Percutaneous mitral repair as treatment in HFrEF (MitraClip/TEER) Future Therapies

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Nehal Eid, M.D.[2]

Future and Investigational Therapies

Emerging approaches to secondary mitral regurgitation in heart failure with reduced ejection fraction include next-generation transcatheter edge-to-edge repair (TEER), transcatheter mitral valve replacement (TMVR), transcatheter annuloplasty, chordal repair, and expansion of mitral intervention to incompletely studied heart-failure phenotypes. Most approaches lack randomized evidence for mortality or heart-failure hospitalization benefit and should not be considered equivalent to established, trial-supported TEER.

Next-generation TEER systems

Device Design and evidence Relevance to secondary MR in HFrEF
MitraClip G4 Independent leaflet grasping; NT, XT, NTW, and XTW sizes. The wider NTW and XTW clips provide approximately 50% more grasping area. Registry data reported residual MR ≤2+ in 97% at 1 year.[1] Established current-generation platform retained as the reference comparator for emerging TEER systems. Cross-generation comparisons with devices used in earlier trials are not randomized.
PASCAL and PASCAL Ace Broad paddles, a central compressible spacer, and independent leaflet capture. In CLASP, MR was ≤2+ in 97% and ≤1+ in 78% at 2 years.[2] A propensity-matched comparison found similar safety and technical success to MitraClip, with lower transmitral gradients; the nonrandomized design limits comparative inference.[3] In CLASP IID, a randomized trial of patients with degenerative MR at prohibitive surgical risk, PASCAL met the primary safety endpoint of 30-day composite major adverse events and the primary effectiveness endpoint of MR ≤2+ at 6 months, establishing noninferiority to MitraClip and supporting regulatory approval in primary MR.[4] CLASP IIF (NCT03706833) compares PASCAL with MitraClip in secondary MR; randomized comparative results have not been published.
DragonFly Adjustable arms and grippers with a compressible nitinol central filler. In the 120-patient DRAGONFLY-DMR study, 1-year clinical success was 87.5% and MR was ≤2+ in 92%.[5] Evidence is derived from degenerative MR rather than secondary MR in HFrEF; clinical-outcome benefit in the target population remains unestablished.

Transcatheter mitral valve replacement

TMVR may address anatomies unsuitable for TEER, including short or calcified leaflets, severe annular calcification, and selected failed prior mitral interventions. Evidence remains limited by stringent anatomic screening, predominantly nonrandomized comparisons, and short follow-up. Left-ventricular outflow tract obstruction is the principal anatomic cause of exclusion from current TMVR trials, and the post-implant LVOT gradient influences procedural mortality.[6]

SAPIEN M3

SAPIEN M3 is a fully percutaneous transseptal system comprising a nitinol dock encircling the mitral apparatus and a 29-mm balloon-expandable valve. ENCIRCLE enrolled patients with symptomatic moderate-to-severe or severe MR considered unsuitable for surgery or TEER. Reported outcomes included:

  • Thirty-day mortality of 0.7%, compared with a Society of Thoracic Surgeons-predicted mortality of 6.6%.
  • MR ≤1+ in at least 95% of treated patients at 30 days and 1 year.
  • Sustained improvement in symptoms and quality of life through 1 year.[7]

Key anatomic criteria included healthy leaflet tissue, a left-ventricular end-diastolic diameter of 35–70 mm with exclusion at ≥75 mm, and commissure-to-commissure distance below 45 mm. For LVEF below 40%, GDMT was independently confirmed by heart-failure cardiologists. ENCIRCLE is registered as NCT04153292 and remains ongoing.[7]

These findings are derived from a single-arm study and do not establish superiority or equivalence to TEER. The reported 72% screening-failure rate emphasizes the restrictive anatomy required for current TMVR systems.[7] The valve design may permit subsequent valve-in-valve treatment, but long-term structural durability and reintervention outcomes remain uncertain.

Tendyne

Tendyne is the only commercially approved TMVR system described in the current literature and uses a transapical approach with an apical tether. Its approved use is restricted in the European Union to patients without severe mitral annular calcification and with a life expectancy below 5 years, and in the United States to patients with severe mitral annular calcification.[7]

Transapical TMVR has reported 30-day all-cause mortality of approximately 6%–14%. In an open-label prospective series of the first 100 Tendyne recipients, MR reduction was durable and symptoms improved, but 2-year all-cause mortality was 39%; 87% of deaths were cardiovascular and 44% occurred within 3 months. In-hospital mortality was 5.5%, and major, life-threatening, or fatal bleeding occurred in approximately one-quarter of patients.[8][6]

SUMMIT includes a randomized comparison of Tendyne with MitraClip and separate nonrandomized cohorts for severe mitral annular calcification and anatomy unsuitable for repair.[9]

Other TMVR platforms

  • Intrepid is being evaluated in APOLLO, a nonrandomized premarket investigation enrolling patients with moderate-to-severe or severe MR and LVEF above 30%.[10]
  • EVOQUE, AltaValve, and HighLife remain at early feasibility or registry stages.[7]
  • In the propensity-matched CHOICE-MI analysis, TMVR—predominantly using transapical systems—was associated with fewer heart-failure hospitalizations than GDMT alone at 2 years (32.8% vs. 54.4%; hazard ratio 0.59), without a mortality difference. Residual confounding precludes causal inference.[11]

Transcatheter annuloplasty

Carillon Mitral Contour System

Carillon is an indirect annuloplasty system implanted through the coronary sinus. Two nitinol anchors connected by a shaping ribbon reduce the anteroposterior annular dimension. In REDUCE FMR, a blinded, sham-controlled randomized trial of 120 patients with NYHA class II–IV symptoms, LVEF below 50%, and functional MR grade ≥2+, median regurgitant volume decreased by 22.4% at 12 months, compared with a 1.5% increase in the sham group. Left-ventricular volumes and functional status also improved.[8][12] A pooled analysis reported favorable remodeling effects even with severe left-ventricular enlargement, but did not establish a mortality benefit.[13]

Carillon is CE-marked and has been included in European guidance for severe MR with a Class IIb recommendation. Anatomic unsuitability affects approximately 10%–20% of patients because of coronary-sinus morphology, vessel size, or potential coronary-artery compromise. Long-term durability of annular reduction remains unestablished. Because the device does not directly interact with the mitral leaflets, subsequent TEER, chordal repair, or TMVR remains technically possible.[14]

EMPOWER is a randomized, double-blind trial enrolling 300 patients with heart failure and mild-to-moderate functional MR. The sham-controlled CARILLON trial is enrolling 352 patients using criteria similar to REDUCE FMR.[8][6][12]

Cardioband

Cardioband is a transseptally delivered direct annuloplasty system anchored along the posterior mitral annulus and cinched under echocardiographic guidance. It is CE-marked, but has had limited adoption and lacks definitive randomized evidence for hard clinical outcomes in secondary MR.

Transcatheter chordal repair

Chordal-repair systems primarily target degenerative MR caused by posterior-leaflet prolapse and currently have little direct relevance to ventricular secondary MR in HFrEF.

  • NeoChord DS 1000 is a transapical, beating-heart system for artificial chordal implantation. Approximately 25% of patients had recurrence exceeding moderate MR at 3 years. A transseptal iteration, NeoChord NeXuS, has undergone first-in-human implantation.[6]
  • Harpoon is a transapical system that implants expanded polytetrafluoroethylene chords under transesophageal echocardiographic guidance; its reported application is limited to isolated posterior-leaflet prolapse.[15]
  • A systematic review of 17 studies involving 3,787 patients reported procedural success of 96.2% and MR ≤mild in 93.9% at discharge, but moderate MR recurred in 17.5% by 30 days and 4.5% required reintervention. These data concern degenerative MR and should not be extrapolated to HFrEF-related secondary MR.[16]

Expanding indications

Atrial secondary MR and HFpEF

Randomized TEER outcome evidence has predominantly involved ventricular secondary MR with reduced or mildly reduced ejection fraction. Atrial secondary MR results from left-atrial and annular remodeling, frequently in association with atrial fibrillation, preserved left-ventricular systolic function, and heart failure with preserved ejection fraction.

The REPAIR registry reported 94% technical success and favorable hemodynamic reduction across atrial and ventricular secondary-MR phenotypes.[17] However, no randomized trial has established that TEER improves clinical outcomes in atrial secondary MR or HFpEF. Exercise-hemodynamic observations suggest that MR in HFpEF may sometimes represent a marker of advanced disease rather than the principal causal driver.[18]

A 2025 European Journal of Heart Failure expert consensus statement addresses transcatheter treatment across secondary-MR phenotypes, but consensus guidance does not replace randomized outcome evidence.[19] TEER for atrial secondary MR or HFpEF should therefore remain limited to appropriately selected patients within trials, registries, or specialist multidisciplinary evaluation.

Combination with advanced heart-failure therapies

Prospective comparative evidence defining the optimal sequencing of TEER with durable mechanical circulatory support or cardiac transplantation is not available. European guidelines nonetheless position TEER or another transcatheter mitral intervention within heart-team decision-making for advanced heart-failure therapies, including in patients who do not fulfill COAPT criteria (Class IIb-C). American guidance bases its TEER recommendation on appropriate anatomy and COAPT-like clinical criteria.[20]

Ongoing and early-stage studies

Study or approach Investigational question Evidence status
CLASP IIF (NCT03706833) PASCAL versus MitraClip in secondary MR Comparative randomized results have not been published.[1]
EMPOWER and CARILLON Coronary-sinus annuloplasty for secondary MR in heart failure Randomized studies with double-blind or sham-controlled designs; definitive clinical-outcome results remain pending.[8][6][12]
ENCIRCLE continued-access and dedicated registries SAPIEN M3 in expanded anatomic populations, including mitral annular calcification and failed prior TEER Intended to extend single-arm pivotal evidence to additional anatomies.[7]
SUMMIT and APOLLO Tendyne versus MitraClip in a randomized SUMMIT arm, with separate mitral-annular-calcification and non-repairable cohorts; Intrepid TMVR in moderate-to-severe or severe MR with LVEF >30% Premarket randomized and nonrandomized investigations; outcome data are not yet definitive for secondary MR in HFrEF.[8][10][9]
Robotic-assisted TEER Robotic catheter control with echocardiographic guidance and no fluoroscopy Limited to a first-in-human report; clinical efficacy, reproducibility, comparative safety, and radiation-reduction benefits remain unestablished.[21]

Clinical interpretation and evidence gaps

  • MitraClip remains the reference TEER platform with randomized clinical-outcome evidence in secondary MR; other devices should not be assumed to have equivalent outcome efficacy.
  • PASCAL is noninferior to MitraClip in degenerative MR, but randomized comparative evidence in secondary MR remains pending.
  • SAPIEN M3 provides promising 1-year TMVR results in patients unsuitable for surgery or TEER, but single-arm evidence, high screening-failure rates, LVOT-obstruction risk, and limited durability data preclude routine substitution for established TEER.
  • Tendyne provides durable MR reduction but transapical access, early cardiovascular mortality, and major bleeding materially limit applicability.
  • Annuloplasty and chordal-repair devices lack definitive randomized evidence for mortality or heart-failure hospitalization benefit in HFrEF.
  • CE marking, feasibility-study success, or regulatory approval in another MR phenotype should not be interpreted as proof of clinical-outcome benefit in secondary MR or as evidence of availability in every jurisdiction.
  • TEER for atrial secondary MR or HFpEF remains evidence-limited because randomized clinical-benefit data are lacking.

References

  1. ↑ 1.0 1.1 Lander MM, Brener MI, Goel K; et al. (2023). "Mitral Interventions in Heart Failure". JACC: Heart Failure. 11 (8 Pt 2): 1055–1069. doi:10.1016/j.jchf.2023.07.016.
  2. ↑ Szerlip M, Spargias KS, Makkar R; et al. (2021). "2-Year Outcomes for Transcatheter Repair in Patients With Mitral Regurgitation From the CLASP Study". JACC: Cardiovascular Interventions. 14 (14): 1538–1548. doi:10.1016/j.jcin.2021.04.001.
  3. ↑ Mauri V, Sugiura A, Spieker M; et al. (2022). "Early Outcomes of 2 Mitral Valve Transcatheter Leaflet Approximation Devices: A Propensity Score-Matched Multicenter Comparison". JACC: Cardiovascular Interventions. 15 (24): 2541–2551. doi:10.1016/j.jcin.2022.10.008.
  4. ↑ Lim DS, Smith RL, Gillam LD; et al. (2022). "Randomized Comparison of Transcatheter Edge-to-Edge Repair for Degenerative Mitral Regurgitation in Prohibitive Surgical Risk Patients". JACC: Cardiovascular Interventions. 15 (24): 2523–2536. doi:10.1016/j.jcin.2022.09.005.
  5. ↑ Wang J, Liu X, Pu Z; et al. (2024). "Safety and Efficacy of the DragonFly System for Transcatheter Valve Repair of Degenerative Mitral Regurgitation: One-Year Results of the DRAGONFLY-DMR Trial". EuroIntervention. 20 (4): e239–e249. doi:10.4244/EIJ-D-23-00361.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 Hahn RT, Lindenfeld J, Lim SD, Mack MJ, Burkhoff D (2024). "Structural Cardiac Interventions in Patients With Heart Failure: JACC Scientific Statement". Journal of the American College of Cardiology. 84 (9): 832–847. doi:10.1016/j.jacc.2024.05.061.
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 Guerrero ME, Daniels DV, Makkar RR; et al. (2025). "Percutaneous Transcatheter Valve Replacement in Individuals With Mitral Regurgitation Unsuitable for Surgery or Transcatheter Edge-to-Edge Repair: A Prospective, Multicountry, Single-Arm Trial". The Lancet. 406 (10519): 2541–2550. doi:10.1016/S0140-6736(25)02073-2.
  8. ↑ 8.0 8.1 8.2 8.3 8.4 Fudim M, Abraham WT, von Bardeleben RS; et al. (2021). "Device Therapy in Chronic Heart Failure: JACC State-of-the-Art Review". Journal of the American College of Cardiology. 78 (9): 931–956. doi:10.1016/j.jacc.2021.06.040.
  9. ↑ 9.0 9.1 Alperi A, Granada JF, Bernier M, Dagenais F, Rodés-Cabau J (2021). "Current Status and Future Prospects of Transcatheter Mitral Valve Replacement: JACC State-of-the-Art Review". Journal of the American College of Cardiology. 77 (24): 3058–3078. doi:10.1016/j.jacc.2021.04.051.
  10. ↑ 10.0 10.1 Hensey M, Brown RA, Lal S; et al. (2021). "Transcatheter Mitral Valve Replacement: An Update on Current Techniques, Technologies, and Future Directions". JACC: Cardiovascular Interventions. 14 (5): 489–500. doi:10.1016/j.jcin.2020.12.038.
  11. ↑ Ludwig S, Conradi L, Cohen DJ; et al. (2023). "Transcatheter Mitral Valve Replacement Versus Medical Therapy for Secondary Mitral Regurgitation: A Propensity Score-Matched Comparison". Circulation: Cardiovascular Interventions. 16 (6): e013045. doi:10.1161/CIRCINTERVENTIONS.123.013045.
  12. ↑ 12.0 12.1 12.2 Salah HM, Fudim M, Burkhoff D (2023). "Device Interventions for Heart Failure". JACC: Heart Failure. 11 (8 Pt 2): 1039–1054. doi:10.1016/j.jchf.2023.07.002.
  13. ↑ Anker SD, Starling RC, Khan MS; et al. (2021). "Percutaneous Mitral Valve Annuloplasty in Patients With Secondary Mitral Regurgitation and Severe Left Ventricular Enlargement". JACC: Heart Failure. 9 (6): 453–462. doi:10.1016/j.jchf.2021.03.002.
  14. ↑ Alkhouli M, Lurz P, Rodés-Cabau J; et al. (2022). "Transcatheter Coronary Sinus Interventions". JACC: Cardiovascular Interventions. 15 (14): 1397–1412. doi:10.1016/j.jcin.2022.05.039.
  15. ↑ Bax JJ, Debonnaire P, Lancellotti P; et al. (2019). "Transcatheter Interventions for Mitral Regurgitation: Multimodality Imaging for Patient Selection and Procedural Guidance". JACC: Cardiovascular Imaging. 12 (10): 2029–2048. doi:10.1016/j.jcmg.2019.03.036.
  16. ↑ Adrejiya P, Mehta K, Patel D; et al. (2026). "Transcatheter Chordal Repair for Degenerative Mitral Regurgitation: Systematic Review and Meta-Analysis". The American Journal of Cardiology. 269: 50–57. doi:10.1016/j.amjcard.2026.03.032.
  17. ↑ von Stein P, Stolz L, Haurand JM; et al. (2025). "Transcatheter Edge-to-Edge Repair for Atrial and Ventricular Secondary Mitral Regurgitation: Insights From the REPAIR Study". JACC: Cardiovascular Interventions. 18 (16): 2020–2032. doi:10.1016/j.jcin.2025.05.031.
  18. ↑ Harada T, Naser JA, Tada A; et al. (2024). "Cardiac Function, Haemodynamics, and Valve Competence With Exercise in Patients With Heart Failure With Preserved Ejection Fraction and Mild to Moderate Secondary Mitral Regurgitation". European Journal of Heart Failure. 26 (7): 1616–1627. doi:10.1002/ejhf.3322.
  19. ↑ Iliadis C, Adamo M, Rudolph V; et al. (2025). "European Journal of Heart Failure Expert Consensus Statement on Transcatheter Treatment of Mitral Regurgitation in Heart Failure". European Journal of Heart Failure. doi:10.1002/ejhf.70043.
  20. ↑ Coisne A, Lancellotti P, Habib G; et al. (2023). "ACC/AHA and ESC/EACTS Guidelines for the Management of Valvular Heart Diseases: JACC Guideline Comparison". Journal of the American College of Cardiology. 82 (8): 721–734. doi:10.1016/j.jacc.2023.05.061.
  21. ↑ Zhu D, Wang S, Ouyang W, Pan X (2024). "First-in-Man Experience of Robotic-Assisted Transcatheter Edge-to-Edge Repair With Pure Echo Guidance". JACC: Cardiovascular Interventions. 17 (12): 1505–1506. doi:10.1016/j.jcin.2024.03.022.
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