Early Mineralocorticoid Receptor Antagonist Treatment to Reduce Myocardial Infarct Size

ST-elevation Myocardial Infarction Clinical Trial

— MINIMISE-STEMI  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01882179
• Other study ID #: 12/0533
• Status: Completed
• Phase: Phase 3
• First received: June 17, 2013
• Last updated: October 25, 2016
• Start date: November 2013
• Est. completion date: May 2016

Study information

• Verified date: May 2016
• Source: University College, London
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 61
• Est. completion date: May 2016
• Est. primary completion date: May 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

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

Related Conditions & MeSH terms

• Infarction
• Myocardial Infarction
• Reperfusion Injury
• ST-elevation Myocardial Infarction

Intervention

Drug:
• Mineralocorticoid receptor antagonist potassium-canrenoate

• placebo

Locations

Country	Name	City	State
United Kingdom	Cardiothoracic Center - Basildon and Thurrock University Hospitals	Basildon	Essex
United Kingdom	Leeds Genereal Infirmary	Leeds
United Kingdom	Heart Hospital London	London
United Kingdom	London Chest Hospital	London

Sponsors (2)

Lead Sponsor	Collaborator
University College, London	British Heart Foundation

Country where clinical trial is conducted

United Kingdom, 

References & Publications (4)

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. — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Myocardial infarct (MI) size, as assessed by cardiac magnetic resonance imaging		12 weeks after STEMI	No
Secondary	Markers of myocardial reperfusion injury	TIMI flow post-PPCI, ST-segment resolution post-PPCI	48 hours	No
Secondary	Microvascular obstruction on cardiac MRI	hypodense area of late gadolinium enhancement	1-3 days after STEMI	No
Secondary	Myocardial salvage	Area at risk assessed by T2 weighted imaging subtract final MI size	12 weeks	No
Secondary	Acute myocardial infarct size	serum biomarkers: hsTnT, CK-MB, CK and cardiac MRI: late gadolinium enhancement	1-3 days	No
Secondary	LV remodelling	LV end-diastolic and end-systolic volumes, LV ejection fraction, LV mass and wall-thickness	12 week cardiac MRI scan	No
Secondary	Clinical outcome measures	cardiovascular death, non-fatal myocardial infarction, revascularisation, hospitalisation for heart failure, hyperkalemia, deterioration of kidney function, need for dialysis	12 weeks	Yes