Clinical trial NCT05198791: Stratified Medicine of Eplerenone in Acute MI/injury (StratMed-MINOCA)
Official title: The Effect of Mineralocorticoid Receptor Antagonist Therapy in Patients with Acute Myocardial Infection or Injury and Cardiovascular Risk Factors: a Registry-based, Stratified-medicine, Randomised, Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Myocardial Infarction, Acute
Myocardial Infarction with Nonobstructive Coronary Arteries
Myocardial Injury
Keywords: Stratified Medicine
Mineralocorticoid receptor antagonists
MINOCA
Myocardial injury
Myocardial infarction
Myocardial Infarction with Nonobstructive Coronary Arteries
Lead sponsor: NHS National Waiting Times Centre Board
Sponsor class: OTHER
Collaborators: name: British Heart Foundation
name: Abbott
First posted: 2022-01-20
Enrollment: 350
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective, randomised, open-label, blinded, end-point (mechanistic, PROBE design).
Primary purpose: TREATMENT

Brief summary: Patients with heart attack or heart injury are tested (angiogram) for blockages in their arteries. Many patients develop heart problems caused by damage to small (microvascular) blood vessels. These issues are also relevant to patients with coronarvirus-19 disease (COVID-19). Eplerenone reduces blood vessel injury and is used to treat heart failure.

Aim: to test the use of eplerenone in patients with heart attack/heart injury who have small vessel disease, including patients with COVID-19

Patients referred to the Golden Jubilee hospital with a suspected heart attack heart / injury 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 allocated to 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) 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 COVID-19.

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.

Hypothesis: In 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).

Aim: To undertake a developmental clinical study, clarify evidence-gaps and provide training in academic cardiology. Prospective randomized open, blinded end-point (PROBE) design: Step-1: Screening in during coronary angiography of patients with acute myocardial infarction including 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), the resistance reserve ratio (RRR abnormal \<2.0) and left ventricular end-diastolic pressure will be prospectively measured.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Within patient change in NTproBNP
timeFrame: Enrolment, thirty days and six months
Secondary outcomes:
measure: Biomarkers of vascular inflammation
timeFrame: Enrolment, thirty days and six months
measure: Myocardial blood flow at 6 months (MRI)
timeFrame: Performed at six months
measure: Health-related quality of life, patient-assessed
timeFrame: Enrolment, thirty days and six months
measure: Left ventricular remodelling at 6 months (MRI)
timeFrame: Within fourteen days of enrolment and at six months
measure: Health economics
timeFrame: Enrolment, thirty days and six months
measure: Fibrosis
timeFrame: Enrolment, thirty days and six months
measure: Haemostasis pathway activation
timeFrame: Enrolment, thirty days and six months
Other outcomes:
Locations:
city: East Kilbride
country: United Kingdom
facility: University Hospital Hairmyres
state: Lanarkshire
city: Glasgow
country: United Kingdom
facility: Golden Jubilee National Hospital
Study officials:
affiliation: University of Glasgow
name: Colin Berry, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.