Stratified Medicine of Eplerenone in Acute Myocardial Infarction or Injury and no Obstructive Coronary Arteries. (StratMedMINOCA)

The Effect of Mineralocorticoid Receptor Antagonist Therapy in Patients With Acute Myocardial Infection or Injury and no Obstructive Coronary Arteries: a Registry-based, Stratified-medicine, Randomized, Controlled Trial

Patients with heart attack or heart injury are tested (angiogram) for blockages in their arteries. Patients may develop heart problems caused by damage to small (microvascular) blood vessels. Eplerenone, a mineralocorticoid receptor-selective antagonist, reduces blood vessel injury and is used to treat high blood pressure and heart failure.

Aim: to test the use of eplerenone in patients with heart attack/heart injury an no obstructive coronary arteries and small vessel problems (coronary microvascular dysfunction).

Patients admitted to hospitals in the West of Scotland (2.5 million) and referred for invasive management to the Golden Jubilee and Hairmyres hospitals because of a suspected heart attack heart will be invited to participate into a registry-based clinical trial. Screening, enrolment and verbal, informed consent will be obtained during the angiogram then written consent on the ward. Small vessel disease will be assessed using a 'diagnostic' guidewire during the standard angiogram. People with small vessel problems will be invited to participate in a clinical trial of usual care or eplerenone. Coronary microvascular dysfunction is defined as an index of microvascular resistance ≥25. Coronary flow reserve (CFR abnormal <2.0), microvascular resistance reserve ratio (MRR, abnormal <2.5), and resistance reserve ratio (RRR abnormal <2.0), measured simultaneously with IMR, are predefined parameters of interest.

Patients will be allocated into one of the 3 groups:

• Group 1: Patients without coronary microvascular dysfunction. No eplerenone
• Group 2: Patient with coronary microvascular dysfunction. Usual care, no eplerenone.
• Group 3: Small vessels abnormal. Eplerenone tablets.

The primary outcome for the trial will be reduced heart injury (biomarkers) in patients with microvascular disease. We will also test heart function (MRI scan) at enrolment and at six months. All patients (Groups 1, 2 and 3) will have an angiogram. Standard blood tests will be collected during the hospital stay, and then again at 1 and 6 months. Other outcomes include questionnaires (health status). We will gather information on longer-term health outcomes (hospitalisation, death) using confidential electronic record linkage. We will ask for permission to store blood samples for future research.

The research will improve scientific knowledge about eplerenone therapy in this patient group. The study will create a repository of clinical samples and images which will provide vital data for studies of endotypes of myocardial infarction or injury with no obstructive coronary arteries.

Study Overview

• Status: Recruiting
• Conditions: Myocardial Injury; Myocardial Infarction, Acute; Myocardial Infarction With Nonobstructive Coronary Arteries
• Intervention / Treatment: Drug: Stratified medicine - Microvascular dysfunction and eplerenone therapy, tablets; Other: Stratification and standard care

Detailed Description

Background: Myocardial infarction with non-obstructive coronary arteries (MINOCA) involves vascular dysfunction, prognosis is impaired and specific treatments are lacking. Mineralocorticoid antagonist (MRA) therapy attenuates left ventricular remodelling in patients with acute MI without heart failure e.g. REMINDER trial.

Stratified medicine is defined by the Medical Research Council Framework (2015) as the identification of key sub-groups of patients within a heterogeneous population; these being distinguishable groups with differing mechanisms of disease, or particular responses to treatments. Stratification can be used to improve mechanistic understanding of disease processes and enable: the identification of new targets for treatments; the development of biomarkers for disease risk, diagnosis, progression and response to treatment; and treatments to be tested and applied in the most appropriate patient groups.

Objective: To implement stratified medicine in MINOCA and nonischemic myocardial injury.

Primary Hypothesis of the registry-based diagnostic study: In patients with suspected MINOCA, elevated coronary microvascular resistance defined by index of microvascular resistance ≥25 mmHg·s, is common and quantifiable, identifying a clinically relevant endotype suitable for stratified care.

Primary hypothesis (Trial): In patients with an initial working diagnosis of MINOCA, early risk stratification by coronary microvascular dysfunction (index of microvascular resistance (IMR) ≥25) coupled with cardio-protective MRA therapy using eplerenone limits myocardial damage reflected by changes in N-terminal (NT)-pro hormone BNP (NT-proBNP).

Secondary hypotheses for predefined mechanistic, clinical and exploratory outcomes in the registry and nested, randomised trial will also be explored.

Overall aim: To undertake a developmental clinical study, clarify evidence-gaps and provide training in academic cardiology.

Design A prospective, registry-based, diagnostic study and nested, randomized, open-label, blinded-endpoint (PROBE) basket trial .

The registry involves a prospective diagnostic study with the aims of endotyping patients through a standardized protocol of invasive and non-invasive diagnostic evaluations. The nested randomized trial evaluates stratified therapy with eplerenone in patients with invasive evidence of coronary microvascular dysfunction, defined as IMR (≥25), and no demonstrable alternative non-ischemic etiology.

Procedures Step-1: Screening in during coronary angiography of patients with acute myocardial infarction including suspected MINOCA without heart failure or left ventricular ejection fraction ≤40%; Step-2: Guidewire-based measurement of microvascular resistance (culprit artery or if unknown, the left anterior descending coronary artery. Registry population, n=300); Step-3: Stratify subgroup with -increased vascular risk (IMR≥25) (Trial, n=150 eligible for MRA, informed consent); Step-4: Randomise this higher-risk group: eplerenone 25-50 mg daily for 6 months or standard care. Coronary physiology parameters including coronary flow reserve (CFR abnormal <2.0), microvascular resistance reserve ratio (MRR, abnormal <2.5), the resistance reserve ratio (RRR abnormal <2.0) and left ventricular end-diastolic pressure will be prospectively measured during the index invasive procedure. A diagnostic algorithm will be followed in line with the 2023 Acute Coronary Syndrome guidelines of the European Society of Cardiology (PMID: 37622654). Cardiovascular magnetic resonance (CMR) imaging (MRI) will be undertaken as soon as possible after diagnosis. For participants who are straified for participation in the randomized trial, CMR imaging with adenosine stress/rest myocardial perfusion imaging will be undertaken at 6-months. They will also be invited to participate in a brain MRI substudy ('heart-brain') including to assess for systemic features of small vesel disease.

Outcomes: Primary: within-subject change in NT-proBNP by group; Secondary: left ventricular ejection fraction; left ventricular volumes; patient reported outcome measures (PROMS).

Value: Evidence-synthesis on stratified medicine for MINOCA.

In order to assess the natural history of clinical endotypes, and effects of the trial intervention, electronic health record linkage of vital status, episodes of healthcare and medication use will be assessed during follow-up of up to 20-years. The study design has benefitted from patient and public involvement (PPI). The study is overseen by a Trial Steering Committee including an indendent Chair, a lived experience representative, a sponsor representative and the lead investigators.

• Study Type: Interventional
• Enrollment (Estimated): 400
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Colin Berry, PhD; Phone Number: 01413303325; Email: colin.berry@glasgow.ac.uk

Study Locations

• United Kingdom
  • Glasgow, United Kingdom
    • Recruiting
    • Golden Jubilee National Hospital
    • Contact: Colin Berry, PhD; Phone Number: 01419515000; Email: colin.berry@glasgow.ac.uk
    • Sub-Investigator: Robert A Sykes, MBChB
    • Principal Investigator: Colin Berry, PhD
  • Lanarkshire
    • East Kilbride, Lanarkshire, United Kingdom, G75 8RG
      • Recruiting
      • University Hospital Hairmyres
      • Contact: David Carrick, MBChB PhD; Phone Number: 01355 585 000; Email: david.carrick@lanarkshire.scot.nhs.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥18 years.
• Acute myocardial infarction or myocardial injury and no obstructive coronary arteries.
• Cardiovascular risk factor (≥1): age >70 years, atrial fibrillation, diabetes, current smoker, eGFR 30 - 60 mL/ minute/1.73 m2, prior MI, treated hypertension or COVID-19 (confirmed or suspected)
• Coronary angiography.

Exclusion Criteria (trial):

• Obstructive coronary artery disease
• Left ventricular ejection fraction ≤40% with evidence of heart failure, following myocardial infarction.
• Estimated glomerular filtration rate <30 mL/ minute/1.73 m2
• Severe liver impairment
• Women who are pregnant, breast-feeding or of child-bearing potential (WoCBP) without a negative pregnancy test and who are unwilling or unable to follow the reproductive restrictions defined in the eligibility criteria and use highly effective contraception as defined in Appendix 2 for the duration of the study treatment and 30 days after last dose of study drug.
• Patients taking one of the following medicines :
• Pre-existing treatment with an MRA :
• Anti-fungal drugs (ketoconazole or itraconazole).
• Antiviral medication (nelfinavir or ritonavir).
• Antibiotics (clarithromycin or telithromycin).
• Nefazodone used to treat depression.
• The combination of an angiotensin converting enzyme (ACE) inhibitor and an angiotensin receptor blocker (ARB)) together.

Exclusion Criteria (registry):

• Contra-indication to cardiovascular magnetic resonance imaging e.g. severe claustrophobia, metallic foreign body.
• Contra-indication to intravenous adenosine, i.e. severe asthma; long QT syndrome; second- or third-degree atrio-ventricular block and sick sinus syndrome.
• Lack of informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Eplerenone; Patients with suspected MINOCA and an index of microvascular resistance (IMR) greater than or equal to 25 will be randomised to receive eplerenone (starting dose 25 mg, uptitrated to 50 mg after two weeks) for six months or standard of care and research protocol study visits. Patients who are screened, give informed consent but are not randomized will enter a followup registry.	Drug: Stratified medicine - Microvascular dysfunction and eplerenone therapy, tablets; Stratified medicine including interventional diagnostic procedure (IDP) and linked treatment with eplerenone. Patients with an increased IMR (strata with microvascular dysfunction, IMR ≥25) will be eligible for randomization to this arm. Patients randomized to receive eplerenone will be commenced on 25 mg once daily, and uptitrated to 50 mg once daily after two weeks. Treatment will be continued for a period of six months.; Other Names: Eplerenone
Sham Comparator: Standard of care; Patients with suspected MINOCA and an index of microvascular resistance (IMR) greater than or equal to 25 will be randomised to receive eplerenone (starting dose 25 mg, uptitrated to 50 mg after two weeks) for six months or standard of care and research protocol study visits. Patients who are screened, give informed consent but are not randomized will enter a followup registry.	Other: Stratification and standard care; Interventional diagnostic procedure (IDP) without linked treatment i.e., standard care. Patients with an increased IMR (strata with microvascular dysfunction, IMR ≥25) will be eligible for randomization to this arm. In the standard care group, the IDP is performed but the results are not disclosed. The IDP is therefore a sham procedure. Patients randomized to receive eplerenone will be commenced on 25 mg once daily, and uptitrated to 50 mg once daily after two weeks. Treatment will be continued for a period of six months.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Within patient change in NTproBNP	NTproBNP will be measured at enrolment, thirty days and six months	Enrolment, thirty days and six months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarkers of vascular inflammation	Vascular cell adhesion molecule (VCAM) is a biological marker of vascular inflammation. VCAM will be measured at enrolment, thirty days and six months	Enrolment, thirty days and six months
Health-related quality of life, patient-assessed	European Quality of Life 5-domain 5-Level (EQ-5D-5L) questionnaire, a patient reported outcome measure. Patient assessed score - Scale 0 (worst), 100 (best)	Enrolment, thirty days and six months
Left ventricular remodelling at 6 months (MRI)	Cardiac MRI performed within fourteen days of enrolment and at six months	Within fourteen days of enrolment and at six months
Health economics	Institute for Medical Technology Assessment Productivity Cost Questionnaire (iPCQ)	Enrolment, thirty days and six months
Fibrosis	Circulating (plasma) concentration of procollagen type-I C-terminal pro-peptide (PICP) and collagen type-1 C-terminal telopeptide (CITP) reflect synthesis and degradation of type-I collagen and PICP/CITP ratio reflects collagen turnover.	Enrolment, thirty days and six months
Haemostasis pathway activation	Circulating (plasma) concentration of factor VIII and other biomarkers of haemostasis pathway activation e.g. D-dimers, fibrinogen	Enrolment, thirty days and six months
Major Adverse Cardiovascular and Cerebrovascular Events	Major Adverse Cardiovascular and Cerebrovascular Events (MACCE) defined as cardiovascular death, resuscitated cardiac arrest, and hospitalisation for non-fatal myocardial infarction, angina, heart failure, atrial fibrillation/atrial flutter, stroke or transient ischaemic attack. These are spontaneous adverse cardiovascular events.	From enrolment to six months (trial) and twenty years (registry and trial)
Major Adverse Cardiac Events	Major Adverse Cardiac Events (Cardiac MACE) including cardiac death, non-fatal myocardial infarction or hospitalization for heart failure.	From enrolment to six months (trial) and twenty years (registry and trial)
Adverse ischaemic cardiac events	Adverse ischaemic cardiac events (AICE) defined as cardiac death, resuscitated cardiac arrest, hospitalisation for myocardial infarction, or hospital episode of unscheduled care for angina with or without admission.	From enrolment to six months (trial) and tweny years (registry and trial)
Left ventricular systolic function	Left ventricular systolic function reflected by left ventricular ejection fraction (%) measured by cardiac magnetic resonance imaging (MRI).	Within fourteen days and at six months
Myocardial blood flow at 6 months (MRI)	Cardiac MRI with adenosine stress perfusion to measure myocardial blood flow (ml/min/g tissue) at rest and during adenosine-induced hypereremia and myocardial perfusion reserve.	Performed at six months
Myocardial extracellular volume fraction	Myocardial extracellular volume fraction (ECV) quantified by cardiovascular magnetic resonance imaging	Within fourteen days and at six months
Illness perception	Brief Illness Perception Questionnaire (B-IPQ). Higher scores indicate a higher perceived threat with regard to the illness.	Enrolment, thirty days and six months
Anxiety and depression	Patient Health Questionnaire-4 (PHQ-4). A higher score reflects greater anxiety and depression	Enrolment, thirty days and six months
Functional capacity	Duke Activity Status Index (DASI). A higher total score indicates better functional and aerobic capacity.	Enrolment, thirty days and six months
Physical activity	International Physical Activity Questionnaire Short Form (IPAQ-SF), estimated in Metabolic Equivalent of Tasks (METS)	Enrolment, thirty days and six months
Cognitive function	Montreal Cognitive Assessment (MoCA). A score of 26 or higher is considered is normal. A score below 26 may indicate mild cognitive impairment.	Enrolment, thirty days and six months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hospital episodes of care for chest pain	Hospital visits for chest pain episodes (emergency department, chest pain clinic) that may not have led to hospital admission, will be documented as a prioritised outcome of interest. These episodes may not fulfil the criteria for a SAE, but nonetheless, are episodes of care that are relevant to patients and healthcare providers. These events include but are not limited to episodes of adjudicated angina.	Enrolment to six months (trial) and twenty years (registry and trial)

Collaborators and Investigators

• Sponsor: NHS National Waiting Times Centre Board
• Collaborators: Abbott; British Heart Foundation
• Investigators: Principal Investigator: Colin Berry, PhD, University of Glasgow

Publications and helpful links

General Publications

• Sykes R, Doherty D, Mangion K, Morrow A, Berry C. What an Interventionalist Needs to Know About MI with Non-obstructive Coronary Arteries. Interv Cardiol. 2021 Jun 10;16:e10. doi: 10.15420/icr.2021.10. eCollection 2021 Apr.
• Pelliccia F, Pepine CJ, Berry C, Camici PG. The role of a comprehensive two-step diagnostic evaluation to unravel the pathophysiology of MINOCA: A review. Int J Cardiol. 2021 Aug 1;336:1-7. doi: 10.1016/j.ijcard.2021.05.045. Epub 2021 Jun 1.
• Ford TJ, Ong P, Sechtem U, Beltrame J, Camici PG, Crea F, Kaski JC, Bairey Merz CN, Pepine CJ, Shimokawa H, Berry C; COVADIS Study Group. Assessment of Vascular Dysfunction in Patients Without Obstructive Coronary Artery Disease: Why, How, and When. JACC Cardiovasc Interv. 2020 Aug 24;13(16):1847-1864. doi: 10.1016/j.jcin.2020.05.052.
• Bairey Merz CN, Pepine CJ, Shimokawa H, Berry C. Treatment of coronary microvascular dysfunction. Cardiovasc Res. 2020 Mar 1;116(4):856-870. doi: 10.1093/cvr/cvaa006.
• Ford TJ, Stanley B, Good R, Rocchiccioli P, McEntegart M, Watkins S, Eteiba H, Shaukat A, Lindsay M, Robertson K, Hood S, McGeoch R, McDade R, Yii E, Sidik N, McCartney P, Corcoran D, Collison D, Rush C, McConnachie A, Touyz RM, Oldroyd KG, Berry C. Stratified Medical Therapy Using Invasive Coronary Function Testing in Angina: The CorMicA Trial. J Am Coll Cardiol. 2018 Dec 11;72(23 Pt A):2841-2855. doi: 10.1016/j.jacc.2018.09.006. Epub 2018 Sep 25.
• Byrne RA, Rossello X, Coughlan JJ, Barbato E, Berry C, Chieffo A, Claeys MJ, Dan GA, Dweck MR, Galbraith M, Gilard M, Hinterbuchner L, Jankowska EA, Juni P, Kimura T, Kunadian V, Leosdottir M, Lorusso R, Pedretti RFE, Rigopoulos AG, Rubini Gimenez M, Thiele H, Vranckx P, Wassmann S, Wenger NK, Ibanez B; ESC Scientific Document Group. 2023 ESC Guidelines for the management of acute coronary syndromes. Eur Heart J. 2023 Oct 12;44(38):3720-3826. doi: 10.1093/eurheartj/ehad191. No abstract available.
• Morrone D, Stefanini G, De Carlo M, Giannini C, Toth G, Prunea D, Zivelonghi C, Benedetti A, De Bruyne B, Wilgenhof A, Kanovsky J, Kala P, Holmvang L, Hasbak M, Hildick-Smith D, Cockburn J, Amabile N, Veugeois A, Hovasse T, Neylon A, Honton B, Farah B, Gori T, Knorr M, Wolf A, Schmit T, Hausleiter J, K KS, Abdel-Waha M, Feistritzer HJ, Woitek F, Linke A, Leick J, Afzal S, Alexopoulos D, Varlamos C, Tsioufis K, Dimitriadis K, Testa L, Squillace M, Conrotto F, D'Ascenzo F, Campo G, Cocco M, Di Mario C, Caniato F, Ribichini FL, Prati D, Tarantini G, Cardaioli F, Burzotta F, Paraggio L, Bedogni F, Arzuffi L, Chieffo A, Ghizzoni G, Davidavicius G, Budrys P, Van Mieghem N, Daemen J, Brinkmann R, Bante H, Lesiak M, Iwanczyk S, Pregowski J, Skowronski J, Madeira S, Raposo L, Estevez-Loureiro R, Sisinni A, Escaned J, Jeronimo A, Moreno R, Jimenez-Valero S, Vriesendorp P, Pustjens T, Van Geuns R, Damman P, Van de Hoef T, Van der Harst P, Mamas MA, Duckett S, Mikhail G, Lucarelli C, Berry C, De Caterina R. Myocardial infarction with nonobstructive coronary arteries - the European PERspective (SNIPER) survey. J Cardiovasc Med (Hagerstown). 2025 Dec 1;26(12):731-740. doi: 10.2459/JCM.0000000000001808. Epub 2025 Dec 5.
• Berry C, Sykes RA, Tan D. MINOCA: a call for randomized trials. Eur Heart J. 2026 Jan 29:ehaf1075. doi: 10.1093/eurheartj/ehaf1075. Online ahead of print. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): February 4, 2022
• Primary Completion (Estimated): July 31, 2026
• Study Completion (Estimated): July 31, 2026

Study Registration Dates

• First Submitted: December 20, 2021
• First Submitted That Met QC Criteria: January 6, 2022
• First Posted (Actual): January 20, 2022

Study Record Updates

• Last Update Posted (Actual): March 16, 2026
• Last Update Submitted That Met QC Criteria: March 12, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Myocardial infarction; Mineralocorticoid receptor antagonists; Stratified Medicine; MINOCA; Myocardial injury; Myocardial Infarction with Nonobstructive Coronary Arteries
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Infarction; Necrosis; Myocardial Ischemia; Ischemia; Pathological Conditions, Signs and Symptoms; MINOCA; Myocardial Infarction; Health Services Administration; Health Care Quality, Access, and Evaluation; Organic Chemicals; Pharmaceutical Preparations; Dosage Forms; Quality of Health Care; Polycyclic Compounds; Quality Indicators, Health Care; Pregnanes; Steroids; Fused-Ring Compounds; Lactones; Pregnenes; Eplerenone; Standard of Care; Tablets
• Other Study ID Numbers: 21/CARD/29

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be shared based on a bon fide research request and sponsor approval.
• IPD Sharing Time Frame: At the end of the study
• IPD Sharing Access Criteria: Bon fide research request and sponsor approval.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No