Safety and Efficacy of Transcatheter Edge-to-Edge Repair for Atrial Functional Mitral Regurgitation

Safety and Efficacy of Transcatheter Edge-to-Edge Repair for Atrial Functional Mitral Regurgitation - The STAR Trial

This study is a prospective, randomized, parallel-control, open-label, multicenter clinical trial. Eligible subjects will be randomized in a 1:1 ratio to the Device group (Interventional group) or to no Device group (Control Group). The objective is to identify the safety and effectiveness of the TEER for the treatment of moderate-to-severe (3+) or severe (4+) atrial functional mitral regurgitation (aFMR) in patients who are symptomatic despite maximally tolerated guideline directed medical therapy.

Atrial functional mitral regurgitation (AFMR) is a complex cardiovascular condition typified by mitral regurgitation (MR), primarily due to atrial fibrillation-induced or diastolic dysfunction-induced left atrial enlargement, with mitral annular dilation and functional alterations of the mitral valve, rather than intrinsic valvular defects, resulting in regurgitation1. The reported prevalence of AFMR varies across studies, attributable to discrepancies in definitions, diagnostic techniques, research designs, and the specific populations investigated2-8. In a cohort study of hospitalized patients undergoing atrial fibrillation ablation, the prevalence of moderate or severe AFMR was 7%1. Conversely, in a community-based screening cohort of patients with moderate or severe MR, AFMR accounted for 27% of cases, marginally lower than the proportions of ventricular functional mitral regurgitation (VFMR, 38%) and primary mitral regurgitation (PMR, 32%)9. It can be anticipated that with the acceleration of aging in the global population, the proportion of AFMR may witness a considerable expansion in the future.

Compared with PMR, patients with AFMR frequently present with greater symptoms, diminished exercise tolerance, and heightened risk for hospitalization due to heart failure and increased mortality9,10, underscoring AFMR as a challenging therapeutic scenario. The conventional management strategies for mitral regurgitation have proven less effective in cases of AFMR2,11,12, due to its unique pathophysiological mechanisms, highlighting the imperative for customized treatment modalities.

Optimized guideline-directed medical therapy (GDMT) has been the cornerstone of treatment for heart failure and associated valvular diseases, including AFMR13. GDMT for heart failure with reduced LVEF typically includes a combination of a beta-blockers, ACE inhibitor, angiotensin receptor blockers or ARNI, a mineralocorticoid receptor antagonist, an SGLT2 inhibitor, and diuretics, along with anticoagulation for atrial fibrillation and cardiac resynchronization therapy for specific patients. However, the effectiveness of GDMT in treating AFMR specifically in whom the LVEF is typically preserved (≥50%) is not well-established14, as most prior studies have focused on PMR or heart failure with reduced ejection fraction. From the pathophysiological perspective of AFMR, strategies that restore sinus rhythm from atrial fibrillation have the potential to improve the prognosis of AFMR. Atrial fibrillation cardioversion may reduce the severity of MR, restore atrial size, enhance cardiac diastolic function, and decrease the incidence of endpoint events15-19. Transcatheter edge-to-edge repair (TEER) has emerged as a promising intervention for MR, in all patients with ventricular FMR and in those with PMR who are at high or prohibitive surgical risk14,20-22. Recent studies have demonstrated the efficacy of TEER in reducing the severity of MR, improving symptoms, and enhancing quality of life in patients with secondary MR23-25. However, its role in AFMR, a subset of secondary MR, is less clear.

Given the distinct pathophysiology of AFMR and the lack of consensus on optimal management, there is a pressing need for clinical trials comparing the efficacy of TEER versus GDMT in this patient population. Such trials are crucial for informing clinical practice and guiding treatment decisions in AFMR. This clinical trial aims to compare the efficacy and safety of TEER and GDMT in the management of AFMR, filling a significant knowledge gap in current research and potentially influencing future guidelines and patient care strategies.

Inclusion Criteria:

1. Age 18 years or older

2. Echocardiographic core laboratory criteria (all must be present):

   1. Atrial FMR (FMR must be atrial in etiology without ventricular leaflet tethering)
   2. Severe MR (3+ or 4+) defined as either 1) an effective regurgitant orifice area (EROA) ≥0.3 cm² or pulmonary-venous systolic flow reversal (PSVFR), or 2) in the absence of PSVFR, EROA measures 0.20-0.29 cm² with one or more of the following: regurgitant volume ≥45 mL/beat, regurgitant fraction ≥40%, or vena contracta width ≥0.5 cm.
   3. LV ejection fraction ≥50% without more than mild regional wall motion abnormalities
   4. No or mild LV dilatation (LV end-diastolic volume index <79 mL/m2 [male] or <71 mL/m² [female])
   5. Left atrial dilation (left atrial volume index ≥34 mL/m²)
   6. Mitral annulus dilatation (AP diameter >35mm)

3. The mechanism of the atrial FMR is likely either atrial fibrillation (persistent/permanent or paroxysmal [documented]) and/or HFpEF. If HFpEF, one or both of the following must also be present:

   1. TTE criteria of diastolic dysfunction i. Average E/e' ≥15, or ii. Average E/e' 9-14 plus both of the following:

1. Septal e' <7 cm/s or lateral e' <10 cm/s 2. TR Vmax >2.8 m/s (or PASP >35 mmHg if TR jet is adequate) AND/OR b) Invasive hemodynamic evidence (measured prior to randomization) of elevated LV filling pressures (PCWP (or LVEDP) ≥15 mmHg at rest or ≥25 mmHg with exercise; Note: If PCWP is 12 to 15 mmHg, the patient may be given a 7-10 mL/kg (approximately 500 mL) rapid infusion (over 5-10 min) of normal saline; if PCWP rises to ≥18 mmHg, the subject may be randomized.

4. NT-proBNP ≥300 pg/mL (or BNP ≥100 pg/mL) if at the time of the test the patient is in sinus rhythm or NT-proBNP ≥600 pg/mL (or BNP ≥200 pg/mL) if the patient is in atrial fibrillation 5. Subject remains symptomatic (NYHA class II, III or ambulatory IV) despite maximally tolerated doses of societal indicated class I GDMT for ≥2 months

a) Diuretics as needed to treat pulmonary congestion and peripheral edema b) If atrial fibrillation: Rate control medication to ensure heart rate <110 bpm c) If HFpEF: i. SGLT2i for at least 2 months (required) ii. MRAs, e.g., spironolactone or finerenone) and angiotensin receptor-neprilysin inhibitors (ARNIs, e.g., sacubitril/valsartan) may be used at the discretion of each center (but should not be changed after randomization) 6. SBP <140 mmHg and HR <100 bpm (<110 bpm if in atrial fibrillation) 7. Atrial fibrillation ablation is determined by the local heart team. If ablation is deemed necessary, it will be performed prior to enrollment; if ablation is considered unsuitable, no ablation will be performed after enrollment.

8. Anatomy suitable for TEER 9. The subject or legal guardian voluntarily agrees to comply with all provisions of this clinical trial, including the possibility of being randomly assigned to the control group, as well as participating in all necessary postoperative follow-ups and provides written informed consent.

Exclusion Criteria:

1. Patient is clinically unstable or has been hospitalized within the prior 30 days.
2. Primary degenerative or organic mitral valve disease such as prolapse, Barlow's disease, rheumatic heart valve disease causing leaflet thickening, leaflet clefts or perforation, endocarditis, etc. Note: A small amount of mitral leaflet thickening or other abnormality may be present, but it cannot be the primary cause of MR.
3. Moderate or severe mitral annular calcification, or any degree of mitral annular calcification if it is the primary cause of the MR or would interfere with TEER.
4. Mitral valve area (MVA) <4.0 cm² or mean trans-mitral valve gradient >4 mmHg.
5. Intent to treat the patient with mitral valve surgery within the next 24 months if randomized to control
6. Known cardiomyopathy such as amyloid, sarcoid or hypertrophic obstructive cardiomyopathy, restrictive cardiomyopathy, or pericardial diseases such as constrictive pericarditis.
7. Previous mitral valve surgery or transcatheter mitral valve intervention.
8. Any severe valvular disease of the pulmonary valve or tricuspid valve, or moderate or severe disease of the aortic valve.
9. Moderate or severe right ventricular dysfunction, defined as TAPSE≤14mm or RVFAV≤30% on the baseline echo.
10. Severe pulmonary hypertension defined as RVSP≥70mmHg on the baseline echo.
11. AF ablation procedure within 2 months prior to enrollment.
12. Any implantation of an intracardiac pressure monitoring system, baroreceptor activation therapy, cardiac contractility modulation within 2 months prior to enrollment or planned any time after enrollment.
13. If taking a chronic oral anticoagulation: Inability to discontinue it for several days prior to the procedure
14. If not taking a chronic oral anticoagulation: Inability to tolerate aspirin or clopidogrel for 6 months
15. Untreated clinically significant coronary artery disease requiring revascularization
16. Coronary artery bypass grafting (CABG) within prior 30 days
17. Percutaneous coronary intervention (PCI) within prior 30 days
18. Acute cerebrovascular event within prior 30 days or any prior intracranial hemorrhage
19. Allergic to heparin or any study drug that cannot be pre-medicated
20. Any contraindication to transesophageal echocardiography
21. IVC filter in place
22. Any atrial septal pathology interfering with mitral TEER (e.g. atrial septal aneurysm, device in place across the atrial septum, etc.)
23. Any major surgery within prior 30 days or anticipated within 24 months
24. Non-cardiac disease with a life expectancy <24 months