Translational Pathway for Transcatheter Mitral and Tricuspid Valve Development
Future of Mitral and Tricuspid Devices
Paul Grayburn, MD
John Laschinger, MD
The development of percutaneous transcatheter aortic valve replacement (TAVR) has set both a precedent and a high standard for the development of similar devices to treat mitral and tricuspid regurgitation. The patient populations for TAVR progressively evolved from inoperable to high surgical risk to intermediate surgical risk, with results in low surgical risk presented in March 2019. Additionally, improvement in device delivery systems and devices themselves has improved procedural time and procedural safety as well as expanded the patient population that can be treated. TAVR devices are currently approved for aortic stenosis in tricuspid valves, but observational data have also shown good results in bicuspid valves and in pure aortic regurgitation. Importantly, the aortic valve is a simpler structure anatomically than the mitral and tricuspid valves.
Moreover, mitral regurgitation (MR) and tricuspid regurgitation (TR) can occur due to primary abnormalities of the leaflets and their chordal attachments (primary MR or TR) or due to tethering of normal leaflets by underlying ventricular dysfunction (secondary MR and TR). Annular dilation may occur with both primary and secondary lesions. The complexity of the valvular anatomy and interaction with underlying ventricular dysfunction makes patient selection critical for any given device. Current devices can be broadly categorized as intended for leaflet approximation, annular reduction, chordal replacement, or valve replacement. Few data exist regarding which patients respond best to which devices. Failure to appropriately match patient anatomy to the device could lead to device and/or clinical trial failure.
The MitraClip™ was approved by the U.S. Food and Drug Administration for use in patients with primary degenerative MR at prohibitive risk for surgical valve repair (1). This represents a group with an unmet clinical need because surgical repair is the gold standard for primary degenerative MR and there is no effective medical therapy for such (2,3). Data from the TVT/STS Registry confirm the high-risk profile of patients currently treated with MitraClip (4). More recently, two randomized trials have been reported in secondary MR. Mitra-FR showed no benefit in a combined endpoint of death or heart failure hospitalization in 307 patients, most of whom had moderate MR (5), while COAPT showed a striking benefit in 614 patients with a number needed to treat of three to prevent a heart failure hospitalization at 2 years and six to prevent a death at 2 years (6). Although on the surface, these trials appear to conflict, a thoughtful analysis suggests that these were very different patient populations, and those in whom MR is severe and left ventricular (LV) volume is not excessively increased, will benefit from MR reduction (7). Further analysis is underway to define which patients with secondary MR do not derive benefit from MR reduction. Understanding this will be critical to device development and patient selection.
Two other important aspects of MitraClip are important. First, MitraClip is delivered via venous transfemoral-transseptal approach with an excellent safety profile. In COAPT, freedom from device-related complications was 96.6%, which sets a very high bar for subsequent devices. Transapical delivery of TAVR devices, once common in patients with poor transfemoral arterial access, has been virtually abandoned in favor of other alternative access approaches, including direct aortic, subclavian, axillary, carotid, or transcaval. Thus, any mitral or tricuspid device will need to offer a safety profile similar to that of MitraClip. Second, there is a consistent finding across registries and clinical trials that about 5% of patients treated with MitraClip have residual 3+/4+ MR, and 1-year mortality in those patients approaches 50% (1,4,6,8). Thus, any device that has a higher percentage of residual or recurrent 3+/4+ MR is not likely to be accepted clinically.
Repair Versus Replacement
The fact that residual MR is present after MitraClip (and other mitral devices that attempt repair) suggests the hypothesis that complete elimination of MR by transcatheter valve replacement is superior to reduction of MR by transcatheter repair. To conduct a clinical trial of that hypothesis is important but requires venous transfemoral/transseptal delivery of a valve replacement with a safety profile similar to MitraClip. It will be important to test primary and secondary MR separately because they are too different diseases and elimination of secondary MR could theoretically worsen LV function.
Replacement devices will need to also have a very low risk of paravalvular leak in the mitral position because of the high risk of hemolysis. Finally, surgically implanted mitral valve bioprostheses are less durable than aortic bioprostheses. Trials comparing transcatheter to surgical mitral valve replacement are underway and durability will be an important secondary endpoint.
Other Devices for MR
Annuloplasty devices have been under development for some time. There is a subset of MR patients for whom the primary mechanism is pure annular dilation (e.g., atrial functional MR). Many of those patients are not at high risk for surgery and can be treated with minimally invasive annuloplasty rings. A randomized trial of minimally invasive mitral annuloplasty compared to transcatheter annuloplasty is needed, but patient selection is critical, as the Cardiothoracic Surgery Network Trials showed a high rate of recurrence of significant MR (58.8%) 2 years after complete ring annuloplasty for secondary MR (9). Because secondary MR is usually caused by tethering of the mitral leaflets by LV dysfunction, annuloplasty alone may not be the ideal approach. Again, patient selection is critical.
It is now accepted that severe TR is associated with high mortality. However, it is not clear that correction of TR reverses mortality. The majority of TR is secondary to pulmonary hypertension and/or right ventricular (RV) or right atrial dilation. Current guidelines recommend that surgical mitral valve replacement not be performed if LV ejection fraction is less than 30% due to the risk of unmasking irreversible LV dysfunction. It is also widely appreciated that a severely dilated, severely hypokinetic right ventricle is associated with very high risk for mitral or tricuspid valve surgery.
Thus, patients with severe TR and severe RV dysfunction may not benefit from correction of the TR, which could actually worsen RV function. Unfortunately, robust and reproducible measurements of RV volumes and function are needed. Measurements of right ventricular “viability” could be helpful in this regard but are lacking. Sizing of tricuspid annuloplasty devices will require further investigation because of the dynamic nature of the tricuspid annulus and TR. It might be reasonable to diurese the patient and possibly to use intravenous inotropes to optimize TR severity and RV size and function prior to sizing. If one sizes the annulus when the patient is in overt right heart failure, the device may be too large to fully reduce the annulus and suboptimal results may be obtained.
Although several tricuspid devices are currently in early feasibility studies, it is too early to know if sufficient and durable reduction of TR can be achieved, and if they will produce clinical improvement and reduction in mortality. Appropriate selection of patients, especially with regard to RV size and function, will be critical. Finally, devices will need to be implanted safely and within a reasonable procedure time without causing damage to important structures adjacent to the tricuspid annulus, such as the atrioventricular node, right coronary artery, membranous ventricular septum or aorta.
Numerous devices are under development and investigation for MR and TR. Careful differentiation of primary versus secondary lesions will be critical, as will attention to selecting appropriate devices for the specific anatomical defect. Consideration of left or right ventricular dilation and dysfunction, in secondary MR or TR, will be an important predictor of success, as we have already learned from the differences between the COAPT and Mitra-FR trials. This requires a heart team that includes surgical expertise in mitral and tricuspid valve surgery, advanced imaging specialists, heart failure specialists, and structural heart interventionalists.
- Lim DS, Reynolds MR, Feldman T, et al. Improved functional status and quality of life in prohibitive surgical risk patients with degenerative mitral regurgitation after transcatheter mitral valve repair. J Am Coll Cardiol. 2014;64:182-92.
- Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/ACC focused update of the 2014 AHA/ACC Guideline for the Management of Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2017;70:252-89.
- O’Gara PT, Grayburn PA, Badhwar V, et al. 2017 ACC Expert Consensus Decision Pathway on the Management of Mitral Regurgitation. J Am Coll Cardiol. 2017;70:2421-49.
- Sorajja P, Vemulapalli S, Feldman T, et al. Outcomes with transcatheter mitral valve repair in the United States: An STS/ACC TCT Registry report. J Am Coll Cardiol. 2017;70:2315-70.
- Obadia JF, Messika-Zeitoun D, Leurent G, et al. Percutaneous repair or medical treatment for secondary mitral regurgitation. N Engl J Med. 2018; 379:2297-2306.
- Stone GW, Lindenfeld J, Abraham WT, et al. Transcatheter mitral valve repair for heart failure. N Engl J Med. 2018;379:2307-18.
- Grayburn PA, Sannino A, Packer M. Proportionate and disproportionate functional mitral regurgitation: A new conceptual framework that reconciles the results of the MITRA-FR and COAPT trials. JACC Cardiovasc Imaging. 2019;12:353-62.
- Ailawadi G, Lim DS, Mack MJ, et al. One year outcomes following MitraClip for functional mitral regurgitation. 2019;139:37-47.
- Goldstein D, Moskowitz AJ, Gelijns AC, et al. Two year outcomes of surgical treatment of severe ischemic mitral regurgitation. N Engl J Med. 2016; 374:344-53.