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Acute Myocardial InfarctionPhase 3BIVALNCT02565147

Bivalirudin Infusion for Ventricular Infarction Limitation

A Phase 3 study testing PPCI, Bivalirudin and Heparin in people with Acute Myocardial Infarction, run by The Medicines Company at 4 sites in 2 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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). Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Acute Myocardial Infarction
What is being tested?
PPCI, Bivalirudin and Heparin
Could I receive a placebo?
No, everyone receives an active treatment
How many people
78 participants
Where
4 sitesin 2 countries
Study dates
19 Dec 2014to 14 Jun 2016
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • ≥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

Who cannot join

  • 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
Show all 30Show fewer
  • 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

Trial locations and contacts

4 sites in 2 countries.

4 sites in 2 countries

France2 sites

  • Hopital Ambroise Paré

    Boulogne, 92104

  • Hospital Lariboisière

    Paris, 75010

Other trials in France

Netherlands2 sites

  • VUMC Amsterdam

    Amsterdam, 1117 HV

  • Erasmus Medical Center

    Rotterdam, 3015 CE

Other trials in Netherlands

About this study

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).

Read the 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
Being tested
PPCI, Bivalirudin, Heparin
Keywords
STEMI, infarct size, CMR, bivalirudin
Medical subject headings
ST Elevation Myocardial Infarction

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PPCIProcedure or surgery

    PPCI for treatment of participants presenting with large STEMI.

  • BivalirudinDrug

    Also called Angiomax, Angiox

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

  • HeparinDrug

    Also called UFH

    Heparin is an anticoagulant.

Study groups in NCT02565147
Study groupRoleWhat they receive
PPCI with BivalirudinExperimentalBivalirudin 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.
Receives: Procedure: PPCI; Drug: Bivalirudin
PPCI with HeparinActive comparatorUFH 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.
Receives: Procedure: PPCI; Drug: Heparin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. CMR Assessment Of Infarct Size At Day 5

    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.

    Measured: 5 days post PPCI

Secondary outcomes (7)

  1. CMR Assessment Of Myocardial Salvage Index (MSI) At Day 5

    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.

    Measured: 5 days post PPCI

  2. CMR Assessment Of Micro-vascular Obstruction (MVO) At Day 5

    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.

    Measured: 5 days post PPCI

  3. CMR Assessment Of Left Ventricular Ejection Fraction (LVEF) At Day 5

    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.

    Measured: 5 days post PPCI

  4. CMR Assessment Of LVEF At Day 90

    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.

    Measured: 90 days post PPCI

  5. TIMI Flow And Myocardial Blush Grade (MBG) At End Of PPCI

    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.

    Measured: 1 day (end of PPCI)

  6. Percentage of Participants With In-Hospital Net Adverse Cardiac Events (NACE) At Day 5

    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.

    Measured: 5 days post PPCI or at discharge, whichever occurs first

  7. Death At Day 90

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

    Measured: 90 days post PPCI

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 Oct 2015 (estimated)
  2. Study start19 Dec 2014
  3. Primary completion14 Jun 2016
  4. Study completion14 Jun 2016

Why it stopped: Futility at the interim analysis.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Single blind
Who is masked
Outcomes assessor
Enrolment
78 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02565147
Sponsor's protocol ID
MDCO-BIV-12-02
Other IDs
2012-002314-39
Acronym
BIVAL
Status last verified
Dec 2017
First submitted
5 Dec 2014
Last updated
5 Oct 2018
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • Alderman EL, Stadius M. The angiographic definitions of the Bypass Angioplasty Revascularization Investigation. Coronary Artery Disease 1992;3: 1189-1207

  • Graham MM, Faris PD, Ghali WA, Galbraith PD, Norris CM, Badry JT, Mitchell LB, Curtis MJ, Knudtson ML; APPROACH Investigators (Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease. Validation of three myocardial jeopardy scores in a population-based cardiac catheterization cohort. Am Heart J. 2001 Aug;142(2):254-61. doi: 10.1067/mhj.2001.116481.

    PubMed 11479464

  • Kim RJ, Fieno DS, Parrish TB, Harris K, Chen EL, Simonetti O, Bundy J, Finn JP, Klocke FJ, Judd RM. Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function. Circulation. 1999 Nov 9;100(19):1992-2002. doi: 10.1161/01.cir.100.19.1992.

    PubMed 10556226

  • Lowe JE, Reimer KA, Jennings RB. Experimental infarct size as a function of the amount of myocardium at risk. Am J Pathol. 1978 Feb;90(2):363-79.

    PubMed 623206

  • Ortiz-Perez JT, Meyers SN, Lee DC, Kansal P, Klocke FJ, Holly TA, Davidson CJ, Bonow RO, Wu E. Angiographic estimates of myocardium at risk during acute myocardial infarction: validation study using cardiac magnetic resonance imaging. Eur Heart J. 2007 Jul;28(14):1750-8. doi: 10.1093/eurheartj/ehm212. Epub 2007 Jun 22.

    PubMed 17586811

  • Reimer KA, Ideker RE, Jennings RB. Effect of coronary occlusion site on ischaemic bed size and collateral blood flow in dogs. Cardiovasc Res. 1981 Nov;15(11):668-74. doi: 10.1093/cvr/15.11.668.

    PubMed 7326685

  • Seiler C, Kirkeeide RL, Gould KL. Basic structure-function relations of the epicardial coronary vascular tree. Basis of quantitative coronary arteriography for diffuse coronary artery disease. Circulation. 1992 Jun;85(6):1987-2003. doi: 10.1161/01.cir.85.6.1987.

    PubMed 1591819

  • Seiler C, Kirkeeide RL, Gould KL. Measurement from arteriograms of regional myocardial bed size distal to any point in the coronary vascular tree for assessing anatomic area at risk. J Am Coll Cardiol. 1993 Mar 1;21(3):783-97. doi: 10.1016/0735-1097(93)90113-f.

    PubMed 8436762

  • Wu E, Judd RM, Vargas JD, Klocke FJ, Bonow RO, Kim RJ. Visualisation of presence, location, and transmural extent of healed Q-wave and non-Q-wave myocardial infarction. Lancet. 2001 Jan 6;357(9249):21-8. doi: 10.1016/S0140-6736(00)03567-4.

    PubMed 11197356

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing PPCI, Bivalirudin and Heparin in people with Acute Myocardial Infarction, run by The Medicines Company at 4 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 5 Oct 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in France, Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 5 Oct 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

CMR Assessment Of Infarct Size At Day 5 (time frame: 5 days post PPCI). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02565147, which also lists 9 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Oct 2018.

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