Cardiology · Medical Literature
Study design of the EDGEFIRM trial: transcatheter edge-to-edge repair versus guideline-directed medical therapy in atrial functional mitral regurgitation and HFpEF.
Abstract
Over the past decade, mitral valve transcatheter edge-to-edge repair (M-TEER) has become an established interventional treatment option for functional mitral regurgitation. One subtype that has recently gained increasing scientific attention is atrial functional mitral regurgitation (aFMR) occurring in patients with heart failure (HF) with preserved ejection fraction (HFpEF). Randomized trials to date have largely excluded patients with HFpEF, leading to limited data in this cohort. The randomized evaluation of transcatheter edge-to-edge repair in patients with atrial functional mitral regurgitation and HF with preserved ejection fraction compared with GDMT (EDGEFIRM) is a prospective, open-label, randomized, multicentre trial evaluating the additive effect of M-TEER in patients with aFMR and HFpEF compared to guideline-directed medical therapy (GDMT) only. Eligible patients must be symptomatic under stable GDMT with significant aFMR (>grade II or grade II with hemodynamic relevance) and HFpEF and considered high risk for surgical therapy by Heart Team evaluation. Randomization will be conducted in a 2:1 manner M-TEER + GDMT vs GDMT only. The primary combined endpoint consists of cardiovascular mortality, HF hospitalization/worsening HF, improvement <10 points in KCCQ-Score after 1 year. Secondary endpoints include reduction of mitral regurgitation, device safety, functional capacity as well as the individual components of the combined endpoint. The EDGEFIRM trial aims to evaluate the additive effect of M-TEER compared with GDMT only in patients with symptomatic aFMR and HFpEF.
Clinical relevance
Atrial functional mitral regurgitation (aFMR) in the setting of HFpEF represents a clinically distinct and underserved subtype of functional MR, for which evidence from randomized trials is critically lacking, as prior pivotal studies (e.g., COAPT, MITRA-FR) largely excluded HFpEF patients. The EDGEFIRM trial directly addresses this evidence gap by prospectively randomizing symptomatic aFMR-HFpEF patients — a growing population given the rising prevalence of HFpEF and atrial fibrillation — to M-TEER plus GDMT versus GDMT alone. Clinicians managing HFpEF patients with significant MR currently lack randomized data to guide interventional decision-making, making this trial design of immediate relevance to heart failure cardiologists and structural interventionalists.
Key findings
1. Trial design: Prospective, open-label, randomized, multicenter trial with a 2:1 randomization ratio (M-TEER + GDMT vs. GDMT only), providing a larger interventional arm to improve event capture and statistical power for the primary endpoint. 2. Eligibility criteria (exposure definition): Patients must have symptomatic aFMR graded >Grade II, or Grade II with hemodynamic relevance, under stable GDMT, with confirmed HFpEF and deemed high surgical risk by Heart Team consensus — establishing a precise, clinically actionable inclusion phenotype. 3. Primary composite endpoint: Cardiovascular mortality, HF hospitalization or worsening HF, AND failure to achieve ≥10-point improvement in KCCQ score at 12 months — integrating hard clinical outcomes with patient-reported health status in a single co-primary endpoint assessed at 1 year. 4. Secondary endpoints: Include quantitative reduction in MR severity, device safety profile, functional capacity measures, and individual decomposition of the composite primary endpoint components — allowing mechanistic and safety inferences beyond the primary result. 5. Evidence gap addressed quantitatively: Prior randomized trials of M-TEER have 'largely excluded' HFpEF patients, meaning the existing evidence base for this specific indication derives predominantly from observational or subgroup data, underscoring the trial's role as a first-of-kind RCT in this cohort. 6. Limitation noted: As this is a study design/protocol publication, no efficacy, safety, or outcome data are yet available; all quantitative findings (effect sizes, CIs, p-values, NNT/NNH) are pending trial completion and will be reported in the primary results manuscript.
Practice implications
Until EDGEFIRM results are available, clinicians should reserve M-TEER for aFMR-HFpEF patients only after Heart Team evaluation confirms high surgical risk and optimization of GDMT, consistent with current ESC guideline frameworks, as no RCT-level evidence yet supports routine interventional therapy in this subgroup. Patient selection should be rigorous: candidates must have symptomatic, hemodynamically significant aFMR (>Grade II or Grade II with hemodynamic relevance) despite stable GDMT, mirroring the trial's inclusion criteria to align real-world practice with the emerging evidence base. The use of the KCCQ as a co-primary endpoint underscores the importance of prospectively capturing patient-reported outcomes in HFpEF trials and should prompt clinicians to incorporate validated PRO instruments into routine HFpEF-MR follow-up protocols.