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Early Mineralocorticoid Receptor Antagonist Treatment to Reduce Myocardial Infarct Size

Information source: University College, London
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: ST-elevation Myocardial Infarction

Intervention: Mineralocorticoid receptor antagonist potassium-canrenoate (Drug); placebo (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: University College, London

Official(s) and/or principal investigator(s):
Derek J Hausenloy, PhD, Study Director, Affiliation: University College London, Hatter Cardiovascular Institute
Georg M Fröhlich, MD, Study Chair, Affiliation: University College London, The Heart Hospital
Pascal Meier, MD, Principal Investigator, Affiliation: University College London, The Heart Hospital
Reto Gamma, MD, Principal Investigator, Affiliation: Basildon and Thurrock University Hospitals
Anthony Mathur, PhD, Principal Investigator, Affiliation: London Chest Hospital
John Greenwood, MD, Principal Investigator, Affiliation: Leeds General Infirmary

Overall contact:
Derek J Hausenloy, PhD, Phone: +44 (0) 203 447 9888, Email: d.hausenloy@ucl.ac.uk

Summary

Heart attacks, or myocardial infarcts, are a major cause of death and disability in the UK. Immediate unblocking of the obstructed heart vessel with a balloon catheter and implantation of a mesh scaffold (stent) in heart centers is warranted in these patients. Morbidity and mortality in this patient group is related to the infarct size. Therefore, there is a need to discover novel therapeutic agents which reduce myocardial infarct size and preserve the contractile heart function. Large trials involving several thousand patients have demonstrated a survival benefit in patients with impaired heart function due to a heart attack, who received a mineralo-corticoid receptor antagonist (MRA, drug name: spironolactone). In these trials patients received the drug late, 3-14 days after the heart attack. Our proposal is to investigate whether MRA therapy administered intravenously prior to unblocking an occluded heart vessel, can reduce infarct size and as such can prevent long term sequelae of heart attacks. 150 patients admitted to 4 tertiary care hospitals (Heart Hospital London, London Chest, Essex Cardiothoracic Center and Leeds General Infirmary) for heart attack will be randomly assigned to receive MRA treatment or placebo. The first dose of the MRA will be applied intravenously immediately in the catheter suite, even before re-opening of the occluded vessel. From the second day on, patients will be prescribed oral MRA treatment, as a pill, for a total of three months. Before hospital discharge and after three months, a magnetic resonance image (MRI) of the heart will accurately investigate the evolution of infarct (scar) size and the contractile heart function and compare the group of patients who received the MRA drug versus the placebo control group. Of note, patients with an ejection fraction <40% AND signs of heart failure OR diabetes will go on open label eplerenone according to current guidelines, instead of the study drug. This study will give first evidence, if very early MRA treatment improves heart function and should be used as early as possible for treatment of patients after a heart attack.

Clinical Details

Official title: MINeralocorticoid Receptor Antagonist Pretreatment to MINIMISE Reperfusion Injury After ST-Elevation Myocardial Infarction (STEMI)

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Myocardial infarct (MI) size, as assessed by cardiac magnetic resonance imaging

Secondary outcome:

Markers of myocardial reperfusion injury

Microvascular obstruction on cardiac MRI

Myocardial salvage

Acute myocardial infarct size

LV remodelling

Clinical outcome measures

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria: Inclusion criteria for entry into trial

- Patients >18 years

- Patients presenting with acute STEMI (as assessed by 12 lead ECG; ST segment

elevation ≥2 mm (0. 2 mV) in 2 or more contiguous precordial leads or ≥1mm (0. 1mm) in 2 or more adjacent limb leads).

- Presentation within 12 hours after symptom onset

Inclusion criteria for randomization (assessed in catheter laboratory)

- Angiographically proven proximal occlusion (TIMI 0) of a major coronary vessel (LAD,

LCX, RCA).

- Normal potassium (<5. 0 mmol/l)

Exclusion Criteria:

- Patients with known LVEF ≤40%

- Participation in another trial

- Cardiogenic shock (positive shock index OR need for catecholamine support OR systolic

blood pressure < 90 mmHg)

- Killip class > 2

- Prior myocardial infarction

- Known compromised renal function (eGFR < 30 ml/min/1. 73 m2) or potassium > 5. 0 mmol/l

- Current treatment with mineralocorticoid receptor antagonists

- Pregnant or lactating females

- Allergies to IMP or its excipients

- Known contraindication to cardiac magnetic resonance imaging (MRI) such as

significant claustrophobia, severe allergy to gadolinium chelate contrast, , presence of MRI contraindicated implanted devices (eg, pacemaker, implanted cardiac defibrillator, cardiac resynchronization therapy device, cochlear implant), imbedded metal objects (eg, shrapnel), or any other contraindication for cardiac MRI.

Locations and Contacts

Derek J Hausenloy, PhD, Phone: +44 (0) 203 447 9888, Email: d.hausenloy@ucl.ac.uk

Leeds Genereal Infirmary, Leeds, United Kingdom; Recruiting
John Greenwood, MD, Email: J.Greenwood@leeds.ac.uk

Heart Hospital London, London W1G 8PH, United Kingdom; Recruiting
Alex Sirker, MD, Email: Alex.Sirker@uclh.nhs.uk
Alex Sirker, MD, Principal Investigator

London Chest Hospital, London E2 9JX, United Kingdom; Recruiting
Anthony Mathur, PhD, Email: Emma.Bastian@bartshealth.nhs.uk
Anthony Mathur, PhD, Principal Investigator

Cardiothoracic Center - Basildon and Thurrock University Hospitals, Basildon, Essex SS16 5NL, United Kingdom; Recruiting
Reto Gamma, MD, Email: retogamma@nhs.net
Reto Gamma, MD, Principal Investigator

Additional Information

Related publications:

Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M; Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003 Apr 3;348(14):1309-21. Epub 2003 Mar 31. Erratum in: N Engl J Med. 2003 May 29;348(22):2271.

Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B; EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011 Jan 6;364(1):11-21. doi: 10.1056/NEJMoa1009492. Epub 2010 Nov 14.

Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999 Sep 2;341(10):709-17.

Schmidt K, Tissier R, Ghaleh B, Drogies T, Felix SB, Krieg T. Cardioprotective effects of mineralocorticoid receptor antagonists at reperfusion. Eur Heart J. 2010 Jul;31(13):1655-62. doi: 10.1093/eurheartj/ehp555. Epub 2009 Dec 21.

Starting date: November 2013
Last updated: January 29, 2015

Page last updated: August 23, 2015

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