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Results of the EUROMAX trial

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1 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

2 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

3 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 ?

4 EUROMAX Trial Design Bivalirudin UFH/LMWH ± GPI Per standard practice
2218 patients with STEMI with symptom onset >20 min and ≤12h Randomized in ambulance or non-PCI hospital Intent for primary PCI Aspirin + P2Y12 inhibitor (any) as soon as possible R 1:1 UFH/LMWH ± GPI Per 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) 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 NCT

5 EUROMAX - A European Trial
France – 795 Netherlands – 768 Germany – 279 Denmark – 150 Slovenia Czech Rep. Poland Italy Austria 206

6 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) 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

7 Procedures, Medications
Bivalirudin (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) 377/957 (39.4) 407/969 (42.0) 2/957 (0.2) 5/969 (0.5) 321/957 (33.5) 298/969 (30.8) 257/957 (26.9) 259/969 (26.7)

8 Procedures, Medications, con’t
Bivalirudin (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 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).

9 Procedural Characteristics
Bivalirudin (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. (%) 18/930 (1.9) 16/932 (1.7) 29/930 (3.1) 31/932 (3.3) 883/930 (94.9) 885/932 (95.0) CABG during hospitalization 21/1089 (1.9) 29/1109 (2.6)

10 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)

11 Primary Endpoint: Death or Major Bleed, 30 day
Bivalirudin Heparins with optional GPI 8.4% Event Rate 5.1% Log-rank p = 0.002 Days from Randomization Date Patients at risk: Bivalirudin 1089 1038 1024 1020 1007 988 791 Heparins with optional GPI 1109 1003 998 984 958 765

12 Principal Secondary Endpoint: Death/Reinfarction/Major Bleed, 30 day
Bivalirudin Heparins with optional GPI 9.1% 6.7% Event Rate Days from Randomization Date Patients at risk: Bivalirudin 1089 1027 1010 1005 990 971 779 Heparins with optional GPI 1109 1020 996 975 949 760

13 Cardiac and Non-Cardiac Death, 30-day
Bivalirudin Heparins with optional GPI Log-rank p = 0.46 3.0% Cardiac 2.4% Event Rate Log-rank p = 0.10 Non-cardiac 0.5% 0.1% 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

14 Non–CABG-related major bleed, 30 day
Bivalirudin Heparins with optional GPI 6.1% Event Rate Log-rank p < 0.001 2.7% 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

15 NACE: Death, Reinfarction, IDR, Stroke, Major Bleed, 30 day
Bivalirudin Heparins with optional GPI 10.7% 7.9% Event Rate Log-rank p = 0.024 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

16 Clinical Outcomes, 30 days
Bivalirudin (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) *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)

17 Heparins with optional GPI (N=1109)
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) 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) 146 (13.2) 0.59 (0.46–0.76) 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) 26 (2.3) 0.55 (0.29–1.04) 0.06 GUSTO any bleeding (non-CABG) 148 (13.3) Blood transfusion 43 (3.9) 0.54 (0.33–0.90) 0.02 Patients may have experienced more than one event.

18 Heparins with optional GPI (N=1109)
Outcomes, 30 days, con’t Bivalirudin (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) 0.09 Stent thrombosis (ARC definition) 17 (1.6) 6 (0.5) 2.89 (1.14–7.29) 0.02 Definite Probable 0 (0) n/a Acute (≤24 hours) 12 (1.1) 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 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 9 (0.8) 0.68 (0.24–1.9) 0.46 Hemorrhagic Not applicable 0.50 Acquired thrombocytopenia 7 (0.7) 14 (1.4) 0.50 (0.20–1.24) 0.13 n/a: not applicable.

19 Subgroup Analysis: Death/Major Bleed at 30 Days (ITT)
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] 0.1 1.0 10.0 Bivalirudin better Heparins with optional GPI better

20 Subgroup Analysis: Death/Major Bleed at 30 Days (ITT)
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 19/377 (5.0) 28/407 (6.9) 0.73 [0.42, 1.29] 0.24 16/321 (5.0) 19/298 (6.4) 0.78 [0.41, 1.49] 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] 0.1 1.0 10.0 Bivalirudin better Heparins with optional GPI better

21 Subgroup Analysis: Death/Reinfarction/Major Bleed at 30 Days (ITT)
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 [ ] 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 24/377 (6.4) 32/407 (7.9) 0.81 [0.49, 1.35] 0.22 22/321 (6.9) 20/298 (6.7) 1.02 [0.57, 1.83] 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] No LAD 36/664 (5.4) 56/686 (8.2) 0.66 [0.44, 1.00] Bivalirudin better Heparins with optional GPI better

22 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) 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 9/377 (2.4) 21/407 (5.2) 0.46 [0.21, 1.00] 0.16 14/321 (4.4) 17/298 (5.7) 0.76 [0.38, 1.52] 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] Bivalirudin better Heparins with optional GPI better

23 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.

24 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.

25 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

26 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 Steg PG, van’t Hof A, Hamm CW et al. N Engl J Med 2013

27 Backup slides

28 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 Principal management strategy: 949/1069 (88.8%) Primary PCI 17/1069 (1.6%) CABG 103/1069 (9.6%) Medical Management 1084/1109 (97.7%) underwent emergent angiography Principal management strategy: 947/1084 (87.4%) Primary PCI 25/1084 (2.3%) 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

29 Components of Major Bleeding Up to 30 Days, ITT
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 0.50 Retroperitoneal 2/1089 (0.2) 0/1109 (0.0) 0.25 Intraocular Cardiac tamponade 1/1089 (0.1) 1/1109 (0.1) 1.02 [0.06, 16.26] 1.00 Access site hemorrhage requiring intervention 3/1089 (0.3) 12/1109 (1.1) 0.25 [0.07, 0.90] 0.02 Clinically overt bleed 4/1109 (0.4) 0.51 [0.09, 2.77] 0.69 Drop in hemoglobin or hematocrit 12/1089 (1.1) 34/1109 (3.1) 0.36 [0.19, 0.69] 0.001 Reoperation for bleeding 0.12 Blood transfusion 8/1089 (0.7) 24/1109 (2.2) 0.34 [0.15, 0.75] 0.005 Hemodynamic compromise 0.51 [0.05, 5.61] * Patients may have experienced more than one event. CI denotes confidence interval, GPI glycoprotein inhibitor, and NA not applicable.

30 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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