CLINICAL RESEARCH CORONARY INTERVENTIONS Euro 1 Intervention 2 3 4 publish-ahead-of-print May 2017 2017;13-online 5 6 7 8 9 10 11 Bivalirudin infusion to reduce ventricular infarction: the open- 12 13 label, randomised Bivalirudin Infusion for Ventricular 14 15 InfArction Limitation (BIVAL) study 16 17 18 Robert Jan van Geuns1*, MD, PhD; Georgios Sideris2, MD, PhD; Niels Van Royen3, MD, PhD; 19 Rami El Mahmoud4, MD; Roberto Diletti1, MD, PhD; Claire Bal dit Sollier2, PhD; 20 Jerome Garot5, MD, PhD; Nina Van Der Hoeven3, MD, PhD; Bernardo Cortese6, MD; 21 Li Ding7, PhD; Ilknur Lechthaler8; Efthymios N. Deliargyris9, MD; Prodromos Anthopoulos8, MD; 22 Ludovic Drouet2, MD, PhD 23 24 1. Erasmus MC, Rotterdam, the Netherlands; 2. Hôpital AP-HP Lariboisière, Paris, France; 3. Vrije Universiteit Amsterdam, 25 Amsterdam, the Netherlands; 4. Hôpital Ambroise Paré, Boulogne, France; 5. Hôpital Privé Jacques Cartier, Ramsay Générale 26 de Santé, ICPS, Massy, France; 6. A.O. Fatebenefratelli, Milan, Italy; 7. The Medicines Company, Parsippany, NJ, USA; 27 8. The Medicines Company, Zurich, Switzerland; 9. Science and Strategy Consulting Group, Basking Ridge, NJ, USA 28 29 30 KEYWORDS Abstract 31 Aims: The aim of the study was to investigate whether bivalirudin versus unfractionated heparin (UFH) 32 • adjunctive reduces infarct size (IS) for primary percutaneous coronary intervention (PPCI) in large acute myocardial 33 pharmacology infarction (AMI). 34 • clinical trials 35 Methods and results: • magnetic This multicentre open-label trial randomised 78 patients undergoing PPCI for large 36 resonance imaging AMI to bivalirudin or UFH. The primary endpoint was IS, assessed by cardiac magnetic resonance (CMR) 37 (MRI) five days after PPCI. Secondary endpoints included index of microcirculatory resistance (IMR), CMR- 38 • other imaging assessed microvascular obstruction (MVO) and ejection fraction, and biomarkers for thrombin activity and 39 modalities cell injury. No difference was observed in mean IS at five days (25.0±19.7 g for bivalirudin vs. 27.1±20.7 g 40 • ST-elevation for UFH; p=0.75). Early MVO was numerically lower with bivalirudin (5.3±5.8 g vs. 7.7±6.3 g; p=0.17), 41 myocardial with no significant difference in ejection fraction at 90 days (54.6±12.0% vs. 49.1±12.1%; p=0.11). In 42 infarction (STEMI) the biomarkers, thrombin-antithrombin complexes were reduced by 4.8 ug/L over the first day for bivali- 43 rudin versus an increase of 1.9 ug/L in the heparin arm (p=0.0003). Acute IMR was lower (43.5±21.6 vs. 44 68.7±35.8 mmHg×s, respectively; p=0.014). In a planned interim analysis, an approximate 11% reduction DOI: 45 in IS was observed with bivalirudin; the trial was discontinued for futility. 46 10.4244/EIJ-D-17-00307 47 Conclusions: This study did not achieve its primary endpoint of significant infarct size reduction in 48 PPCI by prolonged bivalirudin infusion compared to UFH, even though complete thrombin inhibition was 49 achieved in the acute phase, with a lower myocardial microcirculation resistance at the end of the procedure. 50 51 52 *Corresponding author: Thoraxcenter, Room Ba585, Erasmus Medical Center, ‘s-Gravendijkwal 230, 3015 CE Rotterdam, 53 the Netherlands. E-mail: [email protected] © Europa Digital & Publishing 2017. All rights reserved. SUBMITTED ON 07/04/2017- REVISION RECEIVED ON 1st 25/04/2017 / 2 nd 03/05/2017 - ACCEPTED ON 04/05/2017 1 Euro Intervention 54 Abbreviations reduces reperfusion injury and improves myocardial healing, 55 AMI acute myocardial infarction resulting in a smaller final IS. For this we used cardiac magnetic 3 56 APPROACH Alberta Provincial Project for Outcome Assessment resonance (CMR) imaging, the gold standard for measuring IS , 2017;13-online publish-ahead-of-print May 2017 2017;13-online 57 in Coronary Heart Disease which can also provide a reliable quantitative measurement of 58 BARC Bleeding Academic Research Consortium global left ventricular parameters and identify prolonged MVO. In 59 BIVAL Bivalirudin Infusion for Ventricular InfArction a subgroup, we measured invasively the index of microcirculatory 60 Limitation resistance (IMR) at the end of the procedure, which predicts clini- 61 CMR cardiac magnetic resonance cal outcomes4. Finally, we assessed the direct and indirect effects 62 DTPA diethylenetriamine penta-acetic acid of bivalirudin and UFH on coagulation, platelets, and leucocytes 63 EDV end-diastolic volume to explore the effect of thrombin inhibition on IS. 64 IMR index of microcirculatory resistance 65 IQR interquartile range Methods 66 IS infarct size BIVAL was a multicentre, open-label, prospective, randomised con- 67 ITT intention-to-treat trolled trial conducted at four sites in the Netherlands and France 68 LVEF left ventricular ejection fraction in patients undergoing PPCI for a large myocardial infarction. 69 MPO myeloperoxidase Adults with STEMI who presented >20 minutes and <12 hours 70 MSI myocardial salvage index after symptom onset were eligible if they fulfilled the follow- 71 MVO microvascular obstruction ing angiographic criteria: Thrombolysis In Myocardial Infarction 72 PPCI primary percutaneous coronary intervention (TIMI) 0 or 1 flow in the infarct-related artery (IRA); angiographic 73 SD standard deviation score ≥21 (sizeable infarction, based on initial angiogram) accord- 74 STEMI ST-segment elevation myocardial infarction ing to the APPROACH score5; and eligible for PPCI. Patients with 75 TAT thrombin−antithrombin complexes a history of Q-wave myocardial infarction or who had received 76 TIMI Thrombolysis In Myocardial Infarction antithrombotic therapy other than UFH at first medical contact 77 UFH unfractionated heparin were excluded. Use of glycoprotein IIb/IIIa inhibitors was permit- 78 ted only as bail-out therapy for the treatment of no-reflow pheno- 79 Introduction menon or giant thrombus, defined as >2 times the diameter of the 80 Primary percutaneous coronary intervention (PPCI) for vessel. The full study criteria are detailed online (https://clinical- 81 ST-elevation myocardial infarction (STEMI) reduces infarct size trials.gov: NCT02565147). 82 (IS) and improves survival. Even with rapid restoration of epicar- All patients provided written informed consent. The sponsor 83 dial flow, final IS is considerable, with a significant contribution (The Medicines Company, Parsippany, NJ, USA) was responsi- 84 from reperfusion injury and microvascular obstruction (MVO) due ble for funding, protocol development in collaboration with the 85 to oedema and capillary obstruction by microthrombi. Final IS executive committee and the clinical coordinating centre, on-site 86 depends on several factors including the occlusion location, dura- monitoring and safety surveillance, statistical analyses, and data 87 tion of occlusion, the burst of thrombin triggered by plaque rup- management. The institutional review board at each site approved 88 ture and coronary intervention involving thrombus manipulation1. the study protocol and activities. 89 Beyond its role in coagulation, thrombin is proinflamma- 90 tory and is implicated in reperfusion injury. On a cellular level, STUDY MEDICATIONS 91 thrombin activates platelets, endothelial cells and leucocytes; con- All patients received, as soon as logistically possible, aspirin at an 92 sequently, it exerts a potent proinflammatory action, with a throm- initial dose of 150-325 mg orally (or 250-500 mg intravenously) 93 bogenic and deleterious effect on the microcirculation especially and a loading dose of a P2Y12 inhibitor. Administration of UFH at 94 downstream from the culprit lesion2. The formation of monocyte- first medical contact or before the angiogram was allowed as per 95 platelet aggregates increases within minutes after PCI, reaching usual practice. 96 a peak within 2-4 hours2. Thrombin is formed and released from Randomisation (1:1) was carried out using an interactive voice/ 97 the occluding thrombus and by the intra-arterial manipulations of web response system. All patients randomised to the bivalirudin arm 98 vessel reopening during and after completion of PPCI2. Bivalirudin received a bolus of 0.75 mg/kg and an infusion of 1.75 mg/kg/hr for 99 directly inhibits both clot-bound and unbound thrombin, whereas the duration of the procedure and for four hours after completion of 100 heparin is less effective against clot-bound thrombin2. Thrombin PPCI to maintain consistent thrombin inhibition, as (during STEMI) 101 inhibition by a prolonged 4-hour bivalirudin infusion after PPCI thrombin exerts activity beyond the restoration of flow in the IRA. 102 may therefore reduce inflammation and reperfusion injury. Patients randomised to UFH were administered a dose as per stand- 103 The primary objective of the Bivalirudin Infusion for ard institutional practice. In cases where activated clotting time was 104 Ventricular InfArction Limitation (BIVAL) study was to investi- used to inform UFH dosing, a target value of ≥250 seconds was rec- 105 gate whether treatment with bivalirudin infusion for four hours ommended. Randomisation was stratified by duration of symptom 106 versus unfractionated heparin (UFH) for PPCI in large STEMI onset to randomisation (<6 hrs versus ≥6 hrs) and site. 2 The BIVAL study Euro Intervention 107 PRIMARY AND SECONDARY OUTCOMES were measured: TAT and change in TAT (which expresses the 108 The primary outcome was the difference in IS in the bivalirudin net effect of thrombin generation and its inhibition), myeloper- 109 versus UFH arm, assessed by CMR performed five days (defined oxidase, and microparticles. Care was maximum to respect the 110 as 5 days±72 hours from randomisation) after PPCI. Key second- preanalytical requirements strictly. Within two hours of blood publish-ahead-of-print May 2017 2017;13-online 111 ary outcomes were the difference between bivalirudin and UFH collection, platelet-free plasma aliquots were prepared by double 112 in other CMR-derived variables of myocardial recovery five days centrifugation. Plasma aliquots were frozen to –80°C and shipped 113 after PPCI, namely LVEF and MVO. LVEF and IS were also to the core laboratory (<3 months) for measurement of biomark- 114 assessed by CMR at 90 days.