Background

Transcatheter mitral valve replacement (TMVR) is a rapidly evolving therapy for the treatment of symptomatic mitral regurgitation (MR) and mitral stenosis (MS). A major potential benefit of TMVR is the complete elimination of MR as compared to transcatheter edge to edge repair (TEER). These benefits need to be evaluated against unique risks through randomized controlled trials (RCTs).

RCTs are the gold standard for evaluating the safety and effectiveness of novel therapies, help with the assessment of risks versus benefits, and have important influence on clinical guidelines. RCTs to evaluate first-in-class device therapies such as TMVR must consider the nature of mitral valve pathology and existing treatment options in order to identify appropriate control groups.

Mitral Valve Pathologies and Available Treatment Options

The mitral valve is a complex structure which consists of leaflets, an annulus, and a sub-valvular apparatus. Abnormalities of the valve result in either MR, MS, or both. These valve lesions often require treatment as they can cause symptoms and significantly impair cardiovascular function.  MR specifically can be classified in two forms: primary/degenerative MR (PMR) and secondary/functional MR (SMR). PMR is an abnormality of the mitral valve leaflets/apparatus itself while SMR is caused by underlying left ventricular (LV) dysfunction with leaflet tethering and/or annular dilatation.

For patients with symptomatic severe PMR, mitral valve surgery has a class 1 recommendation and TEER has a class 2a recommendation for those at high or prohibitive surgical risk. While GDMT remains the mainstay treatment of heart failure with reduced ejection fracture (HFrEF) and severe SMR, TEER now has a class 2a recommendation for the treatment of refractory patients based on the COAPT trial.¹ The COAPT trial studied a narrow group of SMR patients with specific anatomic and clinical criteria, and the positive results cannot be applied to other mitral valve populations and non-TEER transcatheter therapies. Mitral valve surgery for isolated SMR, in comparison, is only recommended as a class 2b indication.

MS occurs due to restricted leaflet motion either due to rheumatic disease or severe mitral annular calcification (MAC). Both these etiologies can also lead to MR. The preferred treatment option for patients with rheumatic MS remains percutaneous mitral balloon valvotomy (PMBV) with mitral valve surgery reserved for those who are not PMBV candidates or those requiring concomitant cardiac surgeries. MS and MR due to severe MAC is becoming increasingly prevalent in the elderly populations of developed countries. The prognosis of patients with severe MAC is poor without intervention² but they are also at high procedural risk of complications due to extensive calcification. There remains a significant unmet clinical need for the treatment of these patients.

Trial Considerations for TMVR Devices

The design of clinical trials for novel TMVR devices must consider the complexity of mitral valve pathologies and available treatment modalities. The inherent benefits of mitral valve replacement (and complete elimination of MR) must be weighed against its associated risks as compared to current available therapies (Table 1).

Table 1: Treatment Options for Patients with Severe MR and MS

Etiology of MR / MS	Available Treatment Options
Severe Primary MR (Carpentier IIA)	Surgical mitral valve repair if candidate for surgery (Class I Recommendation) TEER if high or prohibitive risk (Class IIa Recommendation
Severe Secondary MR (Carpentier IIIB)	Guideline Directed Medical Therapy (Class I Recommendation) TEER if subjects are symptomatic despite GDMT and meet commercial TEER indications (Class IIa). Surgical mitral valve replacement or repair may also be considered if patients are symptomatic despite GDMT (Class IIb).
Severe MR due to severe MAC (Carpentier IIIA)	Unmet clinical need. Patients may be managed with medical therapy, but the underlying cause of the disease cannot be altered with medical therapy. Surgical intervention may be considered by experienced centers after shared decision making with patient (no guideline recommendation).
Rheumatic severe MS	Percutaneous mitral valve balloon commissurotomy (PMBC) (Class I) Surgical mitral valve replacement or repair if patient is not suitable for PMBC (Class I)
Non-Rheumatic calcific severe MS due to severe MAC	Surgical valve intervention should only be considered only after extensive discussion of the high procedural risk and the individual patient's preference and values (Class IIb).

In patients with PMR, RCTs for transcatheter technologies must compare these devices against surgical mitral valve repair for surgical candidates and TEER for those with prohibitive surgical risk. In patients with SMR, RCTs may be considered against GDMT, TEER, or surgery depending on patient anatomy and surgical candidacy. For patients with an unmet clinical need such as severe MAC, single arm trials may be considered and gain increased validity when performed within the overall construct of an RCT.

Currently, TEER serves as an appropriate transcatheter control group for TMVR RCTs given that TEER is the only approved commercially available transcatheter treatment for both PMR and SMR. For patients who are not TEER candidates, RCTs against GDMT can be considered since it remains standard of care for SMR patients who make up a large majority of patients who qualify for TMVR. For patients who are surgical candidates, RCTs against surgery may also be considered, but such trials may be difficult to enroll as surgery is rarely performed for isolated SMR.

Considerations of Trial Design and Execution

The Mitral Valve Academic Research Consortium (MVARC) guidance documents outline appropriate endpoints that should be considered for RCTs.^3,4 The primary endpoint of TMVR trials should include endpoints related to the high morbidity/morality of untreated MR (i.e., heart failure hospitalizations and mortality). Quality of life indices may be considered as part of a composite primary endpoint but should not be considered in isolation. Trials with TEER as a control group can be designed to demonstrate either superiority or non-inferiority while trials against GDMT must be designed to demonstrate superiority. Secondary endpoints typically include those pertaining to device safety and effectiveness, measures of success, left ventricular dimensions, quality of life, and functional capacity.

Trial oversight for TMVR trials is critical at multiple junctures. An independent clinical events committee (CEC) and a data monitoring committee (DMC) should be utilized to adjudicate adverse events and to monitor the safety of participants. Imaging core laboratories are recommended for the review of echocardiography and computed tomography study data.

Perhaps the most critical component for the oversight of TMVR trials is the evaluation of surgical candidacy, GDMT, and TEER suitability. This oversight is performed by the subject eligibility committee (SEC) which consists of representatives from cardiac surgery, heart failure, and interventional cardiology. The role of an expert TEER operator (an interventional cardiologist) is becoming more important in contemporary trials randomizing against MitraClip™.

Current guidelines⁵ recommend anti-thrombotic therapy with a vitamin K antagonist (warfarin) for the first 3-6 months following surgical mitral valve replacement to minimize the risk of thromboembolic complications. The larger stent frames and additional prosthetic material of TMVR systems means anti-thrombotic therapy is required for at least 6 months with target INR 2.5–3.5. Patients who cannot tolerate anticoagulation have thus far been excluded from TMVR studies.

Final Considerations

TMVR represents a new class of devices for the treatment mitral valve disease. Although promising, the relative risk and benefits are incompletely understood due to limited clinical experience. Randomization of TMVR against existing best therapies for the treatment of mitral regurgitation is paramount to understanding its net clinical benefit. 

Table 2: Potential Risks/Benefits of TMVR (Transapical vs. Transfemoral) versus TEER

TMVR (Transapical)	TMVR (Transfemoral)	TEER
Benefits: Complete, predictable, and durable elimination of MR Strong early safety profile Agnostic to mitral regurgitation pathophysiology Early data that is beneficial for left ventricular remodeling Risks: Implanted via a left thoracotomy Large bore apical delivery system Requires anticoagulation for at least 6 months New operator and site requirements for performance and delivery Anatomic exclusions to therapy (i.e., LVOT obstruction)	Benefits: Transfemoral approach with expedited patient recovery Complete, predictable, and durable elimination of MR Strong early safety profile Agnostic to mitral regurgitation pathophysiology Risks: Unique complications related to large bore access and iatrogenic atrial septal defects Limited size matrix and limited ability to retrieve device after deployment Requires anticoagulation for at least 6 months New operator and site requirements for performance and delivery Anatomic exclusions to therapy (i.e., LVOT obstruction)	Benefits: Transfemoral approach with expedited patient recovery Excellent safety profile Established outcomes and operator familiarity with over 150,000 global implants No requirement for anticoagulation Supported by randomized clinical trial data Risks: Only applicable to anatomies conducive to edge-to-edge repair Results in smaller mitral valve area Risk for residual or recurrent MR Outcomes may vary with operator experience

References

1. Stone GW, Lindenfeld J, Abraham WT, et al. Transcatheter mitral-valve repair in patients with heart failure. N Engl J Med 2018;379:2307-18.
2. Pasca I, Dang P, Tyagi G, Pai RG. Survival in patients with degenerative mitral stenosis: results from a large retrospective cohort study. J Am Soc Echocardiogr 2016;29:461-69.
3. Stone GW, Adams DH, Abraham WT, et al. Clinical trial design principles and endpoint definitions for transcatheter mitral valve repair and replacement: part 2: endpoint definitions: a consensus document from the Mitral Valve Academic Research Consortium. J Am Coll Cardiol 2015;66:308-21.
4. Stone GW, Vahanian AS, Adams DH, et al. Clinical trial design principles and endpoint definitions for transcatheter mitral valve repair and replacement: part 1: clinical trial design principles: a consensus document from the Mitral Valve Academic Research Consortium. J Am Coll Cardiol 2015;66:278-307.
5. Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 2021;77:450-500.

Clinical Topics: Anticoagulation Management, Cardiac Surgery, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Valvular Heart Disease, Cardiac Surgery and Heart Failure, Cardiac Surgery and VHD, Acute Heart Failure, Interventions and Imaging, Interventions and Structural Heart Disease, Echocardiography/Ultrasound, Mitral Regurgitation

Keywords: Mitral Valve, Mitral Valve Insufficiency, Mitral Valve Stenosis, Heart Failure, Balloon Valvuloplasty, Dilatation, Stroke Volume, Rheumatic Diseases, Randomized Controlled Trials as Topic, Quality of Life, Warfarin, Clinical Trials Data Monitoring Committees, International Normalized Ratio, Laboratories, Risk, Standard of Care, Echocardiography, Hospitalization, Anticoagulants, Tomography, Morbidity, Vitamin K, Stents, Heart Valve Prosthesis Implantation

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