Myocardial Infarction, Acute, Myocardial Infarction With Nonobstructive Coronary Arteries, Myocardial Injury
Conditions
Keywords
Stratified Medicine, Mineralocorticoid receptor antagonists, MINOCA, Myocardial injury, Myocardial infarction, Myocardial Infarction with Nonobstructive Coronary Arteries
Brief summary
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.
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.
Interventions
DRUGStratified 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.
OTHERStratification 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.
Sponsors
NHS National Waiting Times Centre Board
British Heart Foundation
Abbott
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Masking description
Participants will be masked on their assignment to either the control group vs. registry. Assessors for the primary outcome (laboratory measurement) will be blinded to treatment group assigment.
Intervention model description
Prospective, randomised, open-label, blinded, end-point (mechanistic, PROBE design).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Within patient change in NTproBNP | Enrolment, thirty days and six months | NTproBNP will be measured at enrolment, thirty days and six months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Major Adverse Cardiovascular and Cerebrovascular Events | From enrolment to six months (trial) and twenty years (registry and trial) | 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. |
| Major Adverse Cardiac Events | From enrolment to six months (trial) and twenty years (registry and trial) | Major Adverse Cardiac Events (Cardiac MACE) including cardiac death, non-fatal myocardial infarction or hospitalization for heart failure. |
| Adverse ischaemic cardiac events | From enrolment to six months (trial) and tweny years (registry and trial) | 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. |
| Left ventricular remodelling at 6 months (MRI) | Within fourteen days of enrolment and at six months | Cardiac MRI performed within fourteen days of enrolment and at six months |
| Left ventricular systolic function | Within fourteen days and at six months | Left ventricular systolic function reflected by left ventricular ejection fraction (%) measured by cardiac magnetic resonance imaging (MRI). |
| Myocardial blood flow at 6 months (MRI) | Performed at six months | 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. |
| Myocardial extracellular volume fraction | Within fourteen days and at six months | Myocardial extracellular volume fraction (ECV) quantified by cardiovascular magnetic resonance imaging |
| Health-related quality of life, patient-assessed | Enrolment, thirty days and six months | 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) |
| Health economics | Enrolment, thirty days and six months | Institute for Medical Technology Assessment Productivity Cost Questionnaire (iPCQ) |
| Illness perception | Enrolment, thirty days and six months | Brief Illness Perception Questionnaire (B-IPQ). Higher scores indicate a higher perceived threat with regard to the illness. |
| Anxiety and depression | Enrolment, thirty days and six months | Patient Health Questionnaire-4 (PHQ-4). A higher score reflects greater anxiety and depression |
| Functional capacity | Enrolment, thirty days and six months | Duke Activity Status Index (DASI). A higher total score indicates better functional and aerobic capacity. |
| Physical activity | Enrolment, thirty days and six months | International Physical Activity Questionnaire Short Form (IPAQ-SF), estimated in Metabolic Equivalent of Tasks (METS) |
| Cognitive function | Enrolment, thirty days and six months | Montreal Cognitive Assessment (MoCA). A score of 26 or higher is considered is normal. A score below 26 may indicate mild cognitive impairment. |
| Fibrosis | Enrolment, thirty days and six months | 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. |
| Haemostasis pathway activation | Enrolment, thirty days and six months | Circulating (plasma) concentration of factor VIII and other biomarkers of haemostasis pathway activation e.g. D-dimers, fibrinogen |
| Biomarkers of vascular inflammation | Enrolment, thirty days and six months | Vascular cell adhesion molecule (VCAM) is a biological marker of vascular inflammation. VCAM will be measured at enrolment, thirty days and six months |
Countries
United Kingdom
Contacts
CONTACTColin Berry, PhD
PRINCIPAL_INVESTIGATORColin Berry, PhD
University of Glasgow
Outcome results
None listed