Transcatheter Mitral Valve Replacement Therapies

Transcatheter mitral valve replacement (MVR) has recently emerged as an exciting new frontier in the field of cardiac structural interventions. Although transcatheter aortic valve replacement (TAVR) is a well-established treatment option for patients with symptomatic severe calcific aortic stenosis, the experience with transcatheter MVR remains at an early stage. There have been important challenges in the development of this technology, including the complexity of the mitral valve anatomy involving a saddle oval shape, the subvalvular apparatus, the interaction with the left ventricular outflow tract (LVOT) and the aortic valve, as well as the large size of transcatheter MVR devices and large catheters for implantation. At this stage of development, all of these limit the delivery approach to transapical in most cases. The wide variety of mitral pathology, from stenosis to multiple mechanisms of regurgitation, also adds to the difficulties of valve design. Furthermore, the patients being considered for transcatheter MVR are usually high risk with multiple comorbidities, including frailty, pulmonary hypertension, or severe left ventricular systolic dysfunction, each of which negatively impact the overall clinical outcome. Despite these technical, anatomic, and clinical limitations, there has been significant progress in the last couple of years.

Overview of Technology and Early Outcomes With Transcatheter MVR

The type of transcatheter heart valve that best suits a specific patient varies according to the underlying pathology to be treated.

Transcatheter MVR in Failed Surgical Bioprostheses or Rings

Patients with failed surgical mitral bioprostheses or rings have been treated with the off-label use of standard aortic transcatheter heart valve devices. The pre-existing circular frame provided by a surgical bioprosthesis and some surgical rings can be used as a landing zone and provide anchoring for a balloon expandable or newer aortic transcatheter heart valve devices. Therefore, aortic transcatheter heart valve technology has been used for this purpose prior to development of dedicated transcatheter heart valve devices specifically designed for the mitral position. Transcatheter mitral valve-in-valve and valve-in-ring have been successfully performed with aortic transcatheter heart valve in hundreds of patients worldwide. Most of the outcomes data reported come from case reports, case series, and the VIVID (Valve In Valve International Database) Registry.1-5 The most frequently used transcatheter heart valves have been the Edwards SAPIEN family of valves (Edwards Lifesciences; Irvine, CA) (Figure 1). The delivery approach in most patients has been transapical. Although the transseptal approach has been increasingly adopted, apical access was used in 80% of cases in the VIVID registry.5 The composite endpoint of 30-day survival free from moderate or severe mitral regurgitation (MR) or clinically evident LVOT obstruction was observed in 88.8% of 349 valve-in-valve and 71% of 88 valve-in-ring patients retrospectively evaluated in the VIVID registry. The MITRAL (Mitral Implantation of Transcatheter Valves) trial is a prospective Food and Drug Adminstration-approved, physician-sponsored multicenter trial evaluating the safety and feasibility of transcatheter MVR with the Edwards SAPIEN 3 valve in three patient populations: native valves with severe mitral annular calcification (MAC), failed surgical rings, and failed surgical bioprosthesis.6 The transvenous transseptal approach is the delivery method of choice in this trial and is being successfully utilized. Enrollment is underway, and it is expected that this trial will provide important information about the safety and outcomes of transseptal transcatheter MVR. Table 1 summarizes the transcatheter MVR clinical trials recruiting patients at the time of this review's publication. These trials are in feasibility stage at this time and are not randomized.

Table 1: Transcatheter MVR Clinical Trials

Trial Name

Device

Enrollment Criteria

Intended Enrollment

PRELUDE (Percutaneous Mitral Valve Replacement Evaluation Utilizing IDE Early Feasibility Study)

Caisson transcatheter MVR system (Caisson Interventional LLC; Maple Grove, MN)

  • 18 years and older
  • Severe MR
  • High risk for surgery

20

RELIEF (Reduction or Elimination of Mitral Regurgitation in Degenerative or Functional Mitral Regurgitation With the CardiaAQ-Edwards™ Transcatheter Mitral Valve)

CardiaAQ-Edwards™ Transcatheter Mitral Valve (Edwards Lifesciences; Irvine, CA)

  • 18 years and older
  • New York Heart Association (NYHA) ≥II
  • Moderate to severe/severe MR
  • Prohibitive risk for open-heart surgery

200

Early Feasibility Study of the CardiAQ™ Transcatheter Mitral Valve Implantation (TMVI) System (Transfemoral and Transapical Delivery Systems) For the Treatment of Moderate to Severe Mitral Regurgitation

CardiaAQ-Edwards™ Transcatheter Mitral Valve (Edwards Lifesciences; Irvine, CA)

  • 18 years and older
  • Clinically significant symptomatic MR
  • High risk for open-heart surgery

28

Early Feasibility Study of the Neovasc Tiara™ Mitral Transcatheter Heart Valve With the Tiara™ Transapical Delivery System

Tiara™ valve and transapical delivery system transcatheter MVR (Neovasc Inc; Richmond, B.C. Canada)

  • 18 years and older
  • NYHA ≥III
  • High risk for open mitral valve surgery

30

TIARA-II Tiara™ (Transcatheter Mitral Valve Replacement Study)

Tiara™ valve and transapical delivery system transcatheter MVR
(Neovasc Inc; Richmond, B.C. Canada)

  • 18 years and older
  • Severe MR
  • High risk for open mitral surgery

115

Evaluation of Safety and Performance of the Twelve Transcatheter Mitral Valve Replacement System in Patients With Severe, Symptomatic Mitral Regurgitation

Twelve transcatheter MVR (Twelve, Inc; Redwood City, CA)

  • 18 years and older
  • NYHA ≥II
  • Severe MR

10

Expanded Clinical Study of Tendyne Mitral Valve System

Tendyne™ Mitral Valve System (Tendyne Holdings, LLC, a subsidiary of Abbott Vascular, Roseville, MN)

  • 18 years and older
  • NYHA ≥II
  • Not suitable for traditional surgical treatment

110

MITRAL

Edwards SAPIEN XT and SAPIEN 3 transcatheter heart valve (Edwards Lifesciences; Irvine, CA)

  • 22 years and older
  • NYHA ≥II
  • Severe MAC
  • Severe mitral stenosis or severe MR with at least moderate mitral stenosis
  • Extremely high risk for standard mitral surgery

30

SITRAL (Surgical Implantation of Transcatheter Valve in Native Mitral Annular Calcification Study)

Edwards SAPIEN 3 transcatheter heart valve (Edwards Lifesciences; Irvine, CA)

  • 22 years and older
  • Severe MAC with mitral stenosis or MR
  • NYHA ≥II
  • High-risk or inoperable

30

NHLBI DIR LAMPOON Study (Intentional Laceration of the Anterior Mitral Leaflet to Prevent Left Ventricular Outflow Tract Obstruction During Transcatheter Mitral Valve Implantation)

Edwards SAPIEN 3 transcatheter heart valve (Edwards Lifesciences; Irvine, CA)

  • 21 years and older
  • Severe mitral valve failure after mitral annuloplasty repair or related to MAC
  • High or prohibitive risk for surgical MVR
  • High or prohibitive risk of LVOT obstruction or transcatheter heart valve dysfunction from long/anterior mitral valve leaflet

60

Transcatheter MVR in Native Mitral Valves

Implantation of a transcatheter heart valve in a native mitral valve is significantly more challenging than mitral valve-in-valve and valve-in-ring procedures where there is a scaffold the operator can use as a landing zone to anchor the new prosthesis. A major problem for transcatheter MVR in native mitral valves is LVOT obstruction from protrusion of the device into the LVOT and/or displacement of the anterior mitral leaflet. During surgical MVR, the anterior mitral valve leaftlet is often removed to mitigate LVOT obstruction. The type of transcatheter mitral valve design is pathology dependent. In patients with MR, novel self-expanding nitinol-framed valves with an anchoring system are being used and developed. In contrast, for severe calcific mitral stenosis, balloon expandable valves, primarily aortic transcatheter heart valve, are being used.

Mitral Regurgitation

Multiple transcatheter heart valve devices designed to treat MR are being developed. Most of them are in early phases of evaluation with mixed technical and clinical results. A few of them were acquired by larger companies and are already under evaluation in early feasibility clinical trials.

The CardiAQ-Edwards™ transcatheter mitral valve (Edwards Lifesciences; Irvine, CA), was the first transcatheter heart valve implanted percutaneously in a native mitral valve in humans.7 The first generation was made of porcine pericardium mounted on a self-expandable nitinol stent (Figure 1). The second generation of the CardiAQ can be delivered via transapical or transfemoral transseptal approach. Thirteen patients have been treated under compassionate use: one with the first generation and the remaining 12 with the second generation device. Technical success, defined as successful valve delivery, valve deployment, and delivery system retrieval was achieved in 92%. There were two procedure-related deaths: one due to interaction with preexisting mechanical aortic valve and one due to malpositioning secondary to sub-leaflet calcification.8 The RELIEF Study has been initiated (Table 1).

The Medtronic Intrepid™ transcatheter heart valve (Medtronic; Minneapolis, MN) has a self-expandable nitinol outer stent, which provides fixation and sealing, and a circular inner stent, which houses a 27 mm tri-leaflet bovine pericardium valve with an effective orifice area of 2.4 cm2 (Figure 1). The valve is implanted via transapical access; a transseptal delivery approach is being developed. Thirty-eight patients have been treated in a pilot study. The valve was successfully deployed in 35 patients, and there were 4 procedure-related deaths. MR severity was reduced to 1(+) in 3 and 0 in 32 patients, resulting in improvement of symptoms of 1 or more functional class in 21 of 25 patients with clinical follow-up data available.9 A clinical trial has been initiated (Table 1).

The Tendyne™ Mitral Valve System (Tendyne Holdings, LLC, a subsidiary of Abbott Vascular, Roseville, MN) has a self-expanding nitinol double-frame design. The inner stent frame is circular and supports a tri-leaflet porcine pericardial valve with an effective orifice area of 3.2 cm2. The outer stent frame has a D-shape to conform to the mitral valve annulus shape. The outer stent has a poly-terephthalate cuff for sealing in the annulus. Its anchoring mechanism is an apical tether (Figure 1). The valve is delivered via a transapical approach through a 34 Fr sheath. The outcomes of the first 30 patients treated in the global feasibility trial were recently published. The valve was successfully implanted in 28 patients (93.3%). Residual MR was grade 1 in 1 patient and 0 in the remaining 27 patients. Despite a high-risk patient population with a Society of Thoracic Surgeons mortality risk score of 7.3%, there were no cardiac deaths, strokes, or myocardial infarctions at 30 days. There was 1 non-cardiac death on post-operative day 13 due to hospital-acquired pneumonia.10 The Expanded Clinical Study of Tendyne Mitral Valve System is ongoing (Table 1).

Figure 1

Figure 1
SAPIEN 3™ valve (A). Reprinted with permission from Edwards Lifesciences (Irvine, CA). CardiAQ-Edwards™ Transcatheter Mitral Valve (B). Reprinted with permission from Edwards Lifesciences (Irvine, CA). Medtronic Intrepid™ transcatheter heart valve (C) Reprinted with permission from Medtronic (Minneapolis, MN). Tendyne™ Mitral Valve System (D) Reprinted with Permission from Tendyne Holdings, LLC, a subsidiary of Abbott Vascular (Roseville, MN).

Calcific Mitral Stenosis

Patients with severe calcific mitral stenosis who are not candidates for standard mitral valve surgery due to surgical risk have been treated successfully with transcatheter MVR with the compassionate use of aortic transcatheter heart valve devices. Most of these patients have been treated with balloon expandable valves. Lately, newer aortic transcatheter heart valve devices such as the LOTUS Edge valve (Boston Scientific; Marlborough, MA) and Direct Flow (Direct Flow Medical; Santa Rosa, CA) have been used successfully to treat patients with severe MAC. However, this experience is limited to few case reports at this time,11,12 and the Direct Flow valve is no longer available. The TMVR in MAC Global Registry was created to collect outcomes data of similar procedures performed worldwide to better understand its safety and efficacy in a larger patient population. The outcomes of the first 64 patients were recently published. Transapical approach was used in 45.3% of the patients, transseptal in 40.6%, and transatrial in 14.1%. Technical success according to the Mitral Valve Academic Research Consortium criteria was achieved in 46 of the 64 patients (72%), primarily limited by the need for a second transcatheter heart valve in 11 (17.2%). At the end of the procedure, the mean MV gradient was 4 ± 2.2 mmHg, the MV orifice area was 2.2 ± 0.95 cm2, and paravalvular regurgitation was mild or absent in all patients. Six patients (9.3%) had severe LVOT obstruction with hemodynamic compromise after valve deployment. The 30-day mortality was 29.7% (cardiovascular in 12.5% and non-cardiac in 17.2%).13 The outcomes improved as the experience increased with more patients treated. A subsequent analysis of 104 patients evaluated outcomes relative to experience, dividing patients in tertiles in chronological order according to date of procedure. Most of the complications occurred in the first third of the patients. Technical success in the first tertile was 62.5%, improved to 84.4% in the second third, and was 80% in the third tertile. Thirty-day mortality was 37.5% in the first tertile and decreased to 21.9% in the second tertile and to 15% in the last tertile. At 30 days, 29 of the 37 patients (78%) with 30-day clinical follow-up data were in NYHA class I or II.14 The MITRAL trial is prospectively evaluating the safety and feasibility of the Edwards SAPIEN XT and SAPIEN 3 in patients with severe native mitral disease with severe MAC who are not candidates for standard surgical MVR. Enrollment started in February of 2015 and is currently ongoing at 10 participating sites.6

How Are Patients Evaluated for Transcatheter Mitral Valve Repair or Replacement?

Patients with symptomatic severe mitral valve disease who are not candidates for standard open mitral valve surgery may be candidates for transcatheter mitral valve repair or transcatheter MVR under a clinical trial. At this early stage of transcatheter MVR development, the safety and efficacy of transcatheter MVR remains uncertain. In contrast, transcatheter mitral valve repair with MitraClip (Abbott; Abbott Park, IL) has proven to provide similar improvement of symptoms and survival compared with surgery despite higher rates of residual MR.15 Therefore, with limited transcatheter MVR data at the time of this review's publication, transcatheter mitral valve repair with MitraClip should be the first choice for patients who have favorable anatomy and meet clinical indication per guidelines. The underlying pathology plays a role when deciding on transcatheter repair versus replacement because repair with MitraClip is approved only for primary MR in the United States. The role of transcatheter mitral valve repair in patients with secondary MR is being evaluated in the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial. Therefore, patients with secondary MR who have favorable anatomy for MitraClip should be considered for participation in the COAPT trial. Patients with secondary MR who have unfavorable anatomy for mitral valve repair with MitraClip could be considered for participation in a transcatheter MVR clinical trial.

Once patients have been evaluated by a structural heart team and have been considered poor surgical candidates and poor candidates for transcatheter mitral valve repair, a cardiac computed tomography scan is obtained for careful evaluation of mitral valve annulus size, presence of MAC, modeling of the valve implant, and estimation of the risk of transcatheter MVR-induced LVOT obstruction. Patients with severe calcific mitral stenosis or regurgitation with severe MAC should be considered for inclusion in the MITRAL trial or other trial when available. Patients with MR without MAC can be considered for participation in any of the clinical trials evaluating transcatheter heart valve devices designed for the mitral position.

Next Steps

An important next step for clinicians is to consider referring patients to transcatheter MVR clinical trials. There are no dedicated mitral devices yet well-developed enough or approved for use in practice anywhere in the world. The development of transcatheter MVR will be more difficult than TAVR and will succeed only if we support clinical trials.

Conclusions

Transcatheter MVR is evolving into an alternative for patients with severe mitral valve disease who are poor candidates or have increased risk for conventional mitral valve surgery. This field is at an early stage, and progress will be significantly slower than the development of TAVR due to the complexity of the mitral valve anatomy and pathology. We have learned important lessons during this early experience. Important challenges exist with the currently available technology. Improved and less bulky valve designs and delivery methods may improve technical success. A better understanding of the kind of anticoagulation needed for transcatheter MVR is just beginning to develop. Optimizing the patient-selection process by using multimodality imaging tools to accurately measure the annulus size and evaluate the risk of LVOT obstruction is essential to minimize complications.

References

  1. Cheung A, Webb JG, Barbanti M, et al. 5-year experience with transcatheter transapical mitral valve-in-valve implantation for bioprosthetic valve dysfunction. J Am Coll Cardiol 2013;61:1759-66.
  2. Bouleti C, Fassa AA, Himbert D, et al. Transfemoral implantation of transcatheter heart valves after deterioration of mitral bioprosthesis or previous ring annuloplasty. JACC Cardiovasc Interv 2015;8:83-91.
  3. Eleid MF, Cabalka AK, Williams MR, et al. Percutaneous Transvenous Transseptal Transcatheter Valve Implantation in Failed Bioprosthetic Mitral Valves, Ring Annuloplasty, and Severe Mitral Annular Calcification. JACC Cardiovasc Interv 2016;9:1161-74.
  4. Dvir D, Webb J, Schäfer U, et al. TCT-797 Transcatheter Mitral Valve-in-Valve / Valve-in-Ring Implantations For Degenerative Post Surgical Valves: Results From The Global Valve-in-Valve Registry. J Am Coll Cardiol 2012;60(Suppl B):B232.
  5. Dvir D. Transcatheter Mitral Valve-in-Valve and Valve-in-Ring Implantations. Data presented at Transcatheter Cardiovascular Therapeutics 2016 2016.
  6. Guerrero M. Mitral Implantation of TRAnscatheter vaLves (MITRAL) (ClinicalTrials website). 2016. Available at: https://clinicaltrials.gov/ct2/show/NCT02370511. Accessed March 29, 2017.
  7. Søndergaard L, De Backer O, Franzen OW, et al. First-in-Human Case of Transfemoral CardiAQ Mitral Valve Implantation. Circ Cardiovasc Interv 2015;8:e002135.
  8. Ussia G. CardiAQ-Edwards: Design and Clinical Trial Updates. Data presented at Transcatheter Cardiovascular Therapeutics 2016.
  9. Reardon M. Transcatheter Mitral Valve Replacement with the Medtronic Intrepid System. Data presented at the STS/AATS Tech-Con Meeting 2017.
  10. Muller DW, Farivar RS, Jansz P, et al. Transcatheter Mitral Valve Replacement for Patients With Symptomatic Mitral Regurgitation: A Global Feasibility Trial. J Am Coll Cardiol 2017;69:381-91.
  11. Mellert F, Sinning JM, Werner N, et al. First-in-man transapical mitral valve replacement using the Direct Flow Medical® aortic valve prosthesis. Eur Heart J 2015;36:2119.
  12. Lim ZY, Boix R, Prendergast B, et al. First reported case of transcatheter mitral valve implantation in mitral annular calcification with a fully repositionable and self-expanding valve. Circ Cardiovasc Interv 2015;8: e003031.
  13. Guerrero M, Dvir D, Himbert D, et al. Transcatheter Mitral Valve Replacement in Native Mitral Valve Disease With Severe Mitral Annular Calcification: Results From the First Multicenter Global Registry. JACC Cardiovasc Interv 2016;9:1361-71.
  14. Guerrero M. Transcatheter Mitral Valve Replacement in Native Mitral Valve Disease with Severe Mitral Annular Cacification. Data presented at EuroPCR 2016.
  15. Feldman T, Kar S, Elmariah S, et al. Randomized Comparison of Percutaneous Repair and Surgery for Mitral Regurgitation: 5-Year Results of EVEREST II. J Am Coll Cardiol 2015;66:2844-54.

Clinical Topics: Cardiac Surgery, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Pulmonary Hypertension and Venous Thromboembolism, Valvular Heart Disease, Aortic Surgery, Cardiac Surgery and Heart Failure, Cardiac Surgery and VHD, Acute Heart Failure, Pulmonary Hypertension, Interventions and Imaging, Interventions and Structural Heart Disease, Mitral Regurgitation

Keywords: Aortic Valve, Aortic Valve Stenosis, Bioprosthesis, Comorbidity, Constriction, Pathologic, Heart Failure, Hemodynamics, Hypertension, Pulmonary, Mitral Valve, Mitral Valve Annuloplasty, Mitral Valve Stenosis, Mitral Valve Insufficiency, Myocardial Infarction, Pericardium, Stents, Stroke, Surgeons, Tomography, Transcatheter Aortic Valve Replacement


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