
Yes
Glycoprotein IIb/IIIa during first
hospital admission
No
Yes
0.2
Patients
Ticagrelor
Clopidogrel
Invasive
Hazard ratio
(95% CI)
p value
(interaction)
0.2548
11329
1713
486 (9.0%)
66 (8.1%)
576 (10.8%)
58 (7.6%)
0.84 (0.75–0.95)
1.04 (0.73–1.48)
0.6440
10289
3109
390 (8.0%) 459 (9.6%)
179 (12.4%) 209 (14.2%)
0.83 (0.73–0.95)
0.88 (0.72–1.07)
0.7235
11119
2279
425 (8.0%) 495 (9.5%)
144 (13.5%) 173 (16.3%)
0.85 (0.75–0.97)
0.81 (0.65–1.01)
0.9509
12661
737
511 (8.5%)
58 (17.8%)
598 (10.1%)
70 (20.0%)
0.84 (0.75–0.95)
0.85 (0.60–1.20)
0.7177
262
13128
19 (13.9%) 17 (14.4%)
550 (8.9%) 649 (10.6%)
0.96 (0.50–1.84)
0.84 (0.75–0.94)
0.3715
8660
4730
349 (8.5%)
220 (9.8%)
422 (10.5%)
244 (10.8%)
0.81 (0.70–0.94)
0.90 (0.75–1.08)
0.5
1.0
2.0
Ticagrelor better
Clopidogrel better
Data are number (Kaplan-Meier estimated % at 360 days), unless otherwise indicated
Vertical dashed line represents the hazard ratio for the overall treatment effect
CABG=coronary artery bypass graft
Cannon CP, et al. Lancet 2010;375:283–293
Figure 5: Hazard ratios of benefit with ticagrelor versus clopidogrel
for primary efficacy endpoint according to patient subgroups, and
clopidogrel dosing before randomisation and percutaneous coronary
intervention (cont’d)
Hazard ratio
(95% CI)
Characteristic
Geographic region
Asia and Australia
Central and South America
Europe, Middle East, Africa
North America
OL clopidogrel dose before
randomisation
<600 mg
≥600 mg
Total clopidogrel (OL+IP) before
randomisation to 24 h after first dose IP
<600 mg
≥600 mg
0.2
Patients
Ticagrelor
Clopidogrel
Invasive
Hazard ratio
(95% CI)
p value
(interaction)
0.1095
1173
865
9743
1627
58 (10.3%)
57 (13.7%)
370 (8.0%)
84 (11.1%)
67 (12.3%)
73 (18.0%)
458 (10.1%)
70 (9.1%)
0.86 (0.60–1.22)
0.75 (0.53–1.07)
0.80 (0.70–0.91)
1.21 (0.86–1.66)
0.8295
11284
2122
498 (9.3%)
71 (7.0%)
585 (11.0%)
83 (8.5%)
0.85 (0.75–0.95)
0.81 (0.59–1.12)
0.7332
9771
3634
431 (9.3%)
138 (7.9%)
514 (11.2%)
154 (9.1%)
0.83 (0.73–0.95)
0.87 (0.69–1.10)
0.5
1.0
2.0
Ticagrelor better
Clopidogrel better
Data are number (Kaplan-Meier estimated % at 360 days), unless otherwise indicated
Vertical dashed line represents the hazard ratio for the overall treatment effect
OL=open label; IP=investigational product
Cannon CP, et al. Lancet 2010;375:283–293
Dyspnea
Invasive
Ticagrelor
(n=6,732)
Clopidogrel
(n=6,676)
p value*
Any dyspnea event
15.4
10.4
<0.0001
Requiring discontinuation of study-
0.9
0.3
< 0.0001
All patients
Dyspnea, %
treatment
*p values calculated using Fisher’s Exact test
Cannon CP, et al. Lancet 2010;375:283–293
Therapeutic considerations
Invasive
• Based on 1,000 patients admitted to hospital for ACS and planned
for invasive strategy, using ticagrelor instead of clopidogrel for 12
months resulted in
– 11 fewer deaths
– 13 fewer myocardial infarctions
– 6 fewer cases with stent thrombosis
– No increase in major bleeding or need for transfusion
• Treating 59 patients with ticagrelor instead of with clopidogrel for
one year will prevent one event of CV death, MI or stroke
• Treating 88 will save one life (in one year)
Cannon CP, et al. Lancet 2010;375:283–293,
presented TCT 2009
Conclusions
Invasive
Ticagrelor seems to be a better option than clopidogrel for
patients with acute coronary syndromes for whom an early
invasive strategy is planned.
These results also support the idea that increased
inhibition of platelet P2Y12 receptors can achieve
substantial reduction in the rate of mortality when not
associated with an increase in the rate of major bleeding.
Cannon CP, et al. Lancet 2010;375:283–293