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

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.

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.

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.