Otamixaban - Clinical Trial Results

Report
Results of the EUROMAX trial
Philippe Gabriel Steg, Arnoud van ‘t Hof, Christian W. Hamm, Peter Clemmensen,
Frédéric Lapostolle, Pierre Coste, Jurrien Ten Berg, Pierre Van Grunsven, Gerrit Jan
Eggink, Lutz Nibbe, Uwe Zeymer, Marco Campo dell' Orto, Holger Nef, Jacob
Steinmetz, Louis Soulat, Kurt Huber, Efthymios N. Deliargyris, Debra Bernstein, Diana
Schuette, Jayne Prats, Tim Clayton, Stuart Pocock, Martial Hamon, Patrick Goldstein,
for the EUROMAX Investigators*
Hôpital Bichat, Assistance Publique – Hôpitaux de Paris, Université Paris –
Diderot, INSERM U-698, Paris, France
and NHLI Imperial College, ICMS, Royal Brompton Hospital, London, UK
• A complete list is available in Steg PG et al. Design and methods of the EUROMAX trial.
Am Heart J 2013
Ph. Gabriel Steg – Disclosures
• Research grant (to INSERM U698): NYU school of Medicine,
Sanofi, Servier
• Speaking or consulting: Amarin, AstraZeneca, Bayer,
Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo,
Glaxo-SmithKline, Iroko Cardio, Lilly, Medtronic, Novartis,
Otsuka, Pfizer, Sanofi, Servier, The Medicines Company, Vivus
• Stockholding: Aterovax
The EUROMAX trial was funded by The Medicines Company
Bivalirudin for PPCI in STEMI
• The HORIZONS AMI trial established the role of bivalirudin in
PPCI, with a reduction in mortality and in bleeding sustained
up to 3 years compared to UFH + GPI
• However, there are new questions:
– What is the role of bivalirudin in the ambulance for patients triaged to
primary PCI (from the pre-hospital setting or from non–PCI-capable
hospitals) ?
– Is it possible to reduce the risk of acute stent thrombosis by using a
prolonged infusion of bivalirudin at the end of PCI ?
– What is the impact of contemporary practice (e.g. novel P2Y12
inhibitors, increased use of radial arterial access, no systematic use of
GPIs) on efficacy and safety of bivalirudin ?
EUROMAX Trial Design
2218 patients with STEMI with symptom onset >20 min and ≤12h
Randomized in ambulance or non-PCI hospital
Intent for primary PCI
R
1:1
UFH/LMWH ± GPI
Per standard practice
Aspirin + P2Y12 inhibitor
(any) as soon as possible
Bivalirudin
(0.75 mg/kg bolus, 1.75 mg/kg/h infusion)
+ prolonged optional infusion
(PCI dose or 0.25 mg/kg/h)
(provisional GPI only)
Primary endpoint: 30-day death or non-CABG related major bleeding
Key Secondary endpoint: Death, Re-infarction or non-CABG major bleeding at 30 days
Clinical FU at 30 days and 1 year
clinicaltrials.gov NCT01087723
EUROMAX - A European Trial
N=2218
Germany – 279
Denmark – 150
Netherlands – 768
Poland
Czech Rep.
France – 795
Austria
Slovenia
Italy
206
Baseline Characteristics
Bivalirudin (N=1089)
Heparins with optional
GPI (N=1109)
Age — median (IQR), yr
61 (52, 71)
62 (52, 72)
Age >65 yr — no. (%)
394 (36.2)
434 (39.1)
Female sex — no. (%)
275 (25.3)
248 (22.4)
Diabetes — no. (%)
127 (11.7)
169 (15.3)*
Hypertension — no. (%)
459 (42.2)
504 (45.5)
Hyperlipidemia‡ — no. (%)
398 (36.6)
417 (37.6)
Current smoker — no. (%)
453 (41.6)
472 (42.6)
Prior myocardial infarction — no. (%)
80 (7.4)
113 (10.2)*
Prior PCI — no. (%)
97 (8.9)
108 (9.7)
Prior CABG — no. (%)
18 (1.7)
29 (2.6)
Killip class II, III, or IV — no. (%)
77 (7.7)
69 (6.9)
129 (13.1)
148 (15.0)
≤60 mL/min
147 (14.7)
165 (16.5)
>60 mL/min
854 (85.3)
833 (83.5)
Anemia — no. (%)
Creatinine clearance — no. (%)
* P < 0.05 between groups
Procedures, Medications
Bivalirudin
(N=1089)
Heparins with optional GPI
(N=1109)
1030 (94.6)
1045 (94.2)
59 (5.4)
64 (5.8)
1088 (100)
1107 (99.8)
1048/1066 (98.3)
1058/1083 (97.7)
Clopidogrel
524/1048 (50.0)
545/1058 (51.5)
Ticlopidine
0 (0.0)
2 (0.2)
Prasugrel
323/1048 (30.8)
306/1058 (28.9)
Ticagrelor
201/1048 (19.2)
205/1058 (19.4)
913/1011 (90.3)
923/1010 (91.4)
Maintenance dose - yes
957/1065 (89.9)
969/1082 (89.6)
Clopidogrel
377/957 (39.4)
407/969 (42.0)
Ticlopidine
2/957 (0.2)
5/969 (0.5)
Prasugrel
321/957 (33.5)
298/969 (30.8)
Ticagrelor
257/957 (26.9)
259/969 (26.7)
Randomized in ambulance no. (%)
Randomized in non–PCI-capable hospital— no. (%)
Aspirin use — no. (%)
P2Y12 inhibitor loading dose — no. (%)
Yes
P2Y12 loading before angiography — no. (%)
Procedures, Medications, con’t
Bivalirudin
(N=1089)
Heparins with optional
GPI (N=1109)
1074 (98.6)
29 (2.6)
24 (2.2)
997 (89.9)
0
94 (8.5)
50.0 (37−67)
50.0 (37−65)
125/1088 (11.5)
766/1109 (69.1)*
Routine
42/1088 (3.9)‡
649/1109 (58.5)*
Bailout§
83/1046 (7.9)
117/460 (25.4)*
Femoral access — no. (%)
558/1069 (52.2)
582/1084 (53.7)
Radial access — no. (%)
510/1069 (47.7)
502/1084 (46.3)
Initial anticoagulation — no. (%)
Bivalirudin
Unfractionated heparin
Enoxaparin
Time from initiating anticoagulation to angiography
— median (IQR), min
Glycoprotein IIb/IIIa inhibitor use — no. (%)
* P < 0.05 between groups
‡ Deviations from the protocol
§ Data given for those eligible for bailout (i.e. who did not receive routine GPI).
Procedural Characteristics
Single vessel disease — no. (%)
Infarct artery treated with primary PCI — no. (%)
Left main coronary artery
Left anterior descending artery
Left circumflex coronary artery
Right coronary artery
Bypass graft (venous or arterial)
Balloon angioplasty only — no. (%)
Stents implanted — no. (%)
Drug-eluting stent
Thrombectomy — no. (%)
Pre-PCI TIMI flow — no. (%)
0/1
2
3
Post-PCI TIMI flow — no. (%)
0/1
2
3
CABG during hospitalization
Bivalirudin
Heparins with optional GPI
(N=1089)
(N=1109)
591/1069 (55.3)
556/1083 (51.3)
6/943 (0.6)
425/943 (45.1)
115/943 (12.2)
417/943 (44.2)
4/943 (0.4)
48/943 (5.1)
868/943 (92.0)
538/943 (57.1)
304/943 (32.2)
13/946 (1.4)
423/946 (44.7)
132/946 (14.0)
412/946 (43.6)
10/946 (1.1)
42/946 (4.4)
865/946 (91.4)
529/946 (55.9)
298/946 (31.5)
593/931 (63.7)
143/931(15.4)
195/931 (20.9)
563/932 (60.4)
158/932 (17.0)
211/932 (22.6)
18/930 (1.9)
29/930 (3.1)
883/930 (94.9)
21/1089 (1.9)
16/932 (1.7)
31/932 (3.3)
885/932 (95.0)
29/1109 (2.6)
Medications at Discharge (ITT)
ACE inhibitor or ARB
Bivalirudin
(N=1089)
718 (65.9)
Heparins + optional GPI
(N=1109)
709 (63.9)
Aspirin
1000 (91.8)
1012 (91.3)
Beta-blocker
944 (86.7)
957 (86.3)
P2Y12 inhibitor
938 (86.1)
941 (84.9)
Statin
968 (88.9)
997 (89.9)
Variable — no. (%)
Primary Endpoint:
Death or Major Bleed, 30 day
10.0
Bivalirudin
Event Rate
8.4%
Heparins with optional GPI
8.0
6.0
5.1%
4.0
2.0
Log-rank p = 0.002
0.0
0
5
10
15
20
25
30
Days from Randomization Date
Patients at risk:
Bivalirudin
1089
1038
1024
1020
1007
988
791
Heparins with
optional GPI
1109
1024
1003
998
984
958
765
Principal Secondary Endpoint:
Death/Reinfarction/Major Bleed, 30 day
12.0
Bivalirudin
10.0
Heparins with optional GPI
9.1%
Event
Rate
8.0
6.7%
6.0
4.0
Log-rank p = 0.03
2.0
0.0
0
5
10
15
20
25
30
Days from Randomization Date
Patients at risk:
Bivalirudin
1089
1027
1010
1005
990
971
779
Heparins with
optional GPI
1109
1020
996
990
975
949
760
Cardiac and Non-Cardiac Death, 30-day
4.0
Bivalirudin
Heparins with optional GPI
Event Rate
3.0
3.0%
Log-rank p = 0.46
Cardiac
2.4%
2.0
1.0
Log-rank p = 0.10
Non-cardiac
0.5%
0.1%
0.0
0
5
10
15
20
25
30
Days from Randomization Date
Patients at risk:
Bivalirudin
1089
1057
1048
1044
1039
1036
1034
Heparins with
optional GPI
1109
1062
1061
1056
1050
1043
1037
Non–CABG-related major bleed, 30 day
8.0
Bivalirudin
Heparins with optional GPI
6.1%
Event Rate
6.0
4.0
Log-rank p < 0.001
2.7%
2.0
0.0
0
5
10
15
20
25
30
Days from Randomization Date
Patients at risk:
Bivalirudin
1089
1040
1025
1022
1010
991
794
Heparins with
optional GPI
1109
1030
1009
1005
990
964
773
NACE: Death, Reinfarction, IDR, Stroke,
Major Bleed, 30 day
12.0
Bivalirudin
Heparins with optional GPI
10.0
10.7%
Event
Rate
8.0
7.9%
6.0
4.0
Log-rank p = 0.024
2.0
0.0
0
5
10
15
20
25
30
Days from Randomization Date
Patients at risk:
Bivalirudin
1089
1018
998
992
977
959
769
Heparins with
optional GPI
1109
1012
983
976
960
934
746
Clinical Outcomes, 30 days
Bivalirudin
(N=1089)
Heparins with
optional GPI
(N=1109)
Relative risk
[95% CI]
P Value
55 (5.1)
94 (8.5)
0.60 (0.43–0.82)
0.001
72 (6.6)
102 (9.2)
0.72 (0.54–0.96)
0.02
32 (2.9)
34 (3.1)
0.96 (0.60–1.54)
0.86
Cardiac causes
27 (2.5)
33 (3.0)
0.83 (0.50–1.38)
0.48
Noncardiac causes
5 (0.5)
1 (0.1)
5.09 (0.60–43.51)
0.12
Major bleeding (non-CABG)
28 (2.6)
67 (6.0)
0.43 (0.28–0.66)
<0.001
Major adverse cardiovascular
events*
65 (6.0)
61 (5.5)
1.09 (0.77–1.52)
0.64
Net adverse clinical events *
85 (7.8)
118 (10.6)
0.73 (0.56–0.96)
0.02
Death or major bleeding (nonCABG) (primary outcome)
Death, reinfarction, or major
bleeding (non-CABG)
(key secondary outcome)
Death
*Patients may have experienced more than one event.
MACE denotes death, reinfarction, ischemia-driven revascularization or stroke;
NACE denotes (death, reinfarction, ischemia-driven revascularization, stroke, or non–CABG major bleeding)
Bleeding rates, 30 days
Bivalirudin
(N=1089)
Heparins with
optional GPI
(N=1109)
Relative risk
[95% CI]
P Value
Major bleeding (non-CABG)
28 (2.6)
67 (6.0)
0.43 (0.28–0.66)
<0.001
Major or minor bleeding (non-CABG)
85 (7.8)
149 (13.4)
0.58 (0.45–0.75)
<0.001
TIMI major bleeding (non-CABG)
14 (1.3)
23 (2.1)
0.62 (0.32–1.20)
0.15
TIMI major/minor bleeding (non-CABG)
85 (7.8)
146 (13.2)
0.59 (0.46–0.76)
<0.001
6 (0.6)
10 (0.9)
0.61 (0.22–1.68)
0.33
14 (1.3)
26 (2.3)
0.55 (0.29–1.04)
0.06
GUSTO any bleeding (non-CABG)
85 (7.8)
148 (13.3)
0.58 (0.45–0.75)
<0.001
Blood transfusion
23 (2.1)
43 (3.9)
0.54 (0.33–0.90)
0.02
GUSTO severe/life-threatening bleeding
(non-CABG)
GUSTO severe/life-threatening or
moderate bleeding (non-CABG)
•
Patients may have experienced more than one event.
Outcomes, 30 days, con’t
Bivalirudin
(N=1089)
Heparins with
optional GPI
(N=1109)
Relative risk
[95% CI]
P Value
19 (1.7)
10 (0.9)
1.93 (0.90–4.14)
0.08
Q-wave
3 (0.3)
2 (0.2)
1.53 (0.26–9.12)
0.68
Non-Q-wave
16 (1.5)
8 (0.7)
2.04 (0.88–4.74)
0.09
17 (1.6)
6 (0.5)
2.89 (1.14–7.29)
0.02
Definite
17 (1.6)
6 (0.5)
2.89 (1.14–7.29)
0.02
Probable
0 (0)
0 (0)
–
n/a
Acute (≤24 hours)
12 (1.1)
2 (0.2)
6.11 (1.37–27.24)
0.007
Subacute (>24 hours to 30 days)
5 (0.5)
4 (0.4)
1.27 (0.34–4.73)
0.75
Ischemia-driven revascularization
24 (2.2)
17 (1.5)
1.44 (0.78–2.66)
0.25
Reinfarction, ischemia-driven
revascularization or stent thrombosis
Any stroke
29 (2.7)
21 (1.9)
1.41 (0.81–2.45)
0.23
6 (0.6)
11 (1.0)
0.56 (0.21–1.50)
0.24
6 (0.6)
9 (0.8)
0.68 (0.24–1.9)
0.46
0
2 (0.2)
Not applicable
0.50
7 (0.7)
14 (1.4)
0.50 (0.20–1.24)
0.13
Reinfarction
Stent thrombosis (ARC definition)
Ischemic
Hemorrhagic
Acquired thrombocytopenia
n/a: not applicable.
Subgroup Analysis:
Death/Major Bleed at 30 Days (ITT)
ALL
Age
>65 years
≤65 years
Sex
Male
Female
Diabetes
Yes
No
Arterial access site
Radial
Femoral
Vessels with stenosis >50%
1 vessel with stenosis >50%
≥2 vessels with stenosis >50%
Stent type
At least one drug-eluting stent
All bare metal stents
0.1
Bivalirudin better
1.0
Bivalirudin
(N=1089)
n/N (%)
55/1089 (5.1)
Heparins with
optional GPI
(N=1109)
n/N (%)
94/1109 (8.5)
Relative Risk
(95% CI)
0.60 [0.43, 0.82)
39/394 (9.9)
16/695 (2.3)
61/434 (14.1)
33/675 (4.9)
0.70 [0.48, 1.03]
0.47 [0.26, 0.85]
0.31
32/814 (3.9)
23/275 (8.4)
64/861 (7.4)
30/248 (12.1)
0.53 [0.35, 0.80]
0.69 [0.41, 1.16]
0.47
12/127 (9.4)
40/946 (4.2)
18/169 (10.7)
71/926 (7.7)
0.89 [0.44, 1.77]
0.55 [0.38, 0.80]
0.26
20/510 (3.9)
31/558 (5.6)
33/502 (6.6)
53/582 (9.1)
0.60 [0.35, 1.03]
0.61 [0.40, 0.94]
0.97
19/591 (3.2)
28/407 (6.9)
33/556 (5.9)
49/462 (10.6)
0.54 [0.31, 0.94]
0.65 [0.42, 1.01]
0.66
22/538 (4.1)
16/330 (4.8)
39/529 (7.4)
27/336 (8.0)
0.55 [0.33, 0.92]
0.60 [0.33, 1.10]
0.84
10.0
Heparins with optional GPI better
Interaction
P-value
Subgroup Analysis:
Death/Major Bleed at 30 Days (ITT)
Killip class
1
2-4
P2Y12 inhibitor loading dose
Clopidogrel
Prasugrel
Ticagrelor
P2Y12 inhibitor maintenance dose
Clopidogrel
Prasugrel
Ticagrelor
Time on drug to angiography
<50 min
≥50 min
Baseline creatinine clearance
≤60
>60
Target Vessel
Left anterior descending (LAD)
No LAD
0.1
Bivalirudin better
1.0
Bivalirudin
(N=1089)
n/N (%)
Heparins with
optional GPI
(N=1109)
n/N (%)
Relative Risk
(95% CI)
Interaction
P-value
32/919 (3.5)
14/ 77 (18.2)
59/931 (6.3)
24/ 69 (34.8)
0.55 [0.36, 0.84]
0.52 [0.29, 0.93]
0.58
25/524 (4.8)
16/323 (5.0)
11/201 (5.5)
38/545 (7.0)
22/306 (7.2)
21/205 (10.2)
0.68 [0.42, 1.12]
0.69 [0.37, 1.29]
0.53 [0.26, 1.08]
0.82
19/377 (5.0)
16/321 (5.0)
7/257 (2.7)
28/407 (6.9)
19/298 (6.4)
21/259 (8.1)
0.73 [0.42, 1.29]
0.78 [0.41, 1.49]
0.34 [0.15, 0.78]
0.24
23/514 (4.5)
27/549 (4.9)
42/495 (8.5)
42/576 (7.3)
0.53 [0.32, 0.86]
0.67 [0.42, 1.08]
0.48
21/147 (14.3)
28/854 (3.3)
30/165 (18.2)
48/833 (5.8)
0.79 [0.47, 1.31]
0.57 [0.36, 0.90]
0.44
30/425 (7.1)
25/664 (3.8)
42/423 (9.9)
52/686 (7.6)
0.71 [0.45, 1.11]
0.50 [0.31, 0.79]
0.30
10.0
Heparins with optional GPI better
Subgroup Analysis:
Death/Reinfarction/Major Bleed at 30 Days (ITT)
ALL
Age
>65 years
≤65 years
Sex
Male
Female
Diabetes
Yes
No
Arterial access site
Radial
Femoral
Vessels with stenosis >50%
1 vessel with stenosis >50%
≥2 vessels with stenosis >50%
Stent type
At least one drug-eluting stent
All bare metal stents
Killip class
1
2-4
P2Y12 inhibitor loading dose
Clopidogrel
Prasugrel
Ticagrelor
P2Y12 inhibitor maintenance dose
Clopidogrel
Prasugrel
Ticagrelor
Time on drug to angiography
<50 min
≥50 min
Baseline creatinine clearance
≤60
>60
Target Vessel
Left anterior descending (LAD)
No LAD
Bivalirudin better 0.1
1.0
Bivalirudin
(N=1089)
n/N (%)
Heparins with
optional GPI
(N=1109)
n/N (%)
Relative Risk
(95% CI)
72/0189 (6.6)
102/1109 (9.2)
0.72 [0.54-0.96]
45/394 (11.4)
27/695 (3.9)
65/434 (15.0)
37/675 (5.5)
0.76 [0.53, 1.09]
0.71 [0.44, 1.15]
0.88
43/814 (5.3)
29/275 (10.5)
71/861 (8.2)
31/248 (12.5)
0.64 [0.44, 0.92]
0.84 [0.52, 1.36]
0.40
14/127 (11.0)
54/946 (5.7)
20/169 (11.8)
77/926 (8.3)
0.93 [0.49, 1.77]
0.69 [0.49, 0.96]
0.43
26/510 (5.1)
42/558 (7.5)
35/502 (7.0)
59/582 (10.1)
0.73 [0.45, 1.20]
0.74 [0.51, 1.08]
0.99
25/591 (4.2)
39/407 (9.6)
35/556 (6.3)
55/462 (11.9)
0.67 [0.41, 1.11]
0.80 [0.55, 1.19]
0.61
29/538 (5.4)
24/330 (7.3)
44/529 (8.3)
29/336 (8.6)
0.65 [0.41, 1.02]
0.84 [0.50, 1.42]
0.46
47/919 (5.1)
14/77 (18.2)
67/931 (7.2)
24/69 (34.8)
0.71 [0.50, 1.02]
0.52 [0.29, 0.93]
0.24
32/524 (6.1)
21/323 (6.5)
15/201 (7.5)
45/545 (8.3)
22/306 (7.2)
22/205 (10.7)
0.74 [0.48, 1.15]
0.90 [0.51, 1.61]
0.70 [0.37, 1.30]
0.80
24/377 (6.4)
22/321 (6.9)
11/257 (4.3)
32/407 (7.9)
20/298 (6.7)
24/259 (9.3)
0.81 [0.49, 1.35]
1.02 [0.57, 1.83]
0.46 [0.23, 0.92]
0.22
34/514 (6.6)
33/549 (6.0)
45/495 (9.1)
47/576 (8.2)
0.73 [0.47, 1.12]
0.74 [0.48, 1.13]
0.96
22/147 (15.0)
44/854 (5.2)
31/165 (18.8)
55/833 (6.6)
0.80 [0.48, 1.31]
0.78 [0.53, 1.15]
0.98
36/425 (8.5)
36/664 (5.4)
46/423 (10.9)
56/686 (8.2)
0.78 [0.51, 1.18]
0.66 [0.44, 1.00]
0.61
Interaction
P-value
10.0 Heparins with optional GPI better
Subgroup Analysis:
Major Bleed at 30 Days (ITT)
Bivalirudin
(N=1089)
n/N (%)
Heparins with
optional GPI
(N=1109)
n/N (%)
Relative Risk
(95% CI)
28 /1089 (2.6)
67 /1109 (6.0)
0.43 [0.28, 0.66]
19/394 (4.8)
9/695 (1.3)
39/434 (9.0)
28/675 (4.1)
0.54 [0.32, 0.91]
0.31 [0.15, 0.66]
0.28
15/814 (1.8)
13/275 (4.7)
43/861 (5.0)
24/248 (9.7)
0.37 [0.21, 0.66]
0.49 [0.25, 0.94]
0.58
5/127 (3.9)
22/946 (2.3)
9/169 (5.3)
58/926 (6.3)
0.74 [0.25, 2.15]
0.37 [0.23, 0.60]
0.25
14/510 (2.7)
14/558 (2.5)
25/502 (5.0)
40/582 (6.9)
0.55 [0.29, 1.05]
0.37 [0.20, 0.66]
0.35
12/591 (2.0)
15/407 (3.7)
27/556 (4.9)
34/462 (7.4)
0.42 [0.21, 0.82]
0.50 [0.28, 0.91]
0.72
15/538 (2.8)
7/330 (2.1)
31/529 (5.9)
20/336 (6.0)
0.48 [0.26, 0.87]
0.36 [0.15, 0.83]
0.59
17/919 (1.8)
9/77 (11.7)
49/931 (5.3)
12/69 (17.4)
0.35 [0.20, 0.61]
0.67 [0.30, 1.50]
0.27
12/524 (2.3)
12/323 (3.7)
4/201 (2.0)
24/545 (4.4)
19/306 (6.2)
16/205 (7.8)
0.52 [0.26, 1.03]
0.60 [0.30, 1.21]
0.25 [0.09, 0.75]
0.41
9/377 (2.4)
14/321 (4.4)
4/257 (1.6)
21/407 (5.2)
17/298 (5.7)
18/259 (6.9)
0.46 [0.21, 1.00]
0.76 [0.38, 1.52]
0.22 [0.08, 0.65]
0.16
13/514 (2.5)
15/549 (2.7)
29/495 (5.9)
35/576 (6.1)
0.43 [0.23, 0.82]
0.45 [0.25, 0.81]
0.93
8/147 (5.4)
18/854 (2.1)
21/165 (12.7)
42/833 (5.0)
0.43 [0.20, 0.94]
0.42 [0.24, 0.72]
0.96
19/425 (4.5)
9/664 (1.4)
30/423 (7.1)
37/686 (5.4)
0.63 [0.36, 1.10]
0.25 [0.12, 0.52]
0.05
ALL
Age
>65 years
≤65 years
Sex
Male
Female
Diabetes
Yes
No
Arterial access site
Radial
Femoral
Vessels with stenosis >50%
1 vessel with stenosis >50%
≥2 vessels with stenosis >50%
Stent type
At least one drug-eluting stent
All bare metal stents
Killip class
1
2-4
P2Y12 inhibitor loading dose
Clopidogrel
Prasugrel
Ticagrelor
P2Y12 inhibitor maintenance dose
Clopidogrel
Prasugrel
Ticagrelor
Time on drug to angiography
<50 min
≥50 min
Baseline creatinine clearance
≤60
>60
Target Vessel
Left anterior descending (LAD)
No LAD
Bivalirudin better
0.01
0.10
1.00
10.00
Heparins with optional GPI better
Interaction
P-value
Limitations of the study
• The study was open-label, for logistical reasons.
• In order to reduce sample size, the primary endpoint was
changed (while still entirely blinded to results) from an
original composite of death/reinfarction/major bleeding to
death/major bleeding, retaining the original composite as key
secondary endpoint.
• The trial was not powered to examine 30-day mortality.
• Although the trial allowed use of UFH or enoxaparin in the
control arm, too few patients received the latter to reliably
test the consistency of the benefit of bivalirudin across
heparins.
Conclusions
•
Prehospital initiation of bivalirudin, as compared with heparin with optional use of
glycoprotein IIb/IIIa inhibitors, reduced the primary composite and the key
secondary outcomes in patients with STEMI who were being transported for
primary PCI.
•
These benefits, which were consistent across subgroups, stemmed from
substantial reductions in major bleeding.
•
However, the risk of acute stent thrombosis was higher in the bivalirudin group.
•
These results were achieved on a background of contemporary care, with a high
rate of radial access, use of novel P2Y12 inhibitors, and optional GPI use in the
control arm.
•
They inform pre-hospital management of STEMI and support a role for bivalirudin
in this setting.
Study Committees
Executive Committee
Ph.G. Steg (Chair), J. Adgey, P. Clemmensen, P. Goldstein,
M. Hamon, A. van ‘t Hof, L. Nibbe, U. Zeymer
International Steering
Committee
C.W. Hamm (Chair); J. Hill, Tom Quinn (UK); P.
Clemmensen, J. Steinmetz (Denmark); P. Coste, F.
Lapostolle (France); C. Cavallini, G. Gordini; F.W.A.
Verheugt, J. ten Berg (Netherlands); U. Zeymer, L. Nibbe
(Germany); M. Hirschl, K. Huber (Austria); A. Cequier
(Spain); D. Dudek (Poland); P. Widimský (Czech Republic);
V. Kanic (Slovenia)
Data Monitoring
Committee
N. Danchin (Chair), I. Ford, A. Maggioni, R. Mehran, G.
Montalescot
Independent statistician
(interim analysis)
C.R. Mehta
Independent statistical
group
T.C. Clayton, S.J. Pocock
Clinical Events
Committee
K. Thygesen, J. Peder Bagger
For full details (including the protocol, statistical
analysis plan and supplementary data appendix),
go to www.nejm.org
Steg PG, van’t Hof A, Hamm CW et al. N Engl J Med 2013
Backup slides
Patient Disposition
2218 Patients with presumed STEMI and symptom
onset ≤12 hours underwent randomization
1102 assigned to bivalirudin after initial consent*
1089/1102 (98.8%) provided written final informed consent
1116 assigned to standard of care after initial consent*
1109/1116 (99.4%) provided written final informed consent
1069/1089 (98.2%) underwent emergent angiography
1084/1109 (97.7%) underwent emergent angiography
Principal management strategy:
949/1069 (88.8%) Primary PCI
17/1069 (1.6%) CABG
103/1069 (9.6%) Medical Management
Principal management strategy:
947/1084 (87.4%) Primary PCI
25/1084 (2.3%) CABG
112/1084 (10.3%) Medical Management
8 withdrew consent
7 were lost to follow-up
8 withdrew consent
15 were lost to follow-up
1074/1089 (98.6%) completed 30 days in the study
1086/1109 (97.9%) completed 30 days in the study
1089 were included in the intention-to-treat analysis
1109 were included in the intention-to-treat analysis
Components of Major Bleeding Up to
30 Days, ITT
Component
Bivalirudin
(N=1089)
Heparins with
optional GPI
(N=1109)
Relative risk
[95% CI]
P Value
Intracranial
Retroperitoneal
Intraocular
Cardiac tamponade
Access site hemorrhage
requiring intervention
Clinically overt bleed
0/1089 (0.0)
2/1089 (0.2)
0/1089 (0.0)
1/1089 (0.1)
3/1089 (0.3)
2/1109 (0.2)
0/1109 (0.0)
0/1109 (0.0)
1/1109 (0.1)
12/1109 (1.1)
N/A
N/A
N/A
1.02 [0.06, 16.26]
0.25 [0.07, 0.90]
0.50
0.25
N/A
1.00
0.02
2/1089 (0.2)
4/1109 (0.4)
0.51 [0.09, 2.77]
0.69
Drop in hemoglobin or
hematocrit
Reoperation for bleeding
12/1089 (1.1)
34/1109 (3.1)
0.36 [0.19, 0.69]
0.001
3/1089 (0.3)
0/1109 (0.0)
N/A
0.12
Blood transfusion
8/1089 (0.7)
24/1109 (2.2)
0.34 [0.15, 0.75]
0.005
Hemodynamic compromise
1/1089 (0.1)
2/1109 (0.2)
0.51 [0.05, 5.61]
1.00
* Patients may have experienced more than one event.
CI denotes confidence interval, GPI glycoprotein inhibitor, and NA not applicable.
Main Inclusion and Exclusion Criteria
• Patients presenting ≤12 h of symptom onset with a presumed
diagnosis of STEMI
– either ST-segment elevation ≥1 mm in 2 contiguous ECG leads, or
– presumed new LBBB or ST-segment depression ≥1 mm in at least 2
leads in V1–V3 with a positive terminal T wave
• Scheduled for angiography with anticipated primary PCI <2 h
after first medical contact
• Excluded:
– treatment with any injectable anticoagulant immediately before
randomization
– previous oral anticoagulation
– recent surgery
– bleeding history

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