Clinical trial NCT01882179: Early Mineralocorticoid Receptor Antagonist Treatment to Reduce Myocardial Infarct Size
Official title: MINeralocorticoid Receptor Antagonist Pretreatment to MINIMISE Reperfusion Injury After ST-Elevation Myocardial Infarction (STEMI)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: ST-elevation Myocardial Infarction
Keywords: Reperfusion injury
myocardial infarct size
MRI
spironolactone
Lead sponsor: University College, London
Sponsor class: OTHER
Collaborators: name: British Heart Foundation
First posted: 2013-06-20
Enrollment: 61
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: 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.


Eligibility 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.

Primary outcomes:
measure: Myocardial infarct (MI) size, as assessed by cardiac magnetic resonance imaging
timeFrame: 12 weeks after STEMI
Secondary outcomes:
measure: Markers of myocardial reperfusion injury
timeFrame: 48 hours
measure: Microvascular obstruction on cardiac MRI
timeFrame: 1-3 days after STEMI
measure: Myocardial salvage
timeFrame: 12 weeks
measure: Acute myocardial infarct size
timeFrame: 1-3 days
measure: LV remodelling
timeFrame: 12 week cardiac MRI scan
measure: Clinical outcome measures
timeFrame: 12 weeks
Other outcomes:
Locations:
city: Basildon
country: United Kingdom
facility: Cardiothoracic Center - Basildon and Thurrock University Hospitals
state: Essex
city: Leeds
country: United Kingdom
facility: Leeds Genereal Infirmary
city: London
country: United Kingdom
facility: London Chest Hospital
city: London
country: United Kingdom
facility: Heart Hospital London
Study officials:
affiliation: University College London, Hatter Cardiovascular Institute
name: Derek J Hausenloy, PhD
role: STUDY_DIRECTOR
affiliation: University College London, The Heart Hospital
name: Georg M Fröhlich, MD
role: STUDY_CHAIR
affiliation: University College London, The Heart Hospital
name: Pascal Meier, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Basildon and Thurrock University Hospitals
name: Reto Gamma, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: London Chest Hospital
name: Anthony Mathur, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Leeds General Infirmary
name: John Greenwood, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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. doi: 10.1056/NEJMoa030207. Epub 2003 Mar 31.
citation: 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.
citation: 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. doi: 10.1056/NEJM199909023411001.
citation: 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.