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

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат 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.
• Другое 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

Первичные конечные точки

• Within patient change in NTproBNP [Срок оценки: Enrolment, thirty days and six months]

Вторичные конечные точки (12)

• Major Adverse Cardiovascular and Cerebrovascular Events [Срок оценки: From enrolment to six months (trial) and twenty years (registry and trial)]
• Major Adverse Cardiac Events [Срок оценки: From enrolment to six months (trial) and twenty years (registry and trial)]
• Adverse ischaemic cardiac events [Срок оценки: From enrolment to six months (trial) and tweny years (registry and trial)]
• Left ventricular remodelling at 6 months (MRI) [Срок оценки: Within fourteen days of enrolment and at six months]
• Left ventricular systolic function [Срок оценки: Within fourteen days and at six months]
• Myocardial blood flow at 6 months (MRI) [Срок оценки: Performed at six months]
• Myocardial extracellular volume fraction [Срок оценки: Within fourteen days and at six months]
• Health-related quality of life, patient-assessed [Срок оценки: Enrolment, thirty days and six months]
• Health economics [Срок оценки: Enrolment, thirty days and six months]
• Illness perception [Срок оценки: Enrolment, thirty days and six months]
• Anxiety and depression [Срок оценки: Enrolment, thirty days and six months]
• Functional capacity [Срок оценки: Enrolment, thirty days and six months]

Критерии участия

Критерии включения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Двойное слепое

Основная цель

Лечение

Центры проведения

Великобритания · 2 центра

• University Hospital Hairmyres — East Kilbride
• Golden Jubilee National Hospital — Glasgow

Публикации

• 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 PMID 41428430
• Berry C, Sykes RA, Tan D. MINOCA: a call for randomized trials. Eur Heart J. 2026 Mar 24;47(12):1467-1469. doi: 10.1093/eurheartj/ehaf1075. No abstract available. PMID 41605253
• 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 syndrom PMID 37622654
• 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. PMID 34188694
• 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. PMID 34087335
• 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. PMID 32819476
• 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. PMID 32087007
• 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 PMID 30266608

Идентификаторы

NCT: NCT05198791 · 21/CARD/29

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗