Clinical trial NCT02565147: Bivalirudin Infusion for Ventricular Infarction Limitation
Official title: Bivalirudin Infusion for Ventricular Infarction Limitation
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Acute Myocardial Infarction
Keywords: STEMI, infarct size, CMR, bivalirudin
Lead sponsor: The Medicines Company
Sponsor class: INDUSTRY
First posted: 2015-10-01
Enrollment: 78
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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).

Detailed description: 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

Eligibility criteria: Inclusion Criteria:

1. ≥18 years
2. 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
3. Provided written informed consent or witnessed consent in countries and sites where such participant consenting is applicable, before initiation of any study-related procedures
4. Had TIMI 0 or 1 flow in the IRA on initial angiogram
5. 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)
6. Were candidates for PPCI
7. 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:

1. Contraindication or known hypersensitivity to bivalirudin or UFH
2. Refusal to receive blood transfusion/products
3. Participants requiring staged coronary artery bypass graft procedure within the first 90 days
4. 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
5. Therapy with vitamin K antagonists within 72 h of PPCI
6. Therapy with dabigatran, rivaroxaban, or other oral anti-Xa or antithrombin agents within 48 h of PPCI
7. History of hemorrhagic stroke, intracranial hemorrhage, intracerebral mass, aneurysm, arteriovenous malformation, or recent head injury (within the last 5 days)
8. Participants with previous history of Q-wave MI
9. Known glomerular filtration rate (GFR) \<30 milliliter/min or dialysis dependent
10. Major surgery within the previous 30 days
11. Minor surgery/biopsy exclusions in the past 3 days
12. Upper gastrointestinal or genitourinary bleed 30 days prior to randomization
13. Stroke or transient ischemic attack 30 days prior to randomization
14. Administration of thrombolytics or glycoprotein IIb/IIIa inhibitor 72 h prior to PPCI
15. Administration of enoxaparin 8 h prior to PPCI
16. Administration of bivalirudin 12 h prior to PPCI
17. Administration of fondaparinux or other low molecular weight heparin 24 h prior to PPCI
18. Known contraindications to aspirin or P2Y12 inhibitors
19. Known allergy that cannot be pre-medicated to iodinated contrast
20. Known contraindication to CMR
21. Women of child bearing potential (see below)
22. Previous enrollment (participants are considered enrolled upon Randomization) in this study
23. 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
24. 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

Primary outcomes:
measure: CMR Assessment Of Infarct Size At Day 5
timeFrame: 5 days post PPCI
Secondary outcomes:
measure: CMR Assessment Of Myocardial Salvage Index (MSI) At Day 5
timeFrame: 5 days post PPCI
measure: CMR Assessment Of Micro-vascular Obstruction (MVO) At Day 5
timeFrame: 5 days post PPCI
measure: CMR Assessment Of Left Ventricular Ejection Fraction (LVEF) At Day 5
timeFrame: 5 days post PPCI
measure: CMR Assessment Of LVEF At Day 90
timeFrame: 90 days post PPCI
measure: TIMI Flow And Myocardial Blush Grade (MBG) At End Of PPCI
timeFrame: 1 day (end of PPCI)
measure: Percentage of Participants With In-Hospital Net Adverse Cardiac Events (NACE) At Day 5
timeFrame: 5 days post PPCI or at discharge, whichever occurs first
measure: Death At Day 90
timeFrame: 90 days post PPCI
Other outcomes:
measure: Index Of Microcirculatory Resistance (IMR)
timeFrame: 1 day (end of PPCI)
Locations:
city: Boulogne Cedex
country: France
facility: Hopital Ambroise Paré
city: Paris
country: France
facility: Hospital Lariboisière
city: Amsterdam
country: Netherlands
facility: VUMC Amsterdam
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
Study officials:
affiliation: Thorax Centrum, Erasmus Medisch Centrum, s-Grave dijkwal 230, 3015 CE Rotterdam, the Netherlands
name: Robert J Van Geuns, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Lariboisiere, Angio-Hematologie, 2 Rue Ambroise Pare, 75475 Paris Cedex 10, France
name: Ludovic Drouet, MD
role: PRINCIPAL_INVESTIGATOR
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