Bivalirudin Clinical Trials Update Evidence and Future Perspectives Andreas Baumbach Consultant Cardiologist/ hon. Reader in Cardiology Bristol Heart Institute University Hospitals Bristol
MY CONFLICTS OF INTEREST ARE Speaker Fees/Research Support: The Medicines Company Research Support/Advisory Board: Astra Zeneca Advisory Boards: Boston Scientific, Abbott Vascular, Medtronic
Update STEMI and Euromax What did we know before Euromax? Which questions does Euromax address? Which trials will address open questions after Euromax?
STEMI
In the base case, treatment with bivalirudin dominated the comparator in that it was both more effective and less expensive than treatment with a glycoprotein IIb/IIIa inhibitor plus heparin.
Harmonizing Outcomes with Revascularization and Stents in AMI 3602 pts with STEMI Randomized UFH + GP IIb/IIIa N=1802 R 1:1 Bivalirudin N=1800 1-Year FU Eligible 30 Not true MI* 29 N=1772 N=1771 26 13 Withdrew Lost to FU 1-Year FU N=1733 (97.8%) N=1730 (97.7%) 17 90 Withdrew Lost to FU 3-Year FU N=1626 (91.7%) N=1634 (92.3%) 22 19 18 78 Stone, GW NEJM 2008 * Biomarkers WNL and no DS >50% by core lab determination (30 day FU only)
All-Cause Mortality (%) 3-Year All-Cause Mortality Number at risk Bivalirudin alone Heparin+GPIIb/IIIa 10 9 8 7 6 5 4 3 2 1 0 Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 4.8% 3.4% 1-yr HR [95%CI]= 0.71 [0.51, 0.98] P=0.04 1800 1689 1660 1802 1670 1643 1611 1568 7.7% 5.9% 3-yr HR [95%CI]= 0.75 [0.58, 0.97] P=0.03 0 3 6 9 12 15 18 21 24 27 30 33 36 Months 1633 1593 1574 1098 1525 1043 Stone, GW TCT 2010
Major Bleeding (%) 3-Year Major Bleeding (non-cabg)* Number at risk Bivalirudin alone Heparin+GPIIb/IIIa 12 10 8 6 4 2 0 0 Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 9.4% 6.0% 1-yr HR [95%CI]= 0.62 [0.49, 0.79] P<0.001 3-yr HR [95%CI]= 0.64 [0.51, 0.80] P<0.001 3 6 9 12 15 18 21 24 27 30 33 36 Months 1800 1601 1572 1544 1523 1485 1039 1802 1534 1509 1465 1442 1402 957 10.5% 6.9% Stone, GW NEJM 2008 * Intracranial intraocular, retroperitoneal, access site bleed requiring intervention/surgery, hematoma 5 cm, hgb 3g/dL with or 4g/dL w/o overt source; reoperation for bleeding; or blood product transfusion
Early Stent Thrombosis Insufficient acute platelet inhibition?
ASPIRIN BIVALIRUDIN Clopidogrel PPCI 24hrs WHY IS THERE AN EXCESS OF EARLY STENT THROMBOSIS IN HORIZONS AMI?
Clopidogrel
Anti-thrombotic activity Time course of Anticoagulant and anti-plt effects in STEMI Bivalirudin Bivalirudin stopped continued at the..(at end of PCI 0.25 mg/kg/h after PCI?) Faster onset of P2Y12 inhibitor action? i.v. Vulnerable P2Y12 inhibition Period Cangrelor? Cangrelor? Bivalirudin Clopidogrel Prasugrel/Ticagrelor Time 24 hours
Post Horizons Results Study Total N Pre PPCI Heparin Prasugrel loading Prolonged BIV >2hrs Major Bleeding Acute Stent Thrombosis INFUSE-AMI 452 287 (63.5%) 125 (27.7%) 0% 19 (4.2%) 0 PROBI VIRI 2 172 0 (0%) 0 (0%) 86 (50%) 0 (0%) 0 UVM-Registry 346 207 (59.8%) 36 (10.4%) 283(81.8%) 15 (4.3%) 3 (0.9%) Bristol-Registry 345 7 (2.0%) 345 (100%) 0% 5 (1.4%) 0 EUROVISION 678 300 (44.2%) 87 (12.8%) 208 (30.7%) 10 (1.5 %) 0 Combined 1993 801(40.2%) 593 (29.8%) 577 (29.0%) 49 (2.4%) 0.15% HORIZONS-AMI 1571 65.40% 0% <12% 5.10% 1.30% Baumbach, Dauerman, Cortese et al. TCT 2012
2013 EuroIntervention. All rights reserved. Leeds Experience 1.2% acute Stent Thrombosis N: 968 consecutive STEMI pts Bivalirudin: 885 (91%) Prolonged infusion 4 hrs at lower rate Prasugrel 5% There was no case of acute stent thrombosis in patients treated with prasugrel
Open Questions 2013 How to reduce acute stent thrombosis Radial access and bleeding benefit Provisional GPIIb/IIIa use Bivalirudin vs Heparin with new P2Y12 inhbitors
EUROMAX Trial
EUROpean AMbulance ACS AngioX Trial Steg PG et al N Engl J Med 2013;DOI:10.1056/NEJMoa1311096 EUROMAX was funded and conducted by The Medicines Company ClinicalTrial.gov ID: NCT 01087723
Study Design International, multicenter, randomized, open-label study To test whether bivalirudin, initiated during transport for primary PCI, is superior to heparins with optional GPIIb/IIIa inhibitor in contemporary practice 2218 patients with STEMI (ECG confirmed) with symptom onset >20 min and 12h Randomized in ambulance or non-pci hospital, Intent for primary PCI UFH/LMWH ± GPIIb/IIIa (per physician/institution) 100 IU/kg without, 60 IU/kg with GPIIb/IIIa R 1:1 Aspirin + P2Y 12 (any) as soon as possible Bivalirudin 0.75 mg/kg bolus + 1.75 mg/kg/h infusion) + At least 4 h post PCI infusion [@ 0.25 mg/kg/h or option to continue at 1.75/mg/kg/h] provisional GPIIb/IIIa 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 Mortality follow-up at 1 year Steg PG et al N Engl J Med 2013;DOI:10.1056/NEJMoa1311096 19
Baseline Procedural Bivalirudin (N=1089) Heparins* + optional GPIIb/IIIa (N=1109) Age median (IQR), yr 61 (52, 71) 62 (52, 72) Diabetes n (%) 127 (11.7) 169 (15.3) Prior MI 80 (7.4) 113 (10.2) Killip class II, III, or IV, n (%) 77 (7.7) 69 (6.9) Creatinine clearance 60 ml/min 147 (14.7) 165 (16.5) P2Y 12 inhibitor loading dose, n (%) 1048 (98.3) 1058 (95.4) Clopidogrel 524 (50.0) 545 (51.5) Ticlopidine 0 (0.0) 2 (0.2) Prasugrel 323 (30.8) 306 (28.9) Ticagrelor 201 (19.2) 205 (19.4) GP IIb/IIIa inhibitor use, n (%) 125 (11.5) 766 (69.1) Routine use 42 (3.9) 649 (58.5) ) Bailout 83/1046 (7.9) 117/460 (25.4) Arterial access site, n (%) Femoral 558 (52.2) 582 (53.7) Radial 510 (47.7) 502 (46.3) *unfractionated or low molecular weight Data given for those eligible for bailout (i.e. who did not receive routine GPI). < 0.05 Steg PG et al N Engl J Med 2013;DOI:10.1056/NEJMoa1311096 20
Event Rate Primary Endpoint 30-Day Death or Non-CABG Major Bleeding STEMI patients (n=2218) intended for primary PCI 10.0 9.0 8.0 7.0 Bivalirudin Heparins* with optional GPIIb/IIIa 8.4% 6.0 5.0 4.0 5.1% 3.0 2.0 Log-rank p = 0.002 1.0 0.0 0 5 10 15 20 25 30 Days from Randomization Date *unfractionated or low molecular weight Steg PG et al N Engl J Med 2013;DOI:10.1056/NEJMoa1311096 21
30-day Outcomes Bivalirudin (N=1089) n (%) Heparins*+ optional GPIIb/IIIa (N=1109) (n (%) Relative risk (95% CI) P Value Primary: Death / major bleeding 55 (5.1) 94 (8.5) 0.60 (0.43 0.82) 0.001 (non-cabg) Death/ reinfarction/major bleeding 72 (6.6) 102 (9.2) 0.72 (0.54 0.96) 0.025 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) <0.0001 Blood transfusion 23 (2.1) 43 (3.9) 0.54 (0.33 0.90) 0.02 Reinfarction 19 (1.7) 10 (0.9) 1.93 (0.90 4.14) 0.08 Stent thrombosis (ARC definition) 17 (1.6) 6 (0.5) 2.89 (1.14 7.29) 0.02 Acute ( 24 h) 12 (1.1) 2 (0.2) 6.11 (1.37 27.24) 0.007 Subacute (>24 h to 30 d) 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 Stroke 6 (0.6) 11 (1.0) 0.56 (0.21 1.50) 0.24 Acquired thrombocytopenia 7 (0.7) 14 (1.4) 0.50 (0.20 1.24) 0.13 MACE 65 (6.0) 61 (5.5) 1.09 (0.77 1.52) 0.64 NACE 85 (7.8) 118 (10.6) 0.73 (0.56 0.96) 0.02 *unfractionated or low molecular weight. CABG= coronary artery bypass graft ; ARC= Academic Research Consortium; MACE=death, reinfarction, ischemia-driven revascularization or stroke; NACE= MACE or non CABG major bleeding Steg PG et al N Engl J Med 2013;DOI:10.1056/NEJMoa1311096 Acute ST 1.1% vs. 0.2% 22
Outcomes, 30 days, con t 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) GUSTO severe/life-threatening bleeding (non-cabg) GUSTO severe/life-threatening or moderate 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 * Patients may have experienced more than one event. CI denotes confidence interval, GPI glycoprotein inhibitor, and NA not applicable. Steg PG et al N Engl J Med 2013;DOI:10.1056/NEJMoa1311096 23
Event Rate Key Secondary Endpoint 30-Day Death, Reinfarction or non-cabg Major Bleeding STEMI patients (n=2218) intended for primary PCI 12.0 Bivalirudin Heparins* with optional GPIIb/IIIa 10.0 9.1% 8.0 6.0 6.7% 4.0 2.0 Log-rank p = 0.032 0.0 0 5 10 15 20 25 30 Days from Randomization Date *unfractionated or low molecular weight Steg PG et al N Engl J Med 2013;DOI:10.1056/NEJMoa1311096 24
Event Rate Non-CABG Major Bleeding, 30 Day STEMI patients (n=2218) intended for primary PCI Bivalirudin Heparins* with optional GPIIb/IIIa 7.0 6.0 6.1% 5.0 4.0 3.0 2.7% 2.0 1.0 Log-rank p <0.001 0.0 0 5 10 15 20 25 30 Days from Randomization Date Steg PG et al N Engl J Med 2013;DOI:10.1056/NEJMoa1311096 *unfractionated or low molecular weight 25
Event Rate Cardiac Non-Cardiac Death, 30-day STEMI patients (n=2218) intended for primary PCI 5.0 Bivalirudin Heparins* with optional GPIIb/IIIa 4.0 3.0 Cardiac Log-rank p = 0.462 3.0% 2.0 2.4% 1.0 0.0 Non-Cardiac Log-rank p = 0.098 0 5 10 15 20 25 30 0.5% 0.1% Days from Randomization Date *unfractionated or low molecular weight Steg PG et al N Engl J Med 2013;DOI:10.1056/NEJMoa1311096 26
Primary Endpoint Subgroup Analysis Death/Major Bleed Events at 30 Days (ITT Population) 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 (yr.) 39 / 394 ( 9.9) 61 / 434 ( 14.1) 0.70 [ 0.48, 1.03] 0.313 65 (yr.) 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] 0.473 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] 0.260 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] 0.974 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] 0.663 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] 0.842 All bare metal stents 16 / 330 ( 4.8) 27 / 336 ( 8.0) 0.60 [ 0.33, 1.10] Killip Class Killip Class 1 32 / 919 ( 3.5) 59 / 931 ( 6.3) 0.55 [ 0.36, 0.84] 0.583 Killip 2-4 14 / 77 ( 18.2) 24 / 69 ( 34.8) 0.52 [ 0.29, 0.93] P2Y 12 Inhibitor Loading Dose Clopidogrel 25 / 524 ( 4.8) 38 / 545 ( 7.0) 0.68 [ 0.42, 1.12] 0.818 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] P2Y 12 Inhibitor Maintenance Dose Clopidogrel 19 / 377 ( 5.0) 28 / 407 ( 6.9) 0.73 [ 0.42, 1.29] 0.238 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] 0.475 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] 0.443 > 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] 0.298 No LAD 25 / 664 ( 3.8) 52 / 686 ( 7.6) 0.50 [ 0.31, 0.79] Radial and femoral 0.1 0.5 1.0 5.0 10.0 Bivalirudin better Heparins with optional GPI better 27
Summary Euromax More radial use, less Clopidogrel, but still 70% GPIIb/IIIa Reduction of bleeding confirmed Acute stent thrombosis 1.1% Awaiting 1 year results Prolonged full dose infusion results ACC14 Prasugrel/Ticagrelor results ACC14
ONGOING TRIALS
PINPOINT-PPCI Observational study (n=108) Patients receiving Prasugrel & Bivalirudin Johnson T et al, ACC2014
How Effective are Antithrombotic Therapies in Primary Percutaneous Coronary Intervention Rod Stables Principal Investigator A Shahzad, I Kemp, C Mars, K Wilson, A Thompson, C Roome Co-investigators
Single centre open label RCT 1800 patients Comparing unfractionated heparin v bivalirudin ST elevation myocardial infarction (STEMI) For planned management with Primary PCI
1800 patients with STEMI activating PPCI service at LHCH Routine oral antiplatelet loading therapy Full eligibility check and Randomization in 1:1 ratio On entry to cardiac catheter laboratory HEPARIN or BIVALIRUDIN Coronary angiography and index PPCI (if indicated) Follow at 28 days for all outcome measures Follow up at 1 year for mortality
First CV trial to adopt a delayed consent model First ever trial to recruit > 99% of all presenting cases True all-comers Results that can be generalised Largest ever single centre trial in CV medicine Largest ever UK trial in interventional cardiology
MATRIX Trial NCT01433627 NSTEACS or STEMI with invasive management Aspirin+P2Y12 blocker 1:1 Trans-Radial Access Trans-Femoral Access 1:1 Bivalirudin Mono-Tx 1:1 Heparin ±GPI Is TRI superior to TFI? Stop Infusion Prolong 6 hs infusion http://www.cardiostudy.it/matrix Is Bivalirudin superior to UFH? Should Bivalirudin be prolonged after PCI?
Planned Recruitment Goals H: 10 pt per month per site (5 pt per month per site in July and August) 8000 7200 7000 6000 5000 3600 4000 Active Sites 3000 2000 1000 0 Oct 11 1000 Dec 11 Feb-1 2 Apr-1 2 Jun 12 Aug 12 Oct 12 Dec 12 Feb-1 3 Apr-1 3 Jun 13 Aug 13 Oct 13 Dec 13 1 2 5 10 10 15 25 25 30 30 30 30 50 50 60 60 60 60 60 60 60 60 60 60 60
Summary Euromax confirmed the benefit of Bivalirudin compared to heparin +/- GPIIb/IIIa Early stent thrombosis was not reduced by a prolonged low dose infusion of Bivalirudin Further analyses and ongoing trials will inform on improved drug regimens HEAT PPCI and Matrix will reevaluate the clinical benefit of Bivalirudin against heparin in radial access procedures The story continues!