Bivalirudin Infusion for Ventricular Infarction Limitation

NCT ID: NCT02565147

Last Updated: 2018-10-05

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 78 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-12-19
• Study Completion Date: 2016-06-14

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

Conditions

Acute Myocardial Infarction

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

PPCI with Bivalirudin

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.

Group Type: EXPERIMENTAL

PPCI

Intervention Type: PROCEDURE

PPCI for treatment of participants presenting with large STEMI.

Bivalirudin

Intervention Type: DRUG

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

PPCI with Heparin

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.

Group Type: ACTIVE_COMPARATOR

PPCI

Intervention Type: PROCEDURE

PPCI for treatment of participants presenting with large STEMI.

Heparin

Intervention Type: DRUG

Heparin is an anticoagulant.

Interventions

PPCI

PPCI for treatment of participants presenting with large STEMI.

Intervention Type: PROCEDURE

Bivalirudin

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

Intervention Type: DRUG

Heparin

Heparin is an anticoagulant.

Intervention Type: DRUG

Other Intervention Names

Angiomax; Angiox; UFH

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

The Medicines Company

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Robert J Van Geuns, MD

Role: PRINCIPAL_INVESTIGATOR

Thorax Centrum, Erasmus Medisch Centrum, s-Grave dijkwal 230, 3015 CE Rotterdam, the Netherlands

Ludovic Drouet, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital Lariboisiere, Angio-Hematologie, 2 Rue Ambroise Pare, 75475 Paris Cedex 10, France

Locations

Hopital Ambroise Paré

Boulogne, , France

Hospital Lariboisière

Paris, , France

VUMC Amsterdam

Amsterdam, , Netherlands

Erasmus Medical Center

Rotterdam, , Netherlands

Countries

France; Netherlands

References

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

Reference Type: BACKGROUND

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.

Reference Type: BACKGROUND

PMID: 11479464 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 10556226 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 623206 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 17586811 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 7326685 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 1591819 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 8436762 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 11197356 (View on PubMed)

Other Identifiers

2012-002314-39

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

MDCO-BIV-12-02

Identifier Type: -

Identifier Source: org_study_id