Bivalirudin Clinical Trials Update Evidence and Future Perspectives

Transcription

1 Bivalirudin Clinical Trials Update Evidence and Future Perspectives Andreas Baumbach Consultant Cardiologist/ hon. Reader in Cardiology Bristol Heart Institute University Hospitals Bristol

2 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

3 Update STEMI and Euromax What did we know before Euromax? Which questions does Euromax address? Which trials will address open questions after Euromax?

4 STEMI

5 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.

6 Harmonizing Outcomes with Revascularization and Stents in AMI 3602 pts with STEMI Randomized UFH + GP IIb/IIIa N=1802 R 1:1 Bivalirudin N= Year FU Eligible 30 Not true MI* 29 N=1772 N= Withdrew Lost to FU 1-Year FU N=1733 (97.8%) N=1730 (97.7%) Withdrew Lost to FU 3-Year FU N=1626 (91.7%) N=1634 (92.3%) Stone, GW NEJM 2008 * Biomarkers WNL and no DS >50% by core lab determination (30 day FU only)

7 All-Cause Mortality (%) 3-Year All-Cause Mortality Number at risk Bivalirudin alone Heparin+GPIIb/IIIa 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= % 5.9% 3-yr HR [95%CI]= 0.75 [0.58, 0.97] P= Months Stone, GW TCT 2010

8 Major Bleeding (%) 3-Year Major Bleeding (non-cabg)* Number at risk Bivalirudin alone Heparin+GPIIb/IIIa 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< yr HR [95%CI]= 0.64 [0.51, 0.80] P< Months % 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

9 Early Stent Thrombosis Insufficient acute platelet inhibition?

10 ASPIRIN BIVALIRUDIN Clopidogrel PPCI 24hrs WHY IS THERE AN EXCESS OF EARLY STENT THROMBOSIS IN HORIZONS AMI?

11

12 Clopidogrel

13 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

14 Post Horizons Results Study Total N Pre PPCI Heparin Prasugrel loading Prolonged BIV >2hrs Major Bleeding Acute Stent Thrombosis INFUSE-AMI (63.5%) 125 (27.7%) 0% 19 (4.2%) 0 PROBI VIRI (0%) 0 (0%) 86 (50%) 0 (0%) 0 UVM-Registry (59.8%) 36 (10.4%) 283(81.8%) 15 (4.3%) 3 (0.9%) Bristol-Registry (2.0%) 345 (100%) 0% 5 (1.4%) 0 EUROVISION (44.2%) 87 (12.8%) 208 (30.7%) 10 (1.5 %) 0 Combined (40.2%) 593 (29.8%) 577 (29.0%) 49 (2.4%) 0.15% HORIZONS-AMI % 0% <12% 5.10% 1.30% Baumbach, Dauerman, Cortese et al. TCT 2012

15 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

16 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

17 EUROMAX Trial

18 EUROpean AMbulance ACS AngioX Trial Steg PG et al N Engl J Med 2013;DOI: /NEJMoa EUROMAX was funded and conducted by The Medicines Company ClinicalTrial.gov ID: NCT

19 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 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: /NEJMoa

20 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: /NEJMoa

21 Event Rate Primary Endpoint 30-Day Death or Non-CABG Major Bleeding STEMI patients (n=2218) intended for primary PCI Bivalirudin Heparins* with optional GPIIb/IIIa 8.4% % Log-rank p = Days from Randomization Date *unfractionated or low molecular weight Steg PG et al N Engl J Med 2013;DOI: /NEJMoa

22 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 ( ) (non-cabg) Death/ reinfarction/major bleeding 72 (6.6) 102 (9.2) 0.72 ( ) Death 32 (2.9) 34 (3.1) 0.96 ( ) 0.86 Cardiac causes 27 (2.5) 33 (3.0) 0.83 ( ) 0.48 Noncardiac causes 5 (0.5) 1 (0.1) 5.09 ( ) 0.12 Major bleeding (non-cabg) 28 (2.6) 67 (6.0) 0.43 ( ) < Blood transfusion 23 (2.1) 43 (3.9) 0.54 ( ) 0.02 Reinfarction 19 (1.7) 10 (0.9) 1.93 ( ) 0.08 Stent thrombosis (ARC definition) 17 (1.6) 6 (0.5) 2.89 ( ) 0.02 Acute ( 24 h) 12 (1.1) 2 (0.2) 6.11 ( ) Subacute (>24 h to 30 d) 5 (0.5) 4 (0.4) 1.27 ( ) 0.75 Ischemia-driven revascularization 24 (2.2) 17 (1.5) 1.44 ( ) 0.25 Stroke 6 (0.6) 11 (1.0) 0.56 ( ) 0.24 Acquired thrombocytopenia 7 (0.7) 14 (1.4) 0.50 ( ) 0.13 MACE 65 (6.0) 61 (5.5) 1.09 ( ) 0.64 NACE 85 (7.8) 118 (10.6) 0.73 ( ) 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: /NEJMoa Acute ST 1.1% vs. 0.2% 22

23 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 ( ) <0.001 Major or minor bleeding (non-cabg) 85 (7.8) 149 (13.4) 0.58 ( ) <0.001 TIMI major bleeding (non-cabg) 14 (1.3) 23 (2.1) 0.62 ( ) 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 ( ) < (0.6) 10 (0.9) 0.61 ( ) (1.3) 26 (2.3) 0.55 ( ) 0.06 GUSTO any bleeding (non-cabg) 85 (7.8) 148 (13.3) 0.58 ( ) <0.001 Blood transfusion 23 (2.1) 43 (3.9) 0.54 ( ) 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: /NEJMoa

24 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 % % Log-rank p = Days from Randomization Date *unfractionated or low molecular weight Steg PG et al N Engl J Med 2013;DOI: /NEJMoa

25 Event Rate Non-CABG Major Bleeding, 30 Day STEMI patients (n=2218) intended for primary PCI Bivalirudin Heparins* with optional GPIIb/IIIa % % Log-rank p < Days from Randomization Date Steg PG et al N Engl J Med 2013;DOI: /NEJMoa *unfractionated or low molecular weight 25

26 Event Rate Cardiac Non-Cardiac Death, 30-day STEMI patients (n=2218) intended for primary PCI 5.0 Bivalirudin Heparins* with optional GPIIb/IIIa Cardiac Log-rank p = % % Non-Cardiac Log-rank p = % 0.1% Days from Randomization Date *unfractionated or low molecular weight Steg PG et al N Engl J Med 2013;DOI: /NEJMoa

27 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] (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] 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] 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] 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] 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] 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] Killip / 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] 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] 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] min 27 / 549 ( 4.9) 42 / 576 ( 7.3) 0.67 [ 0.42, 1.08] Baseline Creatinine Clearance / 147 ( 14.3) 30 / 165 ( 18.2) 0.79 [ 0.47, 1.31] > / 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] No LAD 25 / 664 ( 3.8) 52 / 686 ( 7.6) 0.50 [ 0.31, 0.79] Radial and femoral Bivalirudin better Heparins with optional GPI better 27

28 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

29 ONGOING TRIALS

30 PINPOINT-PPCI Observational study (n=108) Patients receiving Prasugrel & Bivalirudin Johnson T et al, ACC2014

31 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

32 Single centre open label RCT 1800 patients Comparing unfractionated heparin v bivalirudin ST elevation myocardial infarction (STEMI) For planned management with Primary PCI

33 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

34 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

35 MATRIX Trial NCT 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 Is Bivalirudin superior to UFH? Should Bivalirudin be prolonged after PCI?

36 Planned Recruitment Goals H: 10 pt per month per site (5 pt per month per site in July and August) Active Sites Oct 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

37 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!