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
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 400
- 试验地点
- 2
- 主要终点
- Within patient change in NTproBNP
研究概览
简要总结
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.
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Outcomes Assessor)
盲法说明
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.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: Stratified medicine - Microvascular dysfunction and eplerenone therapy, tablets (Drug)
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.
干预措施: Stratification and standard care (Other)
结局指标
主要结局
Within patient change in NTproBNP
时间窗: Enrolment, thirty days and six months
NTproBNP will be measured at enrolment, thirty days and six months
次要结局
- Biomarkers of vascular inflammation(Enrolment, thirty days and six months)
- Health-related quality of life, patient-assessed(Enrolment, thirty days and six months)
- Left ventricular remodelling at 6 months (MRI)(Within fourteen days of enrolment and at six months)
- Health economics(Enrolment, thirty days and six months)
- Fibrosis(Enrolment, thirty days and six months)
- Haemostasis pathway activation(Enrolment, thirty days and six months)
- Myocardial blood flow at 6 months (MRI)(Performed at six months)
- Major Adverse Cardiovascular and Cerebrovascular Events(From enrolment to six months (trial) and twenty years (registry and trial))
- Major Adverse Cardiac Events(From enrolment to six months (trial) and twenty years (registry and trial))
- Adverse ischaemic cardiac events(From enrolment to six months (trial) and tweny years (registry and trial))
- Left ventricular systolic function(Within fourteen days and at six months)
- Myocardial extracellular volume fraction(Within fourteen days and at six months)
- Illness perception(Enrolment, thirty days and six months)
- Anxiety and depression(Enrolment, thirty days and six months)
- Functional capacity(Enrolment, thirty days and six months)
- Physical activity(Enrolment, thirty days and six months)
- Cognitive function(Enrolment, thirty days and six months)
研究者
Colin Berry
Professor
NHS National Waiting Times Centre Board