Overview
No previous study has evaluated the effectiveness of transcatheter edge-to-edge mitral valve repair (TEER) in patients with ATTR-associated cardiomyopathy (ATTR-CM) and significant mitral regurgitation, as this specific patient population was specifically excluded from previous large TEER trials. From a pathophysiological perspective, effective treatment of significant regurgitant volume and consecutive improvement of forward volume appears highly desirable in a condition with intrinsically low output. However, whether this translates into improved functional capacity, better quality of life, and better clinical outcomes compared to conservative heart failure management alone remains to be investigated.
Description
MILLENNIAL is an investigator-initiated, multicentre, prospective, parallel-group, open-label, randomized controlled trial. Patients with proven ATTR-CM and concomitant significant (moderate-to-severe or severe) symptomatic mitral regurgitation, in whom the local heart team has ruled out mitral valve surgery and who are anatomically suitable for TEER, are randomized 1:1 to TEER plus optimal medical therapy (OMT) or OMT alone. Randomization is performed centrally with permuted blocks of variable size (4-8), stratified by the presence of significant tricuspid regurgitation and NYHA class ≥III. ATTR-specific therapy is allowed in both arms at the discretion of the treating physician. Cross-over is not permitted within the first year.
The primary endpoint is a hierarchical composite assessed at 12 months, analysed with the Finkelstein-Schoenfeld method (win ratio as effect measure, stratified by National Amyloidosis Centre stage): (1) all-cause mortality, (2) cumulative frequency of unplanned cardiovascular hospitalizations, (3) change from baseline in 6-minute walk distance (win threshold ≥30 m), (4) change from baseline in KCCQ Overall Summary score (win threshold ≥5 points). Heart transplantation, combined heart-liver transplantation and durable mechanical circulatory support are counted as death. Change in NT-proBNP is the key secondary endpoint; technical, device and procedural success (MVARC) are safety endpoints. Exploratory endpoints include intraprocedural invasive haemodynamics before and after device deployment and advanced echocardiographic indices of myocardial performance.
A sample size of 106 patients (53 per arm) provides 80% power at a two-sided alpha of 0.05 for an assumed win ratio of 2.1, including 10% cross-over and 5% drop-out. Study visits take place at baseline, 6 months (±7 days) and 12 months (±14 days). Interim analyses are performed after every 25 patients and reviewed by an independent data monitoring committee; a pre-specified futility analysis is performed once 50 patients have completed 12-month follow-up (stop if conditional power \<10%).
Eligibility
Inclusion criteria (all must be present)
- Proven ATTR-CM
- Significant symptomatic MR (3+ or 4+ by independent echocardiographic core laboratory assessment)
- Subject has been adequately treated per applicable standards, including for coronary artery disease and heart failure (e.g., diuretics)
- New York Heart Association (NYHA) functional class II, III, or ambulatory IV
- Local heart team has determined that mitral valve surgery will not be offered as a treatment option, even if the subject is randomized to the control group
- Left ventricular ejection fraction ≥20%
- Anatomical feasibility for TEER as per discretion of the implanting investigator
- Age 18 years or older
- Subject or guardian agrees to all provisions of the protocol, including the possibility of randomization to the Control group and returning for all required post-procedure follow-up visits, and has provided written informed consent
Exclusion criteria (all must be absent)
- AL-associated cardiomyopathy
- Aortic valve disease requiring surgery or transcatheter intervention
- Severe right ventricular dysfunction
- Hemodynamic instability requiring inotropic support or mechanical heart assistance
- Leaflet anatomy which may preclude TEER, proper device positioning on the leaflets or sufficient reduction in mitral regurgitation by TEER
- Life expectancy \<12 months due to non-cardiac conditions
- Prior mitral valve leaflet surgery or any currently implanted prosthetic mitral valve, or any prior transcatheter mitral valve procedure
- Echocardiographic evidence of intracardiac mass, thrombus or vegetation
- Active endocarditis or active rheumatic heart disease or leaflets degenerated from rheumatic disease (i.e., noncompliant, perforated)
- Active infections requiring current antibiotic therapy
- Transesophageal echocardiography (TEE) is contraindicated or high risk
- Pregnant or planning pregnancy within next 12 months
- Currently participating in another investigational device study that has not reached its primary endpoint
