Mineralocorticoid Receptor Antagonist Pretreatment to MINIMISE Reperfusion Injury After ST‐Elevation Myocardial Infarction (The MINIMISE STEMI Trial): Rationale and Study Design

Abstract

Novel therapies capable of reducing myocardial infarct (MI) size when administered prior to reperfusion are required to prevent the onset of heart failure in ST‐segment elevation myocardial infarction (STEMI) patients treated by primary percutaneous coronary intervention (PPCI). Experimental animal studies have demonstrated that mineralocorticoid receptor antagonist (MRA) therapy administered prior to reperfusion can reduce MI size, and MRA therapy prevents adverse left ventricular (LV) remodeling in post‐MI patients with LV impairment. With these 2 benefits in mind, we hypothesize that initiating MRA therapy prior to PPCI, followed by 3 months of oral MRA therapy, will reduce MI size and prevent adverse LV remodeling in STEMI patients. The MINIMISE‐STEMI trial is a prospective, randomized, double‐blind, placebo‐controlled trial that will recruit 150 STEMI patients from four centers in the United Kingdom. Patients will be randomized to receive either an intravenous bolus of MRA therapy (potassium canrenoate 200 mg) or matching placebo prior to PPCI, followed by oral spironolactone 50 mg once daily or matching placebo for 3 months. A cardiac magnetic resonance imaging scan will be performed within 1 week of PPCI and repeated at 3 months to assess MI size and LV remodeling. Enzymatic MI size will be estimated by the 48‐hour area‐under‐the‐curve serum cardiac enzymes. The primary endpoint of the study will be MI size on the 3‐month cardiac magnetic resonance imaging scan. The MINIMISE STEMI trial will investigate whether early MRA therapy, initiated prior to reperfusion, can reduce MI size and prevent adverse post‐MI LV remodeling.

Galectin-3 in acute coronary syndrome

“…Up to 30% of patients leaving hospital after ACS event is re-admitted within the first 6-months [2]. In a large US registry consisting of 60.6500 patients with AMI, HF was identified in 20% of patients on admission, with a further 8.6% developing HF during hospitalization [3]. Therefore, identifying reliable biomarkers to improve risk stratification and enhancing patient outcome prediction remains a challenge.…”

Mineralocorticoid receptor antagonist pre-treatment and early post-treatment to minimize reperfusion injury after ST-elevation myocardial infarction: The MINIMIZE STEMI trial

“…The MINIMIZE-STEMI trial ( https://clinicaltrials.gov , NCT01882179 ) was a prospective, proof-of-concept, multi-center, double-blinded randomized placebo controlled clinical trial. 7 The study was conducted in accordance with the Declaration of Helsinki and was approved by the UK National Research Ethics Service. All patients provided written informed consent.…”

“…Therefore, the MINIMIZE STEMI trial 7 was designed to assess the benefit of mineralocorticoid receptor antagonist (MRA) therapy in STEMI patients without heart failure on reducing MI size and preventing adverse left ventricular (LV) remodeling. We hypothesized that early intravenous MRA therapy administered prior to restoration of flow in the infarct-related artery, followed by 3 months oral MRA therapy could reduce MI size and improve LV remodeling in STEMI patients.…”

Design of the Magnetic Resonance Imaging Evaluation of Mineralocorticoid Receptor Antagonism in Diabetic Atherosclerosis (MAGMA) Trial

“…Mineralocorticoid receptor (MR) activation plays an essential role in promoting inflammation, fibrosis, and target organ damage . The importance of antagonizing the MR is well recognized in patients with hypertension, heart failure, and heart failure post–myocardial infarction . Evidence from experimental animal models and humans suggests that MR activation promotes endothelial dysfunction, vascular oxidative stress, inflammation, proliferation, migration, vasoconstriction, vascular remodeling, fibrosis, and hypertrophy .…”

“…[1][2][3][4] The importance of antagonizing the MR is well recognized in patients with hypertension, heart failure, and heart failure post-myocardial infarction. [5][6][7][8][9] Evidence from experimental animal models and humans suggests that MR activation promotes endothelial dysfunction, vascular oxidative stress, inflammation, proliferation, migration, vasoconstriction, vascular remodeling, fibrosis, and hypertrophy. [10][11][12][13][14] Emerging data links MR activation with multiple components of the metabolic syndrome and T2DM (Figure 1).…”