PRECISE-AFMR I: Transcatheter Mitral Valve Edge-to-Edge Repair for Atrial Functional Mitral Regurgitation in Patients at High Surgical Risk

PRECISE-AFMR I is designed to address the limited randomized evidence for transcatheter edge-to-edge repair (TEER) in patients with atrial functional mitral regurgitation (AFMR). The study uses standardized phenotypic and imaging assessment to identify patients in whom AFMR is the predominant mechanism of mitral regurgitation and whose mitral valve anatomy is considered suitable for TEER.

Before randomization, each participant will provide written informed consent and undergo clinical, laboratory, and imaging assessments. Echocardiographic data will be submitted to an independent echocardiography core laboratory (ECL) for confirmation of the AFMR diagnosis, mitral regurgitation severity, left ventricular function, left atrial remodeling, and anatomical suitability for TEER. An eligibility committee will then review the clinical findings, surgical risk, prior treatment, and ECL assessment. Only participants confirmed as eligible by both the ECL and the eligibility committee will proceed to randomization.

Eligible participants will be randomly assigned in a 1:1 ratio to TEER plus optimized guideline-directed medical therapy (GDMT) or optimized GDMT alone. Randomization will be performed through a central randomization system or electronic data capture system using blocked randomization stratified by study center or center group. The allocation sequence will be generated and maintained independently, and treatment assignment will not be released until eligibility and baseline assessments have been completed.

Because TEER is an interventional procedure, participants and treating investigators will not be blinded to treatment assignment. To reduce potential assessment bias, key echocardiographic measurements will be centrally reviewed by the ECL, and major clinical and safety events will be adjudicated by an independent clinical events committee that is blinded to treatment assignment whenever feasible. Both groups will receive comparable follow-up intensity, event collection, heart failure management, atrial fibrillation management, anticoagulation or antiplatelet therapy when clinically indicated, and management of comorbid conditions.

Participants assigned to the TEER group will undergo the procedure in addition to continued optimized GDMT and standardized clinical care. TEER is intended to be performed as soon as clinically feasible after randomization, preferably within 14 days and, when medically delayed, within 30 days whenever possible. Participants assigned to the control group will not undergo planned TEER before completion of the 12-month primary evaluation period and will receive individualized optimization of GDMT and other indicated standard treatments.

All randomized participants will be followed for 12 months, with major assessments conducted at baseline, treatment or discharge, 30 days, 6 months, and 12 months. Rescue TEER or another necessary intervention may be considered for participants in the GDMT group who experience clinically significant deterioration despite optimized treatment. Such treatment will require reassessment by the heart team, confirmation that the anticipated benefit outweighs the risk, and renewed informed consent. Rescue treatment and crossover events will be fully documented, while the primary efficacy analysis will follow the intention-to-treat principle.

Study data will be collected using standardized case report forms or an electronic data capture system. The ECL will centrally review key imaging outcomes, the clinical events committee will adjudicate major clinical and safety events, and an independent data and safety monitoring board will periodically review participant safety and study conduct.

Inclusion criteria

• 1. Aged ≥18 years;

• Presence of symptoms of heart failure, with New York Heart Association (NYHA) functional class II, III, or ambulatory class IV;

• Confirmed by preliminary assessment of the study-site Heart Team and review by the Echocardiography Core Laboratory (ECL) to have at least moderate-to-severe atrial functional mitral regurgitation (AFMR), generally graded as 3+ or 4+;

• At least one hospitalization for heart failure within the 12 months prior to enrollment and/or a plasma B-type natriuretic peptide (BNP) level ≥300 pg/mL or N-terminal pro-B-type natriuretic peptide (NT-proBNP) level ≥1,500 pg/mL;

• As confirmed by a heart failure specialist at the study site, the subject has received maximally optimized guideline-directed medical therapy (GDMT) and other necessary standardized comprehensive treatment in accordance with current guidelines for at least 3 months. For subjects with concomitant atrial fibrillation, coronary artery disease, or other potentially correctable comorbidities, appropriate evaluation and guideline-recommended management must have been completed, or the subject must have been clearly determined to be unsuitable for further treatment;

• Determined by the multidisciplinary Heart Team, in accordance with the process described in Section 4.7, to be at high surgical risk, to have a contraindication to surgery, or to be unsuitable for surgery, or determined after comprehensive assessment that surgical treatment is not the optimal current strategy;

• During the screening period or within 90 days prior to randomization, mitral valve anatomy is assessed by echocardiography at the study site and confirmed by the ECL to be suitable for transcatheter edge-to-edge repair (TEER). Anatomical suitability must meet at least all of the following criteria:
• Mitral valve area >4.0 cm² and baseline mean transmitral pressure gradient <4 mmHg;

• Adequate mobility or sufficient graspable leaflet tissue in the target grasping area, with a mobile/graspable leaflet length ≥10 mm;

• Mitral annular anteroposterior diameter ≤40 mm;

• Left atrial volume index (LAVI) <85 mL/m²;

⑤ Leaflet-to-annulus index (LAI) >1.10;

• The transseptal puncture route and femoral venous access are considered suitable for TEER by the investigator or Heart Team;

• The subject or the subject's legally authorized representative voluntarily agrees to comply with the requirements of the study protocol, including the possibility of being randomized to the optimized GDMT group, and provides written informed consent.

Exclusion criteria

• 1. Presence of primary structural mitral valve disease that can independently account for the mitral regurgitation (MR), such as leaflet prolapse, flail leaflet, rheumatic valvular disease, leaflet perforation, or damage resulting from infective endocarditis;

• Functional mitral regurgitation other than atrial functional mitral regurgitation (AFMR), including ventricular functional mitral regurgitation caused by left ventricular dilatation, regional wall-motion abnormalities, ischemic cardiomyopathy, dilated cardiomyopathy, or other conditions involving the myocardium, including restrictive cardiomyopathy, hypertrophic cardiomyopathy, and infiltrative cardiomyopathy such as amyloidosis, hemochromatosis, or sarcoidosis;

• Presence of pericardial disease, such as constrictive pericarditis, that may be the predominant mechanism underlying heart failure or MR;

• Prior surgical mitral valve intervention or transcatheter mitral valve intervention;

• Concomitant moderate-to-severe or greater disease of another heart valve requiring surgical or transcatheter intervention;

• An acute cerebrovascular event within the previous 30 days;

• Cardiovascular or cerebrovascular surgery or interventional treatment within the previous 30 days, including coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), transcatheter aortic valve replacement (TAVR), or transcatheter carotid artery stenting;

• Severe symptomatic carotid artery stenosis, defined as >70% stenosis on ultrasonography;

• Hemodynamic instability requiring continuous intravenous drug infusion or mechanical circulatory support;

• Pulmonary artery systolic pressure (PASP) >70 mmHg as estimated by echocardiography, or pulmonary vascular resistance (PVR) >3 Wood units as measured by right heart catheterization;

• Symptoms, signs, or echocardiographic evidence of severe right ventricular dysfunction, such as tricuspid annular plane systolic excursion (TAPSE) <15 mm or peak systolic tissue Doppler velocity (S') <10 cm/s;

• Chronic renal insufficiency requiring long-term hemodialysis;

• Severe liver cirrhosis accompanied by esophageal varices;

• Prior heart transplantation;

• Severe chronic obstructive pulmonary disease (COPD) requiring continuous home oxygen therapy or long-term oral glucocorticoid therapy;

• Severe hematologic disease;

• A modified Rankin Scale score ≥4, indicating moderately severe or severe disability;

• Mitral valve anatomical features that, as assessed by echocardiography at the study site and confirmed by the Echocardiography Core Laboratory (ECL), may prevent safe implantation, appropriate positioning, stable leaflet grasping, or adequate reduction of MR with the transcatheter edge-to-edge repair (TEER) device. Such features include, but are not limited to, insufficient leaflet mobility or insufficient graspable leaflet tissue in the target grasping area, significant calcification in the grasping area, a prominent leaflet cleft, leaflet perforation, severe leaflet thickening, fibrosis, retraction, or severely restricted leaflet mobility, insufficient primary or secondary chordal support, or any other anatomical feature that, in the judgment of the ECL, may result in technical failure of TEER, significant residual MR, or an increased risk of clinically significant mitral stenosis after the procedure;

• An intracardiac mass, thrombus, or vegetation detected by echocardiography;

• A contraindication to, or a high risk associated with, transesophageal echocardiography;

• Inadequate echocardiographic image quality;

• Known allergy or contraindication to any medication or device material required for the TEER procedure;

• Pregnancy, breastfeeding, or intention to become pregnant within the following 12 months;

• Anticipated need for emergency surgery or elective cardiac surgery for any reason within the following 12 months;

• Life expectancy of <12 months due to a noncardiac condition;

• The subject is a member of a vulnerable population or has a condition that may impair their ability to provide written informed consent and/or comply with study procedures;

• Current participation in another interventional drug or device trial that may interfere with the assessment of the primary endpoint of this study;

• Any other condition that, in the judgment of the investigator, ECL, or EC, renders the subject unsuitable for participation in this study.