Results of the EUROMAX trialPhilippe 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, Franceand 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 ?
2218 patients with STEMI with symptom onset >20 min and ≤12h Randomized in ambulance or non-PCI hospital
Intent for primary PCI
UFH/LMWH ± GPIPer standard practice
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)
Aspirin + P2Y12 inhibitor (any) as soon as possibleR
1:1
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
EUROMAX Trial Design
clinicaltrials.gov NCT01087723
EUROMAX - A European TrialN=2218
France – 795
Netherlands – 768 Germany – 279 Denmark – 150
Slovenia
Czech Rep.Poland
Italy
Austria 206
Baseline CharacteristicsBivalirudin (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)
Anemia — no. (%) 129 (13.1) 148 (15.0)Creatinine clearance — no. (%)
≤60 mL/min 147 (14.7) 165 (16.5)
>60 mL/min 854 (85.3) 833 (83.5)
* P < 0.05 between groups
Procedures, MedicationsBivalirudin (N=1089)
Heparins with optional GPI (N=1109)
Randomized in ambulance no. (%) 1030 (94.6) 1045 (94.2)
Randomized in non–PCI-capable hospital— no. (%) 59 (5.4) 64 (5.8)Aspirin use — no. (%) 1088 (100) 1107 (99.8)
P2Y12 inhibitor loading dose — no. (%)
Yes 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)
P2Y12 loading before angiography — no. (%) 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)
Procedures, Medications, con’tBivalirudin (N=1089)
Heparins with optional GPI (N=1109)
Initial anticoagulation — no. (%) Bivalirudin 1074 (98.6) 29 (2.6)Unfractionated heparin 24 (2.2) 997 (89.9)Enoxaparin 0 94 (8.5)
Time from initiating anticoagulation to angiography — median (IQR), min
50.0 (37−67) 50.0 (37−65)
Glycoprotein IIb/IIIa inhibitor use — no. (%) 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)
* 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 CharacteristicsBivalirudin (N=1089)
Heparins with optional GPI (N=1109)
Single vessel disease — no. (%) 591/1069 (55.3) 556/1083 (51.3)Infarct artery treated with primary PCI — no. (%) Left main coronary artery 6/943 (0.6) 13/946 (1.4)
Left anterior descending artery 425/943 (45.1) 423/946 (44.7)Left circumflex coronary artery 115/943 (12.2) 132/946 (14.0)Right coronary artery 417/943 (44.2) 412/946 (43.6)Bypass graft (venous or arterial) 4/943 (0.4) 10/946 (1.1)
Balloon angioplasty only — no. (%) 48/943 (5.1) 42/946 (4.4)Stents implanted — no. (%) 868/943 (92.0) 865/946 (91.4)
Drug-eluting stent 538/943 (57.1) 529/946 (55.9)Thrombectomy — no. (%) 304/943 (32.2) 298/946 (31.5)Pre-PCI TIMI flow — no. (%)
0/1 593/931 (63.7) 563/932 (60.4)2 143/931(15.4) 158/932 (17.0)3 195/931 (20.9) 211/932 (22.6)
Post-PCI TIMI flow — no. (%) 0/1 18/930 (1.9) 16/932 (1.7)2 29/930 (3.1) 31/932 (3.3)3 883/930 (94.9) 885/932 (95.0)
CABG during hospitalization 21/1089 (1.9) 29/1109 (2.6)
Medications at Discharge (ITT)
Variable — no. (%) Bivalirudin (N=1089)
Heparins + optional GPI(N=1109)
ACE inhibitor or ARB 718 (65.9) 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)
0 5 10 15 20 25 300.0
2.0
4.0
6.0
8.0
10.0
Days from Randomization Date
Even
t Rat
e
Bivalirudin 1089 1038 1024 1020 1007 988 791
Heparins with optional GPI 1109 1024 1003 998 984 958 765
Bivalirudin
Heparins with optional GPI 8.4%
Log-rank p = 0.002
Patients at risk:
Primary Endpoint:Death or Major Bleed, 30 day
5.1%
0 5 10 15 20 25 300.0
2.0
4.0
6.0
8.0
10.0
Log-rank p = 0.03
Days from Randomization Date
Even
t R
ate
9.1%
Principal Secondary Endpoint: Death/Reinfarction/Major Bleed, 30 day
Bivalirudin
Heparins with optional GPI
Bivalirudin 1089 1027 1010 1005 990 971 779
Heparins with optional GPI 1109 1020 996 990 975 949 760
Patients at risk:
6.7%
0 5 10 15 20 25 300.0
1.0
2.0
3.0
4.0
Cardiac
Non-cardiac
Log-rank p = 0.46
Log-rank p = 0.10
3.0%
Cardiac and Non-Cardiac Death, 30-day
Days from Randomization Date
Bivalirudin 1089 1057 1048 1044 1039 1036 1034
Heparins with optional GPI 1109 1062 1061 1056 1050 1043 1037
Patients at risk:
Bivalirudin
Heparins with optional GPI
2.4%
0.1%
0.5%
Even
t Rat
e
0 5 10 15 20 25 300.0
2.0
4.0
6.0
8.0
2.7%
Log-rank p < 0.001
Non–CABG-related major bleed, 30 day
Days from Randomization Date
Bivalirudin 1089 1040 1025 1022 1010 991 794
Heparins with optional GPI 1109 1030 1009 1005 990 964 773
Patients at risk:
Even
t Rat
e
6.1%
Bivalirudin
Heparins with optional GPI
0 5 10 15 20 25 300.0
2.0
4.0
6.0
8.0
10.0
12.0
Log-rank p = 0.024
NACE: Death, Reinfarction, IDR, Stroke, Major Bleed, 30 dayBivalirudin
Heparins with optional GPI 10.7%
7.9%
Even
t R
ate
Days from Randomization Date
Bivalirudin 1089 1018 998 992 977 959 769
Heparins with optional GPI 1109 1012 983 976 960 934 746
Patients at risk:
Clinical Outcomes, 30 daysBivalirudin (N=1089)
Heparins with optional GPI
(N=1109)
Relative risk [95% CI]
P Value
Death or major bleeding (non-CABG) (primary outcome) 55 (5.1) 94 (8.5) 0.60 (0.43–0.82) 0.001
Death, reinfarction, or major bleeding (non-CABG) (key secondary outcome)
72 (6.6) 102 (9.2) 0.72 (0.54–0.96) 0.02
Death 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
*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
GUSTO severe/life-threatening bleeding (non-CABG) 6 (0.6) 10 (0.9) 0.61 (0.22–1.68) 0.33
GUSTO severe/life-threatening or moderate bleeding (non-CABG) 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
• Patients may have experienced more than one event.
Outcomes, 30 days, con’tBivalirudin (N=1089)
Heparins with optional GPI
(N=1109)
Relative risk [95% CI]
P Value
Reinfarction 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) 0.09Stent thrombosis (ARC definition) 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) 0.75Ischemia-driven revascularization 24 (2.2) 17 (1.5) 1.44 (0.78–2.66) 0.25Reinfarction, ischemia-driven revascularization or stent thrombosis
29 (2.7) 21 (1.9) 1.41 (0.81–2.45) 0.23
Any stroke 6 (0.6) 11 (1.0) 0.56 (0.21–1.50) 0.24 Ischemic 6 (0.6) 9 (0.8) 0.68 (0.24–1.9) 0.46 Hemorrhagic 0 2 (0.2) Not applicable 0.50Acquired thrombocytopenia 7 (0.7) 14 (1.4) 0.50 (0.20–1.24) 0.13
n/a: not applicable.
Bivalirudin(N=1089)n/N (%)
Heparins with optional GPI
(N=1109)n/N (%)
Relative Risk(95% CI)
Interaction P-value
ALL 55/1089 (5.1) 94/1109 (8.5) 0.60 [0.43, 0.82)Age >65 years 39/394 (9.9) 61/434 (14.1) 0.70 [0.48, 1.03] 0.31 ≤65 years 16/695 (2.3) 33/675 (4.9) 0.47 [0.26, 0.85]Sex Male 32/814 (3.9) 64/861 (7.4) 0.53 [0.35, 0.80] 0.47 Female 23/275 (8.4) 30/248 (12.1) 0.69 [0.41, 1.16]Diabetes Yes 12/127 (9.4) 18/169 (10.7) 0.89 [0.44, 1.77] 0.26 No 40/946 (4.2) 71/926 (7.7) 0.55 [0.38, 0.80]Arterial access site Radial 20/510 (3.9) 33/502 (6.6) 0.60 [0.35, 1.03] 0.97 Femoral 31/558 (5.6) 53/582 (9.1) 0.61 [0.40, 0.94]Vessels with stenosis >50% 1 vessel with stenosis >50% 19/591 (3.2) 33/556 (5.9) 0.54 [0.31, 0.94] 0.66 ≥2 vessels with stenosis >50% 28/407 (6.9) 49/462 (10.6) 0.65 [0.42, 1.01]Stent type At least one drug-eluting stent 22/538 (4.1) 39/529 (7.4) 0.55 [0.33, 0.92] 0.84 All bare metal stents 16/330 (4.8) 27/336 (8.0) 0.60 [0.33, 1.10]
Subgroup Analysis:Death/Major Bleed at 30 Days (ITT)
0.1 1.0 10.0Bivalirudin better Heparins with optional GPI better
Bivalirudin(N=1089)n/N (%)
Heparins with optional GPI
(N=1109)n/N (%)
Relative Risk(95% CI)
Interaction P-value
Killip class 1 32/919 (3.5) 59/931 (6.3) 0.55 [0.36, 0.84] 0.58 2-4 14/ 77 (18.2) 24/ 69 (34.8) 0.52 [0.29, 0.93]P2Y12 inhibitor loading dose Clopidogrel 25/524 (4.8) 38/545 (7.0) 0.68 [0.42, 1.12] 0.82 Prasugrel 16/323 (5.0) 22/306 (7.2) 0.69 [0.37, 1.29] Ticagrelor 11/201 (5.5) 21/205 (10.2) 0.53 [0.26, 1.08]P2Y12 inhibitor maintenance dose Clopidogrel 19/377 (5.0) 28/407 (6.9) 0.73 [0.42, 1.29] 0.24 Prasugrel 16/321 (5.0) 19/298 (6.4) 0.78 [0.41, 1.49] Ticagrelor 7/257 (2.7) 21/259 (8.1) 0.34 [0.15, 0.78]Time on drug to angiography <50 min 23/514 (4.5) 42/495 (8.5) 0.53 [0.32, 0.86] 0.48 ≥50 min 27/549 (4.9) 42/576 (7.3) 0.67 [0.42, 1.08]Baseline creatinine clearance ≤60 21/147 (14.3) 30/165 (18.2) 0.79 [0.47, 1.31] 0.44 >60 28/854 (3.3) 48/833 (5.8) 0.57 [0.36, 0.90]Target Vessel Left anterior descending (LAD) 30/425 (7.1) 42/423 (9.9) 0.71 [0.45, 1.11] 0.30 No LAD 25/664 (3.8) 52/686 (7.6) 0.50 [0.31, 0.79]
Bivalirudin better Heparins with optional GPI better
Subgroup Analysis:Death/Major Bleed at 30 Days (ITT)
0.1 1.0 10.0
Bivalirudin(N=1089)
n/N (%)
Heparins with optional GPI
(N=1109)n/N (%)
Relative Risk(95% CI)
Interaction P-value
ALL 72/0189 (6.6) 102/1109 (9.2) 0.72 [0.54-0.96]Age >65 years 45/394 (11.4) 65/434 (15.0) 0.76 [0.53, 1.09] 0.88 ≤65 years 27/695 (3.9) 37/675 (5.5) 0.71 [0.44, 1.15] Sex Male 43/814 (5.3) 71/861 (8.2) 0.64 [0.44, 0.92] 0.40 Female 29/275 (10.5) 31/248 (12.5) 0.84 [0.52, 1.36] Diabetes Yes 14/127 (11.0) 20/169 (11.8) 0.93 [0.49, 1.77] 0.43 No 54/946 (5.7) 77/926 (8.3) 0.69 [0.49, 0.96] Arterial access site Radial 26/510 (5.1) 35/502 (7.0) 0.73 [0.45, 1.20] 0.99 Femoral 42/558 (7.5) 59/582 (10.1) 0.74 [0.51, 1.08] Vessels with stenosis >50% 1 vessel with stenosis >50% 25/591 (4.2) 35/556 (6.3) 0.67 [0.41, 1.11] 0.61 ≥2 vessels with stenosis >50% 39/407 (9.6) 55/462 (11.9) 0.80 [0.55, 1.19] Stent type At least one drug-eluting stent 29/538 (5.4) 44/529 (8.3) 0.65 [0.41, 1.02] 0.46 All bare metal stents 24/330 (7.3) 29/336 (8.6) 0.84 [0.50, 1.42] Killip class 1 47/919 (5.1) 67/931 (7.2) 0.71 [0.50, 1.02] 0.24 2-4 14/77 (18.2) 24/69 (34.8) 0.52 [0.29, 0.93] P2Y12 inhibitor loading dose Clopidogrel 32/524 (6.1) 45/545 (8.3) 0.74 [0.48, 1.15] 0.80 Prasugrel 21/323 (6.5) 22/306 (7.2) 0.90 [0.51, 1.61] Ticagrelor 15/201 (7.5) 22/205 (10.7) 0.70 [0.37, 1.30] P2Y12 inhibitor maintenance dose Clopidogrel 24/377 (6.4) 32/407 (7.9) 0.81 [0.49, 1.35] 0.22 Prasugrel 22/321 (6.9) 20/298 (6.7) 1.02 [0.57, 1.83] Ticagrelor 11/257 (4.3) 24/259 (9.3) 0.46 [0.23, 0.92] Time on drug to angiography <50 min 34/514 (6.6) 45/495 (9.1) 0.73 [0.47, 1.12] 0.96 ≥50 min 33/549 (6.0) 47/576 (8.2) 0.74 [0.48, 1.13] Baseline creatinine clearance ≤60 22/147 (15.0) 31/165 (18.8) 0.80 [0.48, 1.31] 0.98 >60 44/854 (5.2) 55/833 (6.6) 0.78 [0.53, 1.15] Target Vessel Left anterior descending (LAD) 36/425 (8.5) 46/423 (10.9) 0.78 [0.51, 1.18] 0.61 No LAD 36/664 (5.4) 56/686 (8.2) 0.66 [0.44, 1.00]
0.1 1.0 10.0
Subgroup Analysis:Death/Reinfarction/Major Bleed at 30 Days (ITT)
Bivalirudin better Heparins with optional GPI better
Bivalirudin(N=1089)
n/N (%)
Heparins with optional GPI
(N=1109)n/N (%)
Relative Risk(95% CI)
Interaction P-value
ALL 28 /1089 (2.6) 67 /1109 (6.0) 0.43 [0.28, 0.66] Age >65 years 19/394 (4.8) 39/434 (9.0) 0.54 [0.32, 0.91] 0.28 ≤65 years 9/695 (1.3) 28/675 (4.1) 0.31 [0.15, 0.66] Sex Male 15/814 (1.8) 43/861 (5.0) 0.37 [0.21, 0.66] 0.58 Female 13/275 (4.7) 24/248 (9.7) 0.49 [0.25, 0.94] Diabetes Yes 5/127 (3.9) 9/169 (5.3) 0.74 [0.25, 2.15] 0.25 No 22/946 (2.3) 58/926 (6.3) 0.37 [0.23, 0.60] Arterial access site Radial 14/510 (2.7) 25/502 (5.0) 0.55 [0.29, 1.05] 0.35 Femoral 14/558 (2.5) 40/582 (6.9) 0.37 [0.20, 0.66] Vessels with stenosis >50% 1 vessel with stenosis >50% 12/591 (2.0) 27/556 (4.9) 0.42 [0.21, 0.82] 0.72 ≥2 vessels with stenosis >50% 15/407 (3.7) 34/462 (7.4) 0.50 [0.28, 0.91] Stent type At least one drug-eluting stent 15/538 (2.8) 31/529 (5.9) 0.48 [0.26, 0.87] 0.59 All bare metal stents 7/330 (2.1) 20/336 (6.0) 0.36 [0.15, 0.83] Killip class 1 17/919 (1.8) 49/931 (5.3) 0.35 [0.20, 0.61] 0.27 2-4 9/77 (11.7) 12/69 (17.4) 0.67 [0.30, 1.50] P2Y12 inhibitor loading dose Clopidogrel 12/524 (2.3) 24/545 (4.4) 0.52 [0.26, 1.03] 0.41 Prasugrel 12/323 (3.7) 19/306 (6.2) 0.60 [0.30, 1.21] Ticagrelor 4/201 (2.0) 16/205 (7.8) 0.25 [0.09, 0.75] P2Y12 inhibitor maintenance dose Clopidogrel 9/377 (2.4) 21/407 (5.2) 0.46 [0.21, 1.00] 0.16 Prasugrel 14/321 (4.4) 17/298 (5.7) 0.76 [0.38, 1.52] Ticagrelor 4/257 (1.6) 18/259 (6.9) 0.22 [0.08, 0.65] Time on drug to angiography <50 min 13/514 (2.5) 29/495 (5.9) 0.43 [0.23, 0.82] 0.93 ≥50 min 15/549 (2.7) 35/576 (6.1) 0.45 [0.25, 0.81] Baseline creatinine clearance ≤60 8/147 (5.4) 21/165 (12.7) 0.43 [0.20, 0.94] 0.96 >60 18/854 (2.1) 42/833 (5.0) 0.42 [0.24, 0.72] Target Vessel Left anterior descending (LAD) 19/425 (4.5) 30/423 (7.1) 0.63 [0.36, 1.10] 0.05 No LAD 9/664 (1.4) 37/686 (5.4) 0.25 [0.12, 0.52]
0.01 0.10 1.00
Subgroup Analysis:Major Bleed at 30 Days (ITT)
Bivalirudin better Heparins with optional GPI better
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 CommitteesExecutive Committee Ph.G. Steg (Chair), J. Adgey, P. Clemmensen, P. Goldstein,
M. Hamon, A. van ‘t Hof, L. Nibbe, U. ZeymerInternational 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
Steg PG, van’t Hof A, Hamm CW et al. N Engl J Med 2013
For full details (including the protocol, statistical analysis plan and supplementary data appendix),
go to www.nejm.org
Backup slides
Patient Disposition2218 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
Principal management strategy:949/1069 (88.8%) Primary PCI
17/1069 (1.6%) CABG103/1069 (9.6%) Medical Management
1084/1109 (97.7%) underwent emergent angiography
Principal management strategy:947/1084 (87.4%) Primary PCI
25/1084 (2.3%) CABG112/1084 (10.3%) Medical Management
8 withdrew consent7 were lost to follow-up
8 withdrew consent15 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 0/1089 (0.0) 2/1109 (0.2) N/A 0.50Retroperitoneal 2/1089 (0.2) 0/1109 (0.0) N/A 0.25Intraocular 0/1089 (0.0) 0/1109 (0.0) N/A N/ACardiac tamponade 1/1089 (0.1) 1/1109 (0.1) 1.02 [0.06, 16.26] 1.00Access site hemorrhage requiring intervention
3/1089 (0.3) 12/1109 (1.1) 0.25 [0.07, 0.90] 0.02
Clinically overt bleed 2/1089 (0.2) 4/1109 (0.4) 0.51 [0.09, 2.77] 0.69Drop in hemoglobin or hematocrit
12/1089 (1.1) 34/1109 (3.1) 0.36 [0.19, 0.69] 0.001
Reoperation for bleeding 3/1089 (0.3) 0/1109 (0.0) N/A 0.12Blood transfusion 8/1089 (0.7) 24/1109 (2.2) 0.34 [0.15, 0.75] 0.005Hemodynamic 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