Introduction
Mitral valve disease is the most common valvular heart disorder, with more than double the prevalence of aortic valve disease (Nkomo et al. 2006). The rate of moderate to severe mitral valvular disease is ‘over 10% in people over 75 years of age’ (Nkomo et al. 2006, p. 1005), Just over 4% of patients in the same age group have isolated mitral regurgitation (MR) (Dziadzko et al. 2018). Distribution of primary or secondary mitral regurgitation differs in selected studies, but a recent analysis of a prospective echocardiographic registry demonstrated that ‘55% of patients suffered from primary MR, 30% secondary MR, and 14% were found to have mixed aetiology’ (Monteagudo Ruiz et al. 2018, p. 503).
The role of mitral valve surgery and assessment of mitral regurgitation was described in detail in Chapter 8. This chapter aims to describe the clinical challenges in patient selection for mitral valve surgery and the emerging role of transcatheter mitral valve therapies. The chapter also details current transcatheter mitral valve technologies, review assessment and patient selection for transcatheter mitral valve therapies, and, finally, provides insights into likely future developments in the transcatheter mitral valve field.
Mitral regurgitation
Mitral regurgitation is divided into primary mitral regurgitation (a structural or degenerative abnormality of the mitral valve apparatus) and secondary mitral regurgitation (a disease of the left ventricle, which interferes with the function and integrity of the mitral valve apparatus) (Nishimura et al. 2017; Vahanian et al. 2012). Mitral stenosis is usually due to rheumatic disease, but heavy calcification of the mitral annulus is an increasing problem in elderly people, causing both stenosis and regurgitation (Abramowitz et al. 2015; Vahanian et al. 2012).
Open heart surgery for the treatment of severe MR has achieved excellent outcomes in a well-selected population. However, the increased risks linked to advanced age and comorbidities mean that up to 50% of patients with severe MR do not undergo surgical treatment, including minimally invasive approaches (Vahanian et al. 2012). The increase in the numbers of elderly people with complex mitral valve disease has fuelled intense innovation in transcatheter heart valve therapies. These developments are part of wider advances in the valvular heart disease field, providing improved understanding of disease pathology, and enhanced diagnostic and risk stratification capabilities.
A key principle in treating mitral valve disease is the timing of intervention in relation to the magnitude of symptoms. Furthermore, patient selection, prognostic impact and timing of intervention all differ widely according to the different aetiologies of mitral regurgitation.
Degenerative/Primary MR
Surgical experience has demonstrated that early intervention in degenerative MR results in improved survival, with decreased rates of heart failure and atrial fibrillation (Suri, Schaff & Enriquez-Sarano 2014; Ling et al. 1997). Development of New York Heart Association (NYHA) III/IV symptoms resulted in worse survival at 10 years (84% compared to 69%) (Ling et al. 1997). Late surgical intervention not only limits therapeutic benefits but chronic mitral regurgitation results in adverse left ventricular (LV) remodelling, and the development of atrial fibrillation and pulmonary hypertension. Surgical mitral valve (MV) repair in primary MR therefore has a class I recommendation in the EU and US guidelines but only level of evidence B, as no randomised controlled trials (RCTs) have been performed (Baumgartner et al. 2017; Nishimura et al. 2017).
In experienced centres, high success rates of surgical MV repair are associated with acceptable periprocedural morbidity and excellent durability, returning patients to their age/sex-matched expected survival. However, the increase in the numbers of patients with multimorbidities has raised the prospect of transcatheter devices offering improvements in quality of life and, potentially, less morbidity.
Functional/Secondary MR
In functional mitral regurgitation (FMR), apical and lateral distraction of the papillary muscles, due to global or regional LV dilatation, results in tethering and lack of coaptation of otherwise normal mitral leaflets. Treatment of patients with heart failure (HF) and FMR is much more complex than those with degenerative mitral regurgitation (DMR), as the symptoms and prognosis are, to a large extent, determined by the underlying LV dysfunction. Severe FMR is an independent prognostic predictor of mortality and HF hospitalisation (Goliasch et al. 2018; Rossi et al. 2011).
In some cases, HF medications and cardiac resynchronisation therapy (CRT) are the only class I recommended therapies for FMR (Baumgartner et al. 2017; Nishimura et al. 2017). No RCTs of MV surgery, comparing it with medical therapy in FMR, have been performed. Observational data for surgical repair of secondary mitral regurgitation showed no additional benefit with surgical correction (Wu et al. 2015; Bach & Bolling 1996). Prospective surgical studies for secondary MR demonstrated an almost 60% rate of recurrent MR with surgical repair and 17.6% 1-year mortality with mitral valve replacement (Goldstein et al. 2016).
The increasing burden of secondary MR, and limited options due to surgical morbidity, highlights the potential of MR as a target of intervention using transcatheter devices to improve overall survival and reduce morbidity and hospitalisation related to heart failure (de Marchena et al. 2011).
Challenges for transcatheter mitral valve therapies
Despite the dual imperative of an unmet clinical need and substantial investment in device development over the past decade, the transcatheter mitral valve field has seen slow progress – in sharp contrast to the remarkable, rapid advance in TAVI.
The mitral valve apparatus is a complex structure and key considerations for transcatheter device development include the following:
• The mitral valve is integrated with the left ventricle and therefore not only serves the haemodynamic function of ensuring forward flow and cardiac output but is also critical to maintaining the structural and functional integrity of the left ventricle.
• The mitral valve apparatus comprises a saddle-shaped, dynamic annulus which is subject to marked closing forces.
• The trigones of the mitral valve are continuous with the fibrous skeleton of the heart and close to the left ventricular outflow tract.
• Mitral regurgitation may be caused by abnormalities affecting one or more components of the mitral valve (the annulus, leaflets, chordae tendineae and papillary muscles) or the left ventricle.
In MR, more than one component of the mitral valve is often affected. Whilst surgical repair utilises several techniques to restore normal mitral valve function, transcatheter mitral valve replacement has an inherent limitation, as valve repair is confined to a single point of intervention. It is therefore vital that the anticipated advantage of lower morbidity associated with transcatheter mitral valve repair approaches is achieved with significant reduction in mitral regurgitation – either through a single point of intervention or by using multiple techniques. These considerations add to the complexity of transcatheter repair approach. Transcatheter mitral valve implantation techniques are therefore also under evaluation as an alternative option for selected patients.
Transcatheter mitral valve repair
Transcatheter mitral valve repair approaches can broadly be grouped according to their anatomical target within the mitral valve complex, and they are mostly based on established surgical techniques.
The MitraClip
Currently, MitraClip (Abbott Vascular Inc., Menlo Park, CA, USA) is the most widely available transcatheter mitral valve replacement (TMVR) technology in clinical use, with ‘over 60,000 patients treated worldwide’ (Abbott Vascular Incorporated 2018, p.1. It is based on the surgical mitral valve edge-to-edge repair technique pioneered by Alfieri in the 1990s and applied in conventional, minimally invasive and robotic surgical approaches (Alfieri et al. 2001). The MitraClip has been studied in different clinical settings and, following safety, effectiveness and durability data from pivotal EVEREST randomised clinical trials and registry studies, it has been rapidly applied (Attizani et al. 2015).
MitraClip device and procedure
Percutaneous MitraClip repair is performed in the cardiac catheterisation laboratory/hybrid theatre under general anaesthetic with trans-oesophageal echocardiography (TOE) and X-ray fluoroscopy guidance. A percutaneous 24F transvenous, trans-septal approach system is used to access the left atrium and deliver the clip. The clip is passed below the valve and then pulled back to grasp and appose the two segments of the anterior and posterior leaflets that are responsible for the leak. The position of the clip may be adjusted, and further clips placed, to achieve optimal MR reduction. The MitraClip has undergone several iterations to enhance its performance and the new MitraClip XTR has longer clip arms and improved device steerability.
MitraClip safety and efficacy
The randomised EVEREST II trial (Feldman et al. 2015) focused on patients with predominantly degenerative MR; and final five-year results demonstrated that percutaneous repair was safer but less effective than conventional surgery at reducing mitral regurgitation. Nevertheless, the clinical improvements observed with percutaneous therapy were significant and lasted over two to five years.
The advantages of the MitraClip device are its safety and applicability in diverse clinical settings and in both degenerative and functional aetiologies (Kalbacher 2017; Sorajja et al. 2017; Puls et al. 2016; Glower et al. 2014; Maisano et al. 2013). The in-hospital mortality rate reported in different series which include high-risk and inoperable patients is about 2–3%, morbidity rate is low and duration of a hospital stay in many series is less than three days (Sorajja et al. 2017; Glower et al. 2014; Taramasso 2014).
Acute procedural success was the strongest independent predictor of 12-month outcome and risk of re-intervention. The EVEREST II trial reflected the earliest experience with this technology and with TMVR therapy, in general. Improved operator experience and technology iterations have led to better outcomes and an expansion in indications from the classic EVEREST anatomical inclusion criteria. Current practice with MitraClip use in the real world suggests that procedural success is achieved in about 80% of patients (≤2+ MR) and about 65% of patients have residual MR ≤1+ (Puls et al. 2017; Sorajja et al. 2017; Glower et al. 2014; Maisano et al. 2013). The acute safety and efficacy results are similar for both aetiologies, although the one-year mortality rate is, unsurprisingly, higher for FMR patients.
The not insignificant proportion of patients with residual or recurrent significant MR remains a concern. Patients who fall within EVEREST anatomical criteria were found to have lower rates of re-intervention (Lesevic et al. 2017). Furthermore, residual gradients of >5mm are associated with a 2.3-fold increase in the combined endpoint of mortality, LV assist device, surgical mitral valve replacement, and redo procedure (Neuss et al. 2017). This is reinforced by new data demonstrating elevated gradients with residual mitral regurgitation, to be associated with recurrent heart failure and poor outcome (Cheng et al. 2017).
MitraClip in FMR
The class IIb recommendation for MitraClip in FMR reflects the paucity of evidence for surgical repair in this setting. The prognostic benefit of MR as a target of intervention in heart failure was uncertain until the recent publication of two RCTs of MitraClip in HF patients with severe FMR, compared with medical therapy. However, these two trials reported findings that led to diametrically opposite conclusions.
In the Multicentre Study of Percutaneous Mitral Valve Repair MitraClip Device in Patients with Severe Secondary Mitral Regurgitation (MITRA-FR) trial, one-year rates of death or HF hospitalisation were not improved by the addition of MitraClip to background medical therapy. In contrast, the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure (COAPT) trial demonstrated that two-year rates of survival, freedom from HF hospitalisation, quality of life and exercise performance were markedly improved in MitraClip-treated patients, compared with maximally tolerated guideline-directed medical therapy alone (Obadia et al. 2018; Stone et al. 2018). Both studies confirmed the safety of MitraClip therapy and low rates of periprocedural complications.
The differences between these trials may be explained by several factors: most notably, patients enrolled in the COAPT had substantially more severe MR but with smaller LV dimensions than those enrolled in the MITRA-FR. The MR component may therefore be considered to provide a greater haemodynamic contribution to the symptomatology and poorer prognosis in COAPT than in MITRA-FR.
These two trials in fact have complementary value and identify which HF patients with severe MR are likely, or unlikely, to benefit from transcatheter MV repair.
Clinical application of percutaneous mitral valve leaflet repair – MitraClip
In Europe, the MitraClip is approved for treatment of high-risk patients with primary or secondary MR with a class IIB recommendation; whilst in the USA, until recently, the MitraClip has only been approved for primary MR, with a class IIb recommendation (Baumgartner et al. 2017; Nishimura et al. 2017). The FDA has recently approved its application in FMR, reflecting the more complex issues around MR in HF and the absence of RCT data until recently (see MitraClip in FMR).
Differences in healthcare delivery and reimbursement policies across European countries have led to different ways of using this therapy. In the UK, MitraClip is not formally funded by NHS national specialist commissioning and so expertise and experience remain limited.
Transcatheter mitral valve replacement
The transcatheter mitral valve replacement field is still at an early stage of development. The challenges of transcatheter mitral valve replacement technology are described in Table 18.1 (below). These devices are large and present a risk of outflow tract obstruction due to device protrusion in patients with a small left ventricle or shallow aorto-mitral angle. They are currently delivered via a transapical approach, although trans-septal approaches are being developed. Several devices, for both degenerative and functional MR, are at various stages of development or in early feasibility studies (Bapat et al. 2018; De Backer et al. 2014). Detailed assessment with multimodality imaging is essential.
Table 18.1: The challenges of transcatheter mitral valve replacement
| Challenges | Reasons |
| Aetiology | 1. Primary challenges: a. Degenerative b. Rheumatic cases c. Infective cases d. Mitral annular calcification. 2. Secondary challenges: a. Non-ischaemic cases b. Dilated cardiomyopathy c. Ischaemic cardiomyopathy. |
| Anatomical | 1. Lack of calcification 2. Mitral annual calcification 3. Sub-valvular apparatus 4. Dynamic implant environment. |
| Technical | 1. Fixation 2. Paravalvular leak (Haemolysis) 3. Stasis (Thrombosis) 4. Left ventricular outflow tract obstruction 5. Access (large and complex device) 6. Safe and accurate 7. Leaflet problems (quality of the material and poor performance) 8. Frame challenges: a. Multiple components b. Crimping effects c. Mitral annular and left ventricular pressure loops. |
The largest experience with transcatheter mitral valve replacement in native mitral regurgitation is the Tendyne system in 100 patients (Muller et al. 2017). This is a 34–36Fr transapical system and patients were at high or prohibitive surgical risk and had mainly secondary MR. Exclusion criteria included left ventricular end-diastolic diameter >70mm, severe mitral or annular calcification, pulmonary artery systolic pressure >70mmHg, severe tricuspid regurgitation, severe right ventricular dysfunction and left ventricular ejection fraction <30% (Sorajja et al. 2019). Compared to earlier reports on the technical success, safety, MR reduction and one-year outcome of TMVR, this 2017 study shows improvements made in all the key aspects – patient selection, technology development and procedural enhancements.
Degenerated bioprosthesis, failed annuloplasty rings, mitral annular calcification
Case series have reported excellent outcomes for TMVI in patients with degenerated bioprostheses, despite the high surgical risk. However, Valve-in-Ring and Valve-in-Mitral Annular Calcification are associated with higher rates of adverse events and mid-term mortality, compared with Valve-in-Valve (Viv) (Yoon et al. 2019). ViV has the potential to become the first-line therapy to treat degenerated mitral bioprostheses. A number of challenges remain for ViV and ViMAC in order to improve the outcomes. These include optimal procedural planning, improved techniques and better devices.
Eligibility
The Class IIB recommendations reflect the limited evidence available so far to support clinical use of transcatheter mitral repair methods beyond inoperable or high-risk patients with symptomatic severe MR. Transcatheter repair is used to treat patients with symptomatic (NYHA 2–4a) severe mitral regurgitation (grade ≥3+) due to primary abnormality of the mitral valve apparatus. These patients should be categorised as inoperable or high risk for mitral valve surgery by a heart team and anatomically suitable for the technology in question. It is important to assess patients in terms of their frailty and comorbidities and to ensure that they are likely to benefit from reduction in mitral regurgitation. Factors suggesting that they are unlikely to benefit include significant frailty, oxygen-dependent lung disease, severe chronic kidney or liver disease, significant /major bleeding, diathesis or malnutrition with low serum albumin.
Exclusion criteria will vary according to the specific therapy being considered. However, in general, patients are unsuitable if they cannot tolerate procedural anti-coagulation, have active endocarditis or rheumatic mitral valve disease, or echocardiographic evidence of intracardiac mass or thrombus. Transvenous approaches cannot be undertaken if there is evidence of inferior vena cava or femoral venous thrombus.
Evaluation by the multidisciplinary team
Patients with symptomatic severe MR should be evaluated by a multidisciplinary heart team. The multidisciplinary team’s expertise and the patient pathways selected need to reflect the different aetiologies; specifically, transcatheter mitral valve intervention for patients with FMR needs to apply a heart failure algorithm. When symptoms still exist, the mitral valve team should follow the guideline-directed optimal therapy on patients with FMR.
The core members of the heart team include a cardiac surgeon with mitral valve expertise, an expert imaging cardiologist with structural intervention echocardiography skills, a structural heart interventionist, a cardiac anaesthetist and a clinical nurse specialist. Where appropriate, access to elderly care input should be incorporated to aid optimal patient selection.
This multidisciplinary heart team expertise is essential in order to weigh up the potential risks and benefits of the surgical procedure. In this patient group (which is likely to include elderly people and individuals with multimorbidities), when transcatheter or surgical intervention is considered futile, it is also important to have care pathways available that support end of life and palliative needs.
Assessment of mitral regurgitation
The detailed assessment of mitral regurgitation has already been described in Chapter 8. However, there are a few additional imaging modalities which can inform healthcare staff on the indications for, and feasibility of, mitral valve intervention, as described below.
Stress echocardiography
Stress echocardiography, and particularly exercise stress echocardiography, has an important role in the assessment of patients with chronic MR. It can be especially useful when assessing asymptomatic severe MR or symptomatic moderate MR (in other words, when there is a discrepancy between symptoms and severity of MR). Mitral regurgitation is a dynamic process and its severity may increase with exercise. This may explain why patients with at least 3+ MR (Naji et al. 2017) may experience worsening symptoms and a higher risk of mortality and progression to heart failure. Multimodality imaging therefore plays an essential role when assessing anatomical and technical suitability for transcatheter mitral valve therapies.
Transoesophageal echocardiography
The EVEREST criteria for MitraClip demonstrated effective MR reduction in pathology limited to the central A2/P2 portion of the mitral valve. With increasing experience and improvements in device design, this therapy has broadened its applications to include more complex anatomy. However, anatomical features including perforations or clefts, haemodynamically significant mitral stenosis and significant calcification in the leaflet grasping area are considered unsuitable for treatment with percutaneous mitral valve leaflet repair with MitraClip.
Multidetector computed tomography
Multidetector computed tomography with electrocardiographic gating is essential in evaluating patients for transcatheter mitral valve implantation. It has an integral role in annular sizing and determining the risk of left ventricular outflow tract obstruction. It also enables patient-specific fluoroscopic angulation to be determined in advance of the procedure.
There are numerous repair and replacement technologies at various stages of development in the transcatheter armamentarium. However, the transcatheter leaflet edge-to-edge repair with the MitraClip system (Abbott Vascular Inc, Menlo Park, CA, USA) for mitral regurgitation is the only technology thus far that has demonstrated safety and efficacy in different clinical settings.
Transcatheter mitral valve implantation with transcatheter aortic valve implantation prostheses has been performed in patients with surgical degenerated bioprostheses and those with recurrent MR following annuloplasty. Implantation of TAVI prostheses in a calcified native mitral valve has also been reported. The feasibility of TMVI in native non-calcified valves has recently been demonstrated in very high-risk patients, mainly with functional MR. Careful patient selection and effective collaborative multidisciplinary team involvement are critical to ensuring good results in this field. As a safe practitioner, it is vital to know the pros and cons of TMV repair and TMV replacement (see Table 18.2).
Table18.2: The relative pros and cons of transcatheter mitral valve repair and replacement
| Challenges | Transcatheter mitral valve repair | Transcatheter mitral valve replacement |
| Pros | 1. Favourable safety profile 2. Preserved haemodynamics 3. No need for anticoagulation. | 1. More effective in reducing mitral regurgitation 2. Reproducible 3. Broader application across multiple aetiologies. |
| Cons | 1. Procedural complexity 2. Less predictable 3. Residual/recurrent mitral regurgitation. | 1. Anchoring/fixation/deliverability of the device in the annulus 2. Haemodynamic function 3. Risk of paravalvular leak 4. Risk of complications 5. Need for an anticoagulation |
The complexity of mitral valve functional anatomy and the diverse mechanisms of mitral valve disease present great challenges for bioengineering; and clinical trial designs are currently seeking to identify benefits in a heterogenous patient population. This chapter has described a range of transcatheter mitral valve techniques even though there is relatively little evidence available at this stage, due to the above challenges.
Clinicians have to make complex decisions, as they are faced with a multitude of choices and increasing numbers of elderly patients with multimorbidities. In view of all this, there is a need for better risk stratification models to permit more complete risk/benefit assessments for individual patients. Several variables associated with survival require evaluation by the multidisciplinary valve team: aetiology of MR, patient multimorbidity, frailty, individualised risk and efficacy of interventions. By carefully weighing up the clinical and anatomic variables, we can better determine the relative level of benefit for particular transcatheter mitral interventions.
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