Bivalirudin Infusion for Ventricular Infarction Limitation (BIVAL)

The purpose of this study is to evaluate whether the use of bivalirudin will reduce extent of the damage done to the heart muscle in participants who suffered a heart attack, compared to the comparator treatment (heparin).

The study will assess the effect of bivalirudin administration during primary percutaneous coronary intervention (PPCI) and for 4 hours (h) afterwards, looking at contrast enhanced cardiac magnetic resonance imaging (CMR) assessed infarct size and on circulating markers of thrombosis and cell injury in participants treated with PPCI for a large myocardial infarction (MI). The objective of this study is to determine whether bivalirudin, compared to heparin [unfractionated heparin (UFH)], for PPCI in large ST segment elevation myocardial infarction (STEMI) can: Primary Objective • Reduce infarct size assessed by CMR 5 days (defined as 5 days ±72 h from randomisation) after PPCI Secondary Objectives of this study are to determine the effects of bivalirudin compared with UFH treatment for PPCI in STEMI on: Other CMR derived parameters of myocardial recovery 5 days after PPCI (that is, left ventricular ejection fraction [LVEF], myocardial salvage index [MSI], and micro-vascular obstruction [MVO]) LVEF by CMR at 90 days Modulate markers of thrombin activity and cell injury after reperfusion Coronary flow and micro-circulation at the end of PPCI Survival at 90 days Approximately 200 participants will be randomized. Participants will be stratified prior to randomization: (a) according to total duration of ischemic pain (<6 h versus ≥6 h); (b) by site. Diagnosis and Main Criteria for Selection: Adult participants (≥18 years) with an onset of ischemic symptoms of >20 minutes (min) and <12 h; a diagnosis of STEMI with ST segment elevation of ≥1 millimeter (mm) in ≥2 contiguous precordial leads, or presumably new left bundle branch block; had thrombolysis in myocardial infarction (TIMI) 0 or 1 flow in the infarct related artery (IRA); fulfilled angiographic criteria/score for a large infarction; and were candidates for PPCI will be enrolled. All participants should receive as soon as logistically feasible: aspirin (150-325 milligrams [mg] orally or 250-500 mg intravenously [IV]) and a loading dose of any approved P2Y12 inhibitor unless already on maintenance dose. Bivalirudin will be administered at the time of PPCI at the approved dose of 0.75 mg/kilogram (kg) bolus followed by a 1.75 mg/kg/h infusion that will continue for 4 h after the completion of the index procedure. Participants randomized to UFH should be treated according to the standard institutional protocol (including the timing and dosing of the UFH bolus). A target activated clotting time (ACT) of ≥250 seconds (s) was recommended. Criteria for Evaluation: Primary Endpoint: • Infarct size assessed by CMR 5 days post-PPCI Secondary Endpoints: CMR MVO assessment at 5 days CMR MSI at 5 days CMR assessment of LVEF at 5 days CMR assessment of LVEF at 90 days TIMI flow and Myocardial Blush Grade at end of PPCI In-hospital net adverse clinical events up to 5 days or discharge, whichever comes first (death, re-infarction, ischaemia driven revascularization, and Bleeding Academic Research Consortium ≥3 bleeding) Death at 90 days Exploratory assessments: • Assess patterns between comparator groups at various peri-procedural time points with respect to but not limited to: micro-particle release, thrombin anti thrombin complexes, myeloperoxidase Sub-study: • Index microcirculatory resistance

The primary endpoint was evaluated by a core lab totally blinded to clinical information and the treatment groups.

Bivalirudin was administered as a bolus (0.75 mg/kg) and an infusion (1.75 mg/kg/h) for the duration of the PPCI and continued for the first 4 h after completion of the procedure.

UFH was administered as a bolus according to standard of care for completion of PPCI per site. An ACT ≥250 s at the end of the procedure was recommended.

Bivalirudin is an anticoagulant that binds thrombin in a bivalent and reversible fashion and directly inhibits it.

Size of cardiac infarct, expressed as grams, as assessed by CMR. The use of CMR has dramatically improved the ability for accurate infarct size estimations and is therefore currently considered the gold standard. The number of participants and their mean reported infarct size, as grams, at Day 5 are presented.

MSI is a CMR-derived parameter of myocardial recovery and treatment efficacy that allows comparisons among infarcts of different sizes. MSI is calculated as the difference between the area at risk (AAR) and the final infarct size, divided by the AAR, and it is expressed as a percentage of AAR. An MSI of 100% indicates maximum treatment success, whereas an MSI of 0% indicates no treatment benefit. The number of participants and their mean-reported MSI at Day 5 are presented.

Early and late assessment of MVO, expressed as grams, as assessed by CMR. MVO is an established complication of coronary reperfusion therapy for acute myocardial infarction. MVO occurs in the setting of reperfusion following prolonged myocardial ischemia and provides incremental prognostic information beyond infarct size, to which it is related. Early MVO is a prolonged (approximately 60 s) perfusion deficit in dynamic gadolinium (Gd) first-pass images that is determined within 2 minutes (min) of administration of the Gd-based contrast agent. Late MVO is usually assessed as a hypointense infarct core on late-Gd-enhancement images acquired 10 min after contrast administration. The number of participants and their mean reported early and late MVO, as grams, at Day 5 are presented.

Percentage of cardiac LVEF as assessed by CMR. LVEF is a measurement of the percentage of blood ejected out of the left ventricle with each contraction. The number of participants and their mean reported LVEF, as a percentage of blood, at Day 5 are presented.

Percentage of cardiac LVEF as assessed by CMR. LVEF is a measurement of the percentage of blood ejected out of the left ventricle with each contraction. The number of participants and their mean reported LVEF, as a percentage of blood, at Day 90 are presented.

TIMI flow (grade 0-3) is an angiographic determination of briskness of epicardial coronary blood flow: TIMI 0 flow (no perfusion); TIMI 1 flow (penetration without perfusion); TIMI 2 flow (partial reperfusion); TIMI 3 flow (complete perfusion/normal flow). MBG (grade 0-3) is an angiographic method for determination of blood flow in the distal myocardial vascular bed. Blush grades: 0 = failure of dye to enter the micro-vasculature; 1 = dye slowly enters but fails to exit the micro-vasculature; 2 = delayed entry and exit of dye from the micro-vasculature; 3 = normal entry and exit of dye from the micro-vasculature. Blush that is only mildly intense throughout the washout phase, but fades minimally, is also classified as grade 3. The number of participants and their mean reported TIMI flow and MBG grades at the end of PPCI are presented.

The NACE at 5 days is the composite of major bleeding (Bleeding Academic Research Consortium Type 3 or greater [BARC type ≥3]), death, re-infarction, and ischaemia driven revascularization (IDR). In brief, BARC ≥3 includes: Type 3a-3c, clinical, laboratory, and/or imaging evidence of bleeding; Type 4, coronary artery bypass grafting-related bleeding; Type 5, fatal bleeding that directly results in death that is either clinically suspicious or is confirmed as the cause of death. A participant was defined to have a composite event if the participant experienced at least 1 of the components. If the participant did not have any of the components, then he or she did not have the composite endpoint. If a participant had more than 1 of the components, he or she was only counted once in the determination of the total number of participants experiencing the composite endpoint. The percentage of participants with in-hospital NACE up to Day 5 is presented.

Participant survival during the clinical follow-up period is presented as the number of participants with reported death at 90 days post PPCI.

IMR, a predictor of clinical outcome, is a readily available, quantitative, and reproducible method for invasively assessing coronary microvascular function. It is measured using the thermodilution technique and defined as mean distal coronary pressure, expressed in millimeters (mm) of mercury (Hg), multiplied by the mean hyperemic transit time (s) (mmHg*s). Higher IMR values indicate poorer microcirculation and are associated with a worse clinical outcome. A cutoff point of 32 (associated with better clinical outcomes) was selected as the threshold. Only participants at study locations with previous experience in IMR measurements participated in this sub study. The number of participants and their mean reported IMR at the end of PPCI are presented.

Inclusion Criteria: ≥18 years Experienced ischemic symptoms of >20 min and <12 h and had a diagnosis of STEMI with ST segment elevation of ≥1 mm in ≥2 contiguous precordial leads, or presumably new left bundle branch block Provided written informed consent or witnessed consent in countries and sites where such participant consenting is applicable, before initiation of any study-related procedures Had TIMI 0 or 1 flow in the IRA on initial angiogram Fulfilled angiographic criteria/score for a large infarction based on initial angiogram (Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease score of ≥21) Were candidates for PPCI Administration of an initial dose of 150 to 325 mg orally (or 250 to 500 mg IV) and a loading dose of any approved P2Y12 inhibitor Exclusion Criteria: Contraindication or known hypersensitivity to bivalirudin or UFH Refusal to receive blood transfusion/products Participants requiring staged coronary artery bypass graft procedure within the first 90 days Known international normalized ratio ≥2 or known prothrombin time >1.5 times upper limit of normal on the day of the index PPCI, or known history of bleeding diathesis Therapy with vitamin K antagonists within 72 h of PPCI Therapy with dabigatran, rivaroxaban, or other oral anti-Xa or antithrombin agents within 48 h of PPCI History of hemorrhagic stroke, intracranial hemorrhage, intracerebral mass, aneurysm, arteriovenous malformation, or recent head injury (within the last 5 days) Participants with previous history of Q-wave MI Known glomerular filtration rate (GFR) <30 milliliter/min or dialysis dependent Major surgery within the previous 30 days Minor surgery/biopsy exclusions in the past 3 days Upper gastrointestinal or genitourinary bleed 30 days prior to randomization Stroke or transient ischemic attack 30 days prior to randomization Administration of thrombolytics or glycoprotein IIb/IIIa inhibitor 72 h prior to PPCI Administration of enoxaparin 8 h prior to PPCI Administration of bivalirudin 12 h prior to PPCI Administration of fondaparinux or other low molecular weight heparin 24 h prior to PPCI Known contraindications to aspirin or P2Y12 inhibitors Known allergy that cannot be pre-medicated to iodinated contrast Known contraindication to CMR Women of child bearing potential (see below) Previous enrollment (participants are considered enrolled upon Randomization) in this study Treatment with other investigational drugs or devices within the 30 days preceding enrollment or planned use of other investigational drugs or devices before the primary endpoint of this study had been reached Participants with a body weight >150 kg Child bearing potential was defined as: A female participant was considered to have childbearing potential unless she met at least 1 of the following criteria: Age ≥50 years and naturally amenorrheic for ≥1 year (amenorrhea following cancer therapy did not rule out childbearing potential) Premature ovarian failure confirmed by a specialist gynecologist Previous bilateral salpingo-oophorectomy or hysterectomy XY genotype, Turner's syndrome, uterine agenesis

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