Percutaneous Mitral Valve and Tricuspid Valve Repair
Number: 0880
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Aetna considers percutaneous mitral valve repair (PMVR) by means of the MitraClip Clip Delivery System medically necessary for persons with grade 3+ to 4+ symptomatic degenerative mitral regurgitation and at high-risk for traditional open-heart mitral valve surgery.
Aetna considers transcatheter mitral-valve repair using a FDA-approved device (e.g., the MitraClip NTR/XTR Clip Delivery System) medically necessary for individuals with heart failure and moderate-to-severe or severe secondary mitral regurgitation who remained symptomatic despite the use of maximal doses of medical therapy.
Aetna considers transcatheter mitral valve valve-in-valve replacement by means of the Edwards-Sapien valve experimental and investigational because it has not been proven safe and effective for this indication.
Aetna considers PMVR by means of the MitraClip Clip Delivery System experimental and investigational for all other indications including the following (not an all-inclusive list) because its effectiveness for these indications has not been established:
- Persons who are hemodynamically unstable with cardiogenic shock or refractory pulmonary edema and concomitant moderate-to-severe mitral regurgitation
- Persons who cannot tolerate anti-coagulation and anti-platelet medications
- Persons with active inflammation of the heart (endocarditis)
- Persons with blood clots present at the intended site of implant or blood clots in vessels through which access to the defect is gained
- Persons with mitral regurgitation who can be treated with open-heart surgery
- Person with rheumatic mitral valve disease
- Persons with hypertrophic cardiomyopathy/severe congestive heart failure (N-terminal pro-B-type natriuretic peptide (NTproBNP) greater than 10,000 pg/ml).
Aetna considers combined mitral valve repair and left atrial appendage occlusion experimental and investigational because the effectiveness of this approach has not been established.
Aetna considers the use of galectin-3 and ST2 as predictors of therapeutic success in individuals undergoing percutaneous mitral valve repair experimental and investigational because of insufficient evidence.
Aetna considers mitral valve repair using the trans-apical approach (e.g., the NeoChord System and the Permavalve) experimental and investigational because the effectiveness of this approach has not been established.
Aetna consdiers transcatheter mitral valve annuloplasty (e.g., the Carillon Mitral Contour System, and the enCorTC device) for mitral valve repair experimental and investigational because the effectiveness of this approach has not been established.
Aetna considers transcatheter tricuspid valve repair or replacement experimental and investigational because its safety and effectiveness has not been established.
Related Policies
- CPB 0558 - Percutaneous Transluminal Septal Myocardial Ablation (PTSMA)
- CPB 0821 - Transcatheter Pulmonary Valve Implantation
- CPB 0826 - Transcatheter Aortic Valve Implantation
Background
Mitral valve regurgitation, for which surgical mitral valve repair is the treatment of choice, is the second most common clinically relevant valvular heart disease in adults and has an incidence of approximately 2 % to 3 % per year (Seeburger et al, 2011).
A 2009 guideline on percutaneous mitral valve leaflet repair for mitral regurgitation (MR) was issued by the National Institute for Health and Clinical Excellence (NICE). The NICE guideline stated that evidence on the safety and efficacy of percutaneous mitral valve leaflet repair for MR stated that this procedure should only be used with special arrangements for clinical governance, consent and research for patients who are well enough for surgical mitral valve leaflet repair to treat their MR, or in the context of research for patients who are not well enough for surgical mitral valve leaflet reapir to treat their MR (NICE, 2009).
More recently, the Food and Drug Administration (FDA) granted Premarket Approval (PMA) to Abbott Vascular’s MitraClip device (FDA, 2013). The MitraClip Clip Delivery System consists of the MitraClip device and implant catheters. The MitraClip is a permanent implant designed to attach to the mitral valve leaflets, resulting in a double opening of the mitral valve, thus allowing greater closure and reduction of MR. The MitraClip device is inserted via catheter through the femoral vein and advanced into the heart. It is then positioned to grasp both mitral valve leaflets. Following positioning of the MitraClip device the catheter is removed. The goal of the MitraClip device is the reduction of MR to less than or equal to 2+ MR (FDA, 2013).
Glower et al (2012) defined the EVEREST II study as a prospective, multi-center, randomized controlled trial (RCT) comparing percutaneous repair with the MitraClip device to mitral valve surgery in the treatment of mitral regurgitation. They reported on the patient characteristics and treatment effects on mitral repair versus replacement. Of 279 patients enrolled, 80 surgical patients underwent 82 mitral valve operations and 178 underwent an initial MitraClip procedure, of whom 37 underwent a subsequent mitral valve operation within 1 year of their index MitraClip procedure. A logistic regression model was used to predict mitral valve replacement according to valve pathology, etiology of mitral regurgitation, age, previous cardiac surgery, and treatment group which found the rate of percutaneous or surgical mitral valve repair at 1 year to be 89 % (158/178) in patients initially receiving the MitraClip device versus 84 % (67/80) in the surgical patients (p = 0.36). Surgical repair was performed after the MitraClip procedure in 20 (54 %) of 37 patients (p < 0.001 versus surgery). In both the MitraClip device and surgery groups, mitral valve replacement was significantly associated with anterior leaflet pathology (p = 0.035). Logistic regression analysis showed that anterior leaflet pathology predicted mitral valve replacement. In 5 (13.5 %) of 37 patients undergoing surgery after MitraClip therapy, replacement was performed in part because of mitral valve injury associated with the MitraClip procedure. The authors concluded that these data suggested that anterior leaflet pathology is strongly associated with mitral valve replacement in patients undergoing either de novo mitral valve surgery or surgery after MitraClip therapy. They noted that MitraClip therapy has a repair rate similar to surgery through 1 year but also imparts a risk of replacement of a potentially repairable valve.
Hermann et al (2012) conducted a study to characterize patients with MR and atrial fibrillation (AF) treated percutaneously using the MitraClip device and compare the results with traditional surgery in this population. The study population included 264 patients with moderately severe or severe MR assessed by an independent echocardiographic core laboratory and comparison of safety and effectiveness study endpoints at 30 days and 1 year were made using both intention-to-treat and per-protocol (cohort of patients with MR less than or equal to 2+ at discharge) analyses. Pre-existing AF was present in 27 % of patients, who were older, had more advanced disease, and were more likely to have a functional etiology. Similar reduction of MR to less than or equal to 2+ before discharge was achieved in patients with AF (83 %) and in patients without AF (75 %, p = 0.3). Freedom from death, mitral valve surgery for valve dysfunction, and MR greater than 2+ was similar at 12 months for AF patients (64 %) and for no-AF patients (61 %, p = 0.3). The authors reported that at 12 months, MR reduction to less than 2+ was greater with surgery than with MitraClip, but there was no interaction between rhythm and MR reduction, and no difference in all-cause mortality between patients with and patients without AF. The authors noted that atrial fibrillation is associated with more advanced valvular disease and noncardiac comorbidities. However, they concluded that acute procedural success, safety, and 1-year efficacy with MitraClip therapy is similar for patients with AF and without AF.
Smith et al (2012) stated that catheter-based repair of MR with the MitraClip device is performed through a 22-French transseptal guiding catheter. The authors reported on the echocardiographic prevalence of iatrogenic atrial septal defects (iASDs) after the MitraClip procedure. A total of 30 subjects undergoing MitraClip repair during the roll-in phase of the EVEREST II randomized trial who had baseline, 30 day, 6 and 12 month trans-thoracic echocardiograms (TTEs) available for review were included; and patients who underwent surgery for MR within the first 12 months were excluded. Residual iASD size, right ventricular (RV) size, left atrial (LA) volume, and tricuspid/MR grade were quantified and iASDs were found at 12 months in 8 patients (27 %) with a mean diameter of 6.6 ± 3.1 mm. Patients with iASD at 12 months had more residual MR, increased tricuspid regurgitation (TR) and a trend toward larger LA volumes than non-iASD patients; 83 % of non-ASD patients were free from MR greater than 2+ at 12 months versus 38 % of those with iASD (p = 0.016). There were no other significant associations between clinical and echocardiographic variables and the persistence of iASD. The authors concluded that following MitraClip repair, persistent iASDs occur at a rate comparable to reports after other transseptal interventional procedures and did not appear hemodynamically significant. They further noted that patients with persistent iASDs had less MR reduction at 12-months and a trend toward larger LA volumes, suggesting that increased LA pressure may be a mechanism for persistent iASD.
Whitlow et al (2012) reported on the acute and 12 month results with catheter-based mitral valve leaflet repair in the EVEREST II (Endovascular Valve Edge-to-Edge Repair) High Risk Study (HRS). The EVEREST II Study assessed the safety and effectiveness of the MitraClip device in patients with significant MR at high risk of surgical mortality. This study included patients with severe MR (3 to 4+) at high risk of surgery who may benefit from percutaneous mitral leaflet repair. Study subjects included patients with severe symptomatic MR and an estimated surgical mortality rate of greater than or equal to 12 % were enrolled. A group of patients screened concurrently but not enrolled were identified retrospectively and consented to serve as a comparison group for survival in patients treated by standard care. A total of 78 patients underwent the MitraClip procedure with a mean age of 77 years. Greater than 50 % had previous cardiac surgery, 46 had functional MR and 32 had degenerative MR. MitraClip devices were successfully placed in 96 % of patients . Surgical mortality rate in the HRS and concurrent comparator group was 18.2 % and 17.4 %, respectively. The Society of Thoracic Surgeons calculator estimated mortality rate was 14.2 % and 14.9 %, respectively and the 30-day procedure-related mortality rate was 7.7 % in the HRS and 8.3 % in the comparator group (p = NS). T he 12-month survival rate was 76 % in the HRS and 55 % in the concurrent comparator group (p = 0.047). In the evaluation of surviving patients with matched baseline and 12-month data, 78 % had an MR grade of less than or equal to 2+. Left ventricular end-diastolic volume improved from 172 ml to 140 ml and end-systolic volume improved from 82 ml to 73 ml (both p = 0.001). New York Heart Association (NYHA) functional class improved from III/IV at baseline in 89% to class I/II in 74 % (p < 0.0001). Quality of life was also evaluated and reported as improved (Short Form-36 physical component score increased from 32.1 to 36.1 [p = 0.014] with the mental component score from 45.5 to 48.7 [p = 0.065]) at 12 months. The annual rate of hospitalization for congestive heart failure in surviving patients with matched data decreased from 0.59 to 0.32 (p = 0.034). The investigators concluded that the MitraClip device reduced MR in a majority of patients deemed at high risk of surgery, resulting in improvement in clinical symptoms and significant left ventricular reverse remodeling over 12 months.
Andalib et al (2014) conducted a systematic review to evaluate the outcomes of mitral valve surgery in octogenarians with severe symptomatic mitral regurgitation (MR) and meta-analysis of data on octogenarians who underwent mitral valve replacement (MVR) or mitral valve repair (MVRpr). Their search yielded 16 retrospective studies. Using Bayesian hierarchical models, they estimated the pooled proportion of 30-day mortality, postoperative stroke, and long-term survival. The pooled proportion of 30-day postoperative mortality was 13 % following MVR (10 studies, 3,105 patients, 95 % credible interval (CI): 9 to 18 %), and 7 % following MVRpr (6 studies, 2,642 patients, 95 % CI: 3 to 12 %). Furthermore, pooled proportions of post-operative stroke were 4 % (6 studies, 2,945 patients, 95 % CI: 3 to 7 %) and 3 % (3 studies, 348 patients, 95 % CI: 1 to 8 %) for patients undergoing MVR and MVRpr, respectively. Pooled survival rates at 1 and 5 years following MVR (4 studies, 250 patients) were 67 % (95 % CI: 50 to 80 %) and 29 % (95 % CI: 16 to 47 %), and following MVRpr (3 studies, 333 patients) were 69 % (95 % CI: 50 to 83 %) and 23 % (95 % CI: 12 to 39 %), respectively. The authors concluded that surgical treatment of MR in octogenarians is associated with high peri-operative mortality and poor long-term survival with an uncertain benefit on quality of life and that these data highlight the importance of patient selection for operative intervention and suggest that future transcatheter mitral valve therapies such as transcatheter mitral valve repair (TMVR) and/or transcatheter mitral valve implantation (TMVI), may provide an alternative therapeutic approach in selected high-risk elderly patients.
Armstrong et al (2013) reported on the predictors of the number of MitraClip devices implanted during percutaneous repair of mitral regurgitation (MR), and the long-term reduction in MR. In the EVEREST trials, 1 or 2 MitraClip devices were implanted to reduce MR, as needed. Pre-procedural TTE and transesophageal echocardiograms (TEE) of 233 subjects who received 1 or 2 MitraClip devices in the EVEREST II Study were analyzed. TEEs were reviewed for etiology of MR and pathoanatomic features of the valve, valve apparatus, and the regurgitant jet and follow-up MR was assessed by TTE post-procedure and at 12 months. A total of 97 subjects (42 %) had 2 MitraClip devices implanted. Those subjects with quantitatively more severe MR were more likely to receive 2 devices [mean regurgitant volume (RV) 45.9 ± 21.9 versus 36.3 ± 18.5 ml, p < 0.001]. Multi-variate analysis showed increased anterior leaflet thickness (odds ratio [OR] 1.7 per mm, p = 0.007) and greater baseline RV (OR 1.21 per 10 ml, p = 0.01) were associated with increased odds of implanting 2 devices. The frequency of 2+ MR or less at discharge was similar regardless of the number of devices implanted. The authors concluded that after propensity matching, patients had quantitatively similar MR at 12-month follow-up, regardless of whether 1 or 2 MitraClip devices were implanted (p = 0.6). The authors concluded that subjects with thicker anterior mitral leaflets and more severe MR were more likely to receive 2 MitraClip devices. Immediate and long-term reduction in MR was similar regardless of the number of devices implanted at the time of the procedure.
Foster et al (2013) conducted an analysis to determine the extent of reverse remodeling at 12 months after successful percutaneous reduction of MR with the MitraClip device; 49 of 64 patients with 3+ and 4+ MR who achieved acute procedural success after treatment with the MitraClip device had moderate or less MR at 12-month follow-up. Baseline and 12-month echocardiograms were compared between the group with and without left ventricular (LV) dysfunction. In patients with persistent MR reduction and pre-existing LV dysfunction, there was a reduction in LV wall stress, reduced LV end-diastolic volume, LV end-systolic volume and increase in LV ejection fraction in contrast to those with normal baseline LV function, who showed reduction in LV end-diastolic volume, LV wall stress, no change in LV end-systolic volume, and a fall in LV ejection fraction. Patients with pre-existing LV dysfunction demonstrated reverse remodeling and improved LV ejection fraction after percutaneous mitral valve repair.
Lim et al (2014) studied the treatment of MR in patients with severe degenerative MR (DMR) at prohibitive surgical risk undergoing transcatheter mitral valve repair with the MitraClip. A prohibitive risk DMR cohort was identified by a multi-disciplinary heart team that retrospectively evaluated high risk DMR patients enrolled in the EVEREST II studies. The study enrolled 141 high risk DMR; 127 of these patients were retrospectively identified as meeting the definition of prohibitive risk and had one-year follow-up data (median of 1.47 years) available. Patients were elderly (mean age of 82 years), severely symptomatic (87 % NYHA Class III/IV), and at prohibitive surgical risk (Society of Thoracic Surgeons [STS] score 13.2 ± 7.3 %). MitraClip was successfully implanted in 95.3 %; hospital stay was 2.9 ± 3.1 days. Major adverse events at 30 days included death in 6.3 %, myocardial infarction in 0.8 %, and stroke in 2.4 %. Through 1 year there were a total of 30 (23.6 %) deaths, with no survival difference between patients discharged with MR less than or equal to 1+ or MR = 2+. A majority of surviving patients (82.9 %) remained MR less than or equal to 2+ at 1 year and 86.9 % were in NYHA Functional Class I or II. Left ventricular end-diastolic volume decreased (125.1 ± 40.1 ml to 108.5 ± 37.9 ml, p < 0.0001, n = 69 survivors with paired data). SF-36 quality-of-life scores improved and hospitalizations for heart failure were reduced in patients whose MR was reduced. The authors concluded that transcatheter mitral valve repair in prohibitive surgical risk patients is associated with safety and good clinical outcomes, including rehospitalization decrease, functional improvements and favorable ventricular remodeling at 1 year.
Mauri et al (2013) conducted a study to evaluate 4-year outcomes of percutaneous repair versus surgery for mitral regurgitation. Patients with grade 3+ or 4+ MR were randomly assigned to percutaneous repair with the MitraClip device or conventional mitral valve surgery in a 2:1 ratio (184:95). Patients prospectively consented to 5 years of follow-up. At 4 years, the rate of the composite endpoint of freedom from death, surgery, or 3+ or 4+ MR in the intention-to-treat population was 39.8 % versus 53.4 % in the percutaneous repair group and surgical groups, respectively (p = 0.070). Rates of death were 17.4 % versus 17.8 % (p = 0.914), and 3+ or 4+ MR was present in 21.7 % versus 24.7 % (p = 0.745) at 4 years of follow-up, respectively. Surgery for mitral valve dysfunction, however, occurred in 20.4 % versus 2.2 % (p < 0.001) at 1 year and 24.8 % versus 5.5 % (p < 0.001) at 4 years. The authors concluded that patients treated with percutaneous repair of the mitral valve more commonly required surgery to treat residual MR; however, after the first year of follow-up, there were few surgeries required after either percutaneous or surgical treatment and no difference in the prevalence of moderate-severe and severe MR or mortality at 4 years.
Puls et al (2014) conducted a study to identify predictors of midterm mortality and heart failure rehospitalisation after percutaneous mitral valve repair with MitraClip. A total of 150 consecutive patients were followed for a median of 463 days. Survival analyses were performed for baseline characteristics, risk scores and failure of acute procedural success (APS) defined as persisting MR grade 3+ or 4+. Univariate significant risk stratifiers were tested in multivariate analyses using a Cox proportional hazards model. Overall survival was 96 % at 30 days, 79.5 % at 12 months, and 62 % at 2 years. Multivariate analysis identified APS failure (hazard ratio [HR] 2.13, p = 0.02), NYHA Class IV at baseline (HR 2.11, p = 0.01) and STS score greater than or equal to 12 (HR 2.20, p < 0.0001) as significant independent predictors of all-cause mortality, and APS failure (HR 2.31, p = 0.01) and NYHA Class IV at baseline (HR 1.89, p = 0.03) as significant independent predictors of heart failure rehospitalisation. Also, a post-procedural significant decrease in hospitalisation rate could only be observed after successful interventions (0.89 ± 1.07 per year before versus 0.54 ± 0.96 after implantation, p = 0.01). Patients with severely dilated and overloaded ventricles who did not meet EVEREST II eligibility criteria were at higher risk of APS failure. The authors concluded that failure of acute procedural success proved to have the most important impact on outcome after MitraClip implantation.
Gonzalez et al (2015) stated that in recent years, MitraClip has become available as a treatment option for MR in high-risk surgical patients. Focusing on the incremental effectiveness of MitraClip versus the current standard of care, these investigators provided a comparative review of the evidence on MitraClip and standard medical therapy (MT) in high-risk MR patients. Evidence was retrieved from 7 major databases. Results suggested that MitraClip presented a high safety profile and a good middle-term effectiveness performance. Evidence on long-term effectiveness is limited both for MitraClip and MT. Few studies allowed a comparison with MT and comparative results on different endpoints were mixed. Therefore, the available evidence does not conclusively inform whether or under which circumstances MitraClip should be preferred over MT in the treatment of high-risk patients. The authors concluded that head-to-head real-world studies would be needed, as they would provide great and timely insights to support policy decisions when medical devices are at stake.
MitraClip for the Treatment of Hypertrophic Cardiomyopathy/Severe Congestive Heart Failure
Schau et al (2016) investigated mortality following transcatheter mitral valve repair with the MitraClip System (MC) in patients with MR and moderate-to-severe symptomatic heart failure (HF) in comparison to mortality predicted by the Seattle Heart Failure Model (SHFM) and the HF calculator of the meta-analysis global group in chronic HF (MAGGIC). This retrospective study included 194 consecutive patients, who received a MC implantation between 2009 and 2013 at the authors’ institution. The observed mortality was compared with that predicted by the SHFM and the MAGGIC after 1 year: 24 % observed, 18 % by SHFM (p = 0.185) and 20.9 % by MAGGIC (p = 0.542). At 2 years: 32 % observed versus 33 % by SHFM (p = 0.919). The subgroup of patients with end-stage HF and N-terminal pro-B-type natriuretic peptide (NTproBNP) greater than 10,000pg/ml (n = 41) had significantly worse mortality after 1 year (49 %) than predicted by SHFM (24 %, p = 0.034) and MAGGIC (24.8 %, p = 0.041). The authors concluded that in the overall patient cohort defined by 3+ to 4+ mitral valve regurgitation with NYHA III and IV symptomatic HF, mortality following MC is consistent with that predicted by SHFM and MAGGIC for patients that are not at high risk. However, the subset of patients with severe HF defined by NTproBNP greater than 10,000 pg/ml had worse than predicted mortality and may not benefit from MC therapy, mainly due to a high 30-day mortality.
Guerrero et al (2016) conducted a study to evaluate the early experience of transcatheter mitral valve replacement (TMVR) with balloon-expandable valves in patients with severe mitral annular calcification (MAC). These investigators presented the first large retrospective series from a multicenter global registry. The investigators noted that there are isolated reports of successful TMVR with balloon-expandable valves in this patient population. From September 2012 to July of 2015, 64 patients in 32 centers underwent TMVR with compassionate use of balloon-expandable valves. The mean age of patients was 73 ± 13 years, 34% were male, and the mean Society of Thoracic Surgeons score was 14.4 ± 9.5%. They reported that the mean mitral gradient was 11.45 ± 4.4 mm Hg and the mean mitral area was 1.18 ± 0.5 cm(2). SAPIEN valves (Edwards Lifesciences, Irvine, California) were used in 7.8%, SAPIEN XT in 59.4%, SAPIEN 3 in 28.1%, and Inovare (Braile Biomedica, Brazil) in 4.7%. The patient population access was transatrial in 15.6%, transapical in 43.8%, and transseptal in 40.6%. The Mitral Valve Academic Research Consortium criteria indicated success was achieved in 46 (72%) patients, primarily limited by the need for a second valve in 11 (17.2%). Six study participants (9.3%) had left ventricular tract obstruction with hemodynamic compromise. Mean mitral gradient post-procedure was 4 ± 2.2 mm Hg, paravalvular regurgitation was mild or absent in all. Study results showed that thirty-day all-cause mortality was 29.7% (cardiovascular = 12.5% and noncardiac = 17.2%) and that 84% of the survivors with follow-up data available were in New York Heart Association functional class I or II at 30 days (n = 25). The authors concluded that TMVR with balloon-expandable valves in patients with severe MAC is feasible but may be associated with significant adverse events. This strategy might be an alternative for selected high-risk patients with limited treatment options.
Sorajja and colleagues (2016) noted that few therapeutic options exist for patients with severe HF due to obstructive hypertrophic cardiomyopathy (HCM) who are at unacceptable surgical risk. These researchers hypothesized that percutaneous plication of the mitral valve could reduce left ventricular outflow tract (LVOT) obstruction and associated MR, thereby leading to amelioration of HF symptoms. These investigators evaluated the potential effectiveness of percutaneous mitral valve plication as a therapy for patients with symptomatic, obstructive HCM. A total of 6 patients (aged 83 ± 8 years; 5 women), judged as not optimal candidates for septal myectomy, were referred for management of severe, drug-refractory HF symptoms due to obstructive HCM (NYHA functional class III). Each underwent percutaneous mitral valve leaflet plication to reduce systolic anterior motion (SAM) and MR using the transcatheter mitral clip system. The procedure was completed in 5 patients with placement of a single clip at the A2 to P2 segments of the mitral valve. One other patient experienced cardiac tamponade, leading to termination of the procedure. Among the 5 treated patients, percutaneous plication with the eliminated SAM and consequently decreased the intra-operative LVOT gradient (91 ± 44 mm Hg to 12 ± 6 mm Hg; p = 0.007), left atrial pressure (29 ± 11 mm Hg to 20 ± 8 mm Hg; p = 0.06), and mitral regurgitation grade (3.0 ± 0 versus 0.8 ± 0.4; p = 0.0002) associated with improved cardiac output (in n = 4; 3.0 ± 0.6 L/min to 4.3 ± 1.2 L/min; p = 0.03). Over follow-up of 15 ± 4 months, symptom improvement to NYHA functional class I or II occurred in all patients. Follow-up echocardiography after 15 ± 4 months demonstrated continued absence of SAM and significant reduction in MR, although high systolic LVOT velocities (i.e., greater than 4 m/s) were evident in 3 of the 5 treated patients. The authors concluded that this was a report of percutaneous mitral valve plication as a primary therapy in the management of severely symptomatic, obstructive HCM patients. They stated that this initial experience suggested that percutaneous mitral valve plication may be effective for symptom relief in such patients via reduction of SAM and mitral regurgitation; and the significance of persistent elevations of LVOT velocities in some patients requires further study.
Philipson and associates (2017) stated that HCM is the most common inherited heart disease. Although it was first described over 50 years ago, there has been little in the way of novel disease-specific therapeutic development for these patients. Current treatment aims primarily at symptomatic control using medications made for other diseases and does little to change the disease course. Septal reduction by surgical myectomy or percutaneous alcohol septal ablation are well-established treatments for pharmacologic-refractory LVOT obstruction in HCM patients. In recent years, there has been a relative surge in the development of innovative therapeutics that target the complex molecular pathophysiology and resulting hemodynamics that underlie HCM. These investigators reviewed the new and emerging therapeutics for HCM, which include pharmacologic attenuation of sarcomeric calcium sensitivity, allosteric inhibition of cardiac myosin, myocardial metabolic modulation, and renin-angiotensin-aldosterone (RAS) system inhibition, as well as structural intervention by percutaneous mitral valve plication and endocardial radiofrequency ablation of septal hypertrophy. The authors concluded that while further development of these therapeutic strategies is ongoing, they each mark a significant and promising advancement in the treatment of patients with HCM.
Transcatheter Mitral Valve Replacement for Degenerated Bioprosthetic Valves and Failed Annuloplasty Rings
Yoon and colleagues (2017) noted that limited data exist regarding TMVR for patients with failed mitral valve replacement and repair. These researchers evaluated the outcomes of TMVR in patients with failed mitral bioprosthetic valves (valve-in-valve [ViV]) and annuloplasty rings (valve-in-ring [ViR]). From the TMVR multi-center registry, procedural and clinical outcomes of mitral ViV and ViR were compared according to Mitral Valve Academic Research Consortium criteria. A total of 248 patients with mean STS score of 8.9 ± 6.8 % underwent TMVR. Trans-septal access and the balloon-expandable valve were used in 33.1 % and 89.9 %, respectively. Compared with 176 patients undergoing ViV, 72 patients undergoing ViR had lower left ventricular ejection fraction (LVEF; 45.6 ± 17.4 % versus 55.3 ± 11.1 %; p < 0.001). Overall technical and device success rates were acceptable, at 92.3 % and 85.5 %, respectively. However, compared with the ViV group, the ViR group had lower technical success (83.3 % versus 96.0 %; p = 0.001) due to more frequent 2nd valve implantation (11.1 % versus 2.8 %; p = 0.008), and lower device success (76.4 % versus 89.2 %; p = 0.009) due to more frequent re-intervention (16.7 % versus 7.4 %; p = 0.03). Mean mitral valve gradients were similar between groups (6.4 ± 2.3 mm Hg versus 5.8 ± 2.7 mm Hg; p = 0.17), whereas the ViR group had more frequent post-procedural MR moderate or higher (19.4 % versus 6.8 %; p = 0.003). Furthermore, the ViR group had more frequent life-threatening bleeding (8.3 % versus 2.3 %; p = 0.03), acute kidney injury (11.1 % versus 4.0 %; p = 0.03), and subsequent lower procedural success (58.3 % versus 79.5 %; p = 0.001). The 1-year all-cause mortality rate was significantly higher in the ViR group compared with the ViV group (28.7 % versus 12.6 %; log-rank test, p = 0.01). On multi-variable analysis, failed annuloplasty ring was independently associated with all-cause mortality (HR: 2.70; 95 % CI: 1.34 to 5.43; p = 0.005). The authors concluded that the TMVR procedure provided acceptable outcomes in high-risk patients with degenerated bioprostheses or failed annuloplasty rings, but mitral ViR was associated with higher rates of procedural complications and mid-term mortality compared with mitral ViV.
Chiarito and associates (2018) stated that differences in terms of safety and effectiveness of percutaneous edge-to-edge mitral repair between patients with functional and degenerative MR are not well established. These investigators performed a systematic review and meta-analysis to clarify these differences. PubMed, Embase, Google scholar database and international meeting abstracts were searched for all studies about MitraClip. Studies with less than 25 patients or where 1-year results were not delineated between MR etiology were excluded. A total of 9 studies investigating the mid-term outcome of percutaneous edge-to-edge repair in patients with functional versus degenerative MR were included in the meta-analysis (n = 2,615). At 1 year, there were no significant differences among groups in terms of patients with MR grade less than or equal to 2 (719/1,304 versus 295/504; 58 % versus 54 %; risk ratio (RR) 1.12; 95 % CI: 0.86 to 1.47; p = 0.40), while there was a significantly lower rate of mitral valve re-intervention in patients with functional MR compared with those with degenerative MR (77/1,770 versus 80/818; 4 % versus 10 %; RR 0.60; 95 % CI: 0.38 to 0.97; p = 0.04); 1-year mortality rate was 16 % (408/2,498) and similar among groups (RR 1.26; 95 % CI: 0.90 to 1.77; p = 0.18). Functional MR group showed significantly higher percentage of patients in NYHA functional class III/IV (234/1,480 versus 49/583; 16 % versus 8 %; p < 0.01) and re-hospitalization for HF (137/605 versus 31/220; 23 % versus 14 %; p = 0.03). No differences were found in terms of single leaflet device attachment (25/969 versus 20/464; 3 % versus 4 %; p = 0.81) and device embolization (no events reported in both groups) at 1 year. The authors concluded that the findings of this meta-analysis suggested that percutaneous edge-to-edge repair is likely to be a safe and effective option in patients with both functional and degenerative MR. Moreover, they stated that large, randomized clinical trials are ongoing and awaited to fully evaluate the clinical impact of the procedure in these 2 different MR etiologies.
MitraClip for the Treatment of Tricuspid Regurgitation
Panaich and Eleid (2018) MR affects approximately 4 million people in the U.S. alone, increasing in prevalence with age. In October 2013, the FDA approved the MitraClip system for percutaneous edge-to-edge transcatheter mitral valve repair; and it has been used in over 40,000 patients globally. Additionally, there is keen interest and early exploration into the use of MitraClip for treatment of severe symptomatic TR, another undertreated disease with significant morbidity and mortality.
Pfister and Baldus (2017) stated that TR is frequently found as a result of right ventricular remodeling due to advanced left heart diseases; and drug treatment is limited to diuretics. Due to the high risk only a small percentage of patients are amenable to surgical treatment of TR in those who undergo left-sided surgery for other reasons. Catheter-based procedures are an attractive treatment alternative, particularly since the strong prognostic impact of TR suggests an unmet need of treatment, independent of the underlying heart disease. A vast amount of clinical experience exists for the MitraClip system for treatment of MR. A first case series showed that the application of MitraClip for treatment of TR is technically feasible, appeared to be safe and the degree of TR can be reduced.
In an observational study, Nickenig and colleagues (2017) evaluated the safety and feasibility of transcatheter repair of chronic severe TR with the MitraClip system. In addition, the effects on clinical symptoms were assessed. Patients with HF symptoms and severe TR on optimal medical treatment were treated with the MitraClip system. Safety, defined as peri-procedural adverse events (AEs) such as death, myocardial infarction (MI), stroke, or cardiac tamponade; and feasibility, defined as successful implantation of 1 or more MitraClip devices and reduction of TR by at least 1 grade, were evaluated before discharge and after 30 days. In addition, functional outcome, defined as changes in NYHA functional class and 6-minute walking distance (6MWD), were assessed. These researchers included 64 consecutive patients (mean age of 76.6 ± 10 years) deemed unsuitable for surgery who underwent MitraClip treatment for chronic, severe TR for compassionate use. Functional TR was present in 88 %; in addition, 22 patients were also treated with the MitraClip system for MR as a combined procedure. The degree of TR was severe or massive in 88 % of patients before the procedure. The MitraClip device was successfully implanted in the tricuspid valve in 97 % of the cases. After the procedure, TR was reduced by at least 1 grade in 91 % of the patients, thereof 4 % that were reduced from massive to severe. In 13 % of patients, TR remained severe after the procedure. Significant reductions in effective regurgitant orifice area (0.9 ± 0.3 cm2 versus 0.4 ± 0.2 cm2; p < 0.001), vena contracta width (1.1 ± 0.5 cm versus 0.6 ± 0.3 cm; p = 0.001), and regurgitant volume (57.2 ± 12.8 ml/beat versus 30.8 ± 6.9 ml/beat; p < 0.001) were observed. No intra-procedural deaths, cardiac tamponade, emergency surgery, stroke, MI, or major vascular complications occurred; 3 (5 %) in-hospital deaths occurred; NYHA functional class was significantly improved (p < 0.001), and 6-6MWD increased significantly (165.9 ± 102.5 m versus 193.5 ± 115.9 m; p = 0.007). The authors concluded that transcatheter treatment of TR with the MitraClip system appeared to be safe and feasible in this cohort of pre-selected patients. Initial efficacy analysis showed encouraging reduction of TR, which may potentially result in improved clinical outcomes.
Fender and associates (2017) stated that chronic TR is usually associated with left-sided heart disease or pulmonary hypertension. Although severe TR carries a poor prognosis, isolated surgery is rarely performed due to high in-hospital mortality and an unclear impact on long-term survival. The lack of adequate surgical treatment has resulted in a large population of patients with an unmet clinical need. Transcatheter therapies have revolutionized the management of high-risk patients with left-sided valvular disease, and have sparked interest in translating minimally invasive therapies to the tricuspid valve. These investigators discussed some of the challenges of percutaneous tricuspid interventions, and reviewed the novel therapies that are in early development. The authors concluded that transcatheter therapies for the tricuspid valve are in early development, and are not yet appropriate for clinical use. They stated that in select non-surgical patients transcatheter devices may ultimately provide a therapeutic approach to palliate symptoms; however, further studies are needed to demonstrate their safety and effectiveness before these devices are introduced to clinical practice.
Furthermore, an UpToDate review on “Management and prognosis of tricuspid regurgitation” (Otto, 2017) stated that “Studies are in progress on the possibility of treating TR with transcatheter approaches similar to those used for mitral valve disease with either a clip on the valve leaflets or an annular remodeling device. However, these approaches are in preclinical or early clinical trials and are not available for general clinical use”.
Combined Mitral Valve Implantation and Left Atrial Appendage Occlusion
Francisco and colleagues (2017) stated that patients referred for PMVR using the MitraClip system frequently have AF, which imposes additional challenges due to the need for oral anti-coagulation. Left atrial appendage occlusion(LAAO) is currently regarded as a non-inferior alternative to anti-coagulation in patients with non-valvular AF and both high thromboembolic and bleeding risk. Considering that both MitraClip implantation and LAAO are percutaneous techniques that require trans-septal puncture, it is technically attractive to consider their concomitant use. These researchers evaluated the feasibility of a combined approach with MitraClip implantation and LAAO in a single procedure. These investigators reported the 1st case series regarding this issue, discussing the specific advantages, pitfalls and technical aspects of combining these 2 procedures. A total of 5 patients underwent LAAO with the Watchman device followed by MitraClip implantation in the same procedure. All patients experienced significant reduction in MR of at least 2 grades, optimal occluder position, no associated complications and significant clinical improvement assessed by NYHA functional class (reduction of at least 1 functional class, with 4 patients in class I at 1-month follow-up). The authors concluded that in selected patients rejected for surgical mitral valve repair, with AF and increased risk of bleeding and embolic events, a combined approach with MitraClip implantation and LAAO in a single procedure was feasible, safe and effective.
The main drawbacks of this study were its small sample size (n = 5) and short-term follow-up (1 month). It also had several potential disadvantages:- the high trans-septal puncture for the MitraClip is less well suited for LAAO.
- overall procedure time may be prolonged, with an added risk of volume over-load or hemodynamic instability, especially considering the severely depressed systolic function of many of these patients. These investigators experienced no difficulties with either issue, and overall procedure time was acceptable (103.0 ± 60.8 mins), and
- another aspect of the technique that is the subject of debate is the appropriate sequence of procedures in this combined approach.
These researchers decided to perform LAAO before MitraClip implantation based on the rationale of using sheaths with sequentially increasing diameters. They considered that this strategy would reduce the risk of bleeding at the access site and would impose less trauma on the atrial septum. Reversing the order of the procedures may have the advantage of eliminating the risk of interference of the MitraClip delivery system with the implanted Watchman device. However, the authors found that the presence of the Watchman device served as a useful anatomical reference during manipulation of the MitraClip delivery system. Performing the MitraClip implantation first would require an exchange for a shorter sheath compatible with the 14-F Watchman delivery sheath, to avoid massive bleeding at the access site. Alternatively, the 24-F could be exchanged directly for the 14-F using the pre-deployed Perclose Proglide systems to close the orifice around the sheath. This approach may compromise final access occlusion success.
Freixa and associates (2017) evaluated the feasibility, safety, and technical considerations of the combination of PMVR using the MitraClip system and LAAO. The present study described the multi-center experience of combined MitraClip and LAAO procedures. Between April 2012 and April 2016, a total of 6 patients were successfully treated with the combined procedure. In all patients, mitral valve repair was performed before LAAO. Both procedures were successfully performed in all cases without any relevant procedural complication or mortality. The authors concluded that according to the findings of the present study, a combination of both techniques appeared to be feasible and safe, with favorable in-hospital outcomes.
Kuwata and co-workers (2017) reported their experience with concomitant MitraClip (MC) and left atrial appendage occlusion (LAAO) and examined the feasibility, safety and short-term outcome of such an approach. A total of 25 consecutive patients underwent MC with concomitant LAAO at the authors’ hospital (combined group). As a control group, 25 consecutive patients with AF undergoing stand-alone MC were selected. Baseline parameters were equal between the 2 groups. Patients in the combined group had longer procedural time (90.0 mins versus 66.0 mins, p = 0.02) and radiation time (32.0 mins versus 18.0 mins, p = 0.01). There were no procedural deaths. At 30 days, 1 patient died due to cerebral hemorrhage (combined versus control: 4 % versus 0 %, p = 0.32) and 2 had acute kidney injury (combined versus control: 4 % versus 4 %, p = 1.00). In multi-variate analysis, the association of LAAO with device or procedural success was insignificant. The authors concluded that LAAO along with MC in a single-stage procedure was feasible. Moreover, they stated that these preliminary results have to be validated in a large randomized study with longer follow-up.
Combined Transcatheter Aortic and Mitral Valve Interventions
Ando and colleagues (2017) stated that combined transcatheter aortic and mitral valve intervention (CTAMVI), a combination of either transcatheter aortic valve replacement (TAVR) or transcatheter aortic valve-in-valve (TAViV) and TMVR, transcatheter mitral ViV/ViR (TMViV/ViR), or PMVR is an attractive alternative in high-surgical risk patients with combined aortic and mitral valve disease. However, its procedural details and clinical outcomes have not been well described. These investigators summarized the published data of CTAMVI. They performed a systematic review of all the published articles from PubMed and Embase. A total of 37 studies with 60 patients were included. The indication for CTAMVI was high or inoperable surgical risk and symptomatic severe aortic stenosis (92 %) or severe aortic regurgitation (8 %) combined with moderate-to-severe/severe mitral stenosis (30 %) or moderate/severe MR (65 %) or both (5 %). In majority of the cases, aortic valve intervention was performed prior to the mitral valve. Mortality rate were 25 % for TAVR + TMVR (range of 42 days to 10 months), 17 % for TAVR + TMViV/ViR (range of 13 days to 6 months), 0 % for TAViV + TMViV/ViR (range of 6 to 365 days), and 15 % for TAVR/ViV + PMVR (range of 17 days to 419 days). Significant (more than moderate) para-valvular regurgitation post-procedure was rare. The authors concluded that CTAMVI appeared to confer reasonable clinical outcome. Moreover, they stated that further large clinical trials are needed to clarify the optimal strategy, procedural details and clinical outcomes in the future.
Use of Galectin-3 and ST2 as Predictors of Therapeutic Success in Individuals Undergoing Percutaneous Mitral Valve Repair
Dorr and colleagues (2018) stated that PMVR is a therapeutic option in patients with severe MR and at high risk for open-heart surgery. Currently, limited information exists about predictors of procedural success after PMVR. Galectin-3 (Gal-3) and suppression of tumorigenicity 2 (ST2) induce fibrotic alterations in severe MR and HF. These researchers examined the predictive value of Gal-3 and ST2 as specific indicators of therapeutic success in high-risk patients undergoing PMVR. They hypothesized that extended cardiac fibrotic alterations might have impact on successful MR reduction after the MitraClip procedure. A total of 210 consecutive patients undergoing PMVR using the MitraClip system were included in this study. Procedural success was defined as an immediate reduction of MR by greater than or equal to 2 grades, assessed by echocardiography. Venous blood samples were collected prior to PMVR and at 6 months follow-up for biomarker analysis. After PMVR there was a significant reduction in the severity of MR (MR grade: 3 ± 0.3 versus 1.6 ± 0.6, p < 0.001). Low baseline Gal-3 levels (PMVRsuccess : 22.0 ng/ml [inter-quartile range [IQR], 17.3 to 30.9] versus PMVRfailure : 30.6 ng/ml [IQR, 24.8 to 42.3], p < 0.001) and ST2 levels (PMVRsuccess : 900.0 pg/ml [IQR, 619.5 to 1114.5] versus PMVRfailure : 1,728.0 pg/ml [IQR, 1,051 to 1,930], p < 0.001) were associated with successful MR reduction after PMVR. Also, receiver operating characteristic (ROC) analysis identified low baseline Gal-3 and ST2 levels as predictors of therapeutic success after PMVR (AUCGal-3 :0.721 [IQR, 0.64 to 0.803], p < 0.001; AUCST2 : 0.807 [IQR, 0.741 to 0.872], p < 0.001). The authors concluded that there was an association between low Gal-3 and ST2 plasma levels and successful MR reduction in patients with severe MR undergoing PMVR using the MitraClip system; thus; these specific biomarkers of cardiac fibrotic alterations may be useful.
These investigators stated that this was the 1st study to examine the use of specific biomarkers of cardiac fibrotic alterations for an immediate assessment of the success of MR reduction after the MitraClip procedure. They noted that this study had several drawbacks. First, this trial was not randomized and did not have a control group. Second, the results of the study were based on a pre-treatment biomarker analysis and were therefore exploratory in nature. Finally, the present study included patients with degenerative MR as well as functional MR and did not discriminate between different underlying pathophysiology and further anatomical characteristics.
Transcatheter Mitral-Valve Repair in Patients with Severe Secondary Mitral Regurgitation
Lavall and co-workers (2018) noted that secondary MR results from LV dilatation and dysfunction. Quantification of secondary MR is challenging because of the underlying myocardial disease. Clinical and echocardiographic evaluation requires a multi-parametric approach. Severe secondary MR occurs in up to 25 % of patients with HF with reduced ejection fraction, which is associated with a mortality rate of 40 % to 50 % in 3 years. Percutaneous edge-to-edge mitral valve repair (MitraClip) has emerged as an alternative to surgical valve repair to improve symptoms, functional capacity, HF hospitalizations, and cardiac hemodynamic. Further new transcatheter strategies addressing MR are evolving. The Carillion, Cardioband, and Mitralign devices were designed to reduce the annulus dilatation, which is a frequent and important determinant of secondary MR. Several transcatheter mitral valve replacement systems (Tendyne, CardiAQ-Edwards, Neovasc, Tiara, Intrepid, Caisson, HighLife, MValve System, and NCSI NaviGate Mitral) are emerging because valve replacement might be more durable compared with valve repair. In small studies, these interventional therapies demonstrated feasibility and efficiency to reduce MR and to improve HF symptoms. However, neither transcatheter nor surgical mitral valve repair or replacement has been proven to impact on the prognosis of HF patients with severe MR, which remains high with a mortality rate of 14 % to 20 % at 1 year. To-date, the primary indication for treatment of secondary severe MR is the amelioration of symptoms, reinforcing the value of a Heart Team discussion. The authors concluded that randomized studies examining the treatment effect and long-term outcome for any transcatheter or surgical mitral valve intervention compared with optimized medical treatment are needed and underway.
Stone and colleagues (2018) noted that the prognosis is poor among patients with HF who have MR due to LV dysfunction. Transcatheter mitral-valve repair may improve their clinical outcomes. At 78 sites in the U.S. and Canada, these researchers enrolled patients with HF and moderate-to-severe or severe secondary MR who remained symptomatic despite the use of maximal doses of guideline-directed medical therapy. Patients were randomly assigned to TMVR plus medical therapy (device group) or medical therapy alone (control group). The primary effectiveness end-point was all hospitalizations for HF within 24 months of follow-up. The primary safety end-point was freedom from device-related complications at 12 months; the rate for this end-point was compared with a pre-specified objective performance goal of 88.0 %. Of the 614 patients who were enrolled in the trial, 302 were assigned to the device group and 312 to the control group. The annualized rate of all hospitalizations for HF within 24 months was 35.8 % per patient-year in the device group as compared with 67.9 % per patient-year in the control group (HR, 0.53; 95 % CI: 0.40 to 0.70; p < 0.001). The rate of freedom from device-related complications at 12 months was 96.6 % (lower 95 % confidence limit, 94.8 %; p < 0.001 for comparison with the performance goal). Death from any cause within 24 months occurred in 29.1 % of the patients in the device group as compared with 46.1 % in the control group (HR, 0.62; 95 % CI: 0.46 to 0.82; p < 0.001). The authors concluded that among patients with HF and moderate-to-severe or severe secondary MR who remained symptomatic despite the use of maximal doses of guideline-directed medical therapy, TMVR resulted in a lower rate of hospitalization for HF and lower all-cause mortality within 24 months of follow-up than medical therapy alone. The rate of freedom from device-related complications exceeded a pre-specified safety threshold.
Obadia and associates (2018) stated that in patients who have chronic HF with reduced LVEF, severe secondary MR is associated with a poor prognosis. Whether percutaneous mitral-valve repair improves clinical outcomes in this patient population is unknown. These investigators randomly assigned patients who had severe secondary MR (defined as an effective regurgitant orifice area of greater than 20 mm2 or a regurgitant volume of greater than 30 ml per beat), a LVEF between 15 % and 40 %, and symptomatic HF, in a 1:1 ratio, to undergo percutaneous mitral-valve repair in addition to receiving medical therapy (intervention group; 152 patients) or to receive medical therapy alone (control group; 152 patients). The primary efficacy outcome was a composite of death from any cause or unplanned hospitalization for HF at 12 months. At 12 months, the rate of the primary outcome was 54.6 % (83 of 152 patients) in the intervention group and 51.3 % (78 of 152 patients) in the control group (OR, 1.16; 95 % CI: 0.73 to 1.84; p = 0.53). The rate of death from any cause was 24.3 % (37 of 152 patients) in the intervention group and 22.4 % (34 of 152 patients) in the control group (HR, 1.11; 95 % CI: 0.69 to 1.77). The rate of unplanned hospitalization for HF was 48.7 % (74 of 152 patients) in the intervention group and 47.4 % (72 of 152 patients) in the control group (HR, 1.13; 95 % CI: 0.81 to 1.56). The authors concluded that among patients with severe secondary MR, the rate of death or unplanned hospitalization for HF at 1 year did not differ significantly between patients who underwent percutaneous mitral-valve repair in addition to receiving medical therapy and those who received medical therapy alone.
In an editorial that accompanied the afore-mention studies by Stone et al (2018) and Obadia et al (2018), Nishimura and Bonow (2018) stated that it is difficult to fully reconcile the differences in patient outcomes between these 2 trials. However, there are several important take-home messages. Secondary MR is a disease of the left ventricle. Management of LV dysfunction with guideline-directed medical therapy and, when indicated, bi-ventricular pacing, should be pursued before any intervention involving the mitral valve is considered. Edge-to-edge transcatheter mitral-valve repair can be performed in experienced centers with a high degree of success and can result in a sustained reduction in the severity of MR. Whether this translates into lower rates of death and hospitalization appears to depend, at least in part, on patient characteristics. These investigators hypothesized that the patients enrolled in the COAPT trial had HF symptoms that were truly refractory to medical therapy, with a greater degree of MR and less LV dilatation than the patients enrolled in the MITRA-FR trial. If this was so, the results of the 2 trials suggested a possible role for the device in treating patients with HF who have at least moderately severe MR only when all other options (including increases in medication dose and bi-ventricular pacing) have failed. Further investigation is needed to identify the patients who have the greatest chance of benefiting, which will most likely be determined by the relative contribution of the MR rather than the LV dysfunction to the patient’s clinical condition. Finally, even in the device group of each trial, approximately 1/3 to 1/2 of the patients either died or had continued HF symptoms that resulted in hospitalization at 1 year. Thus, as with any invasive technology, management decisions warrant detailed assessment of frailty and co-existing conditions that will potentially limit life-span and quality of life (QOL) independent of MR, with provider-patient discussions that provided the patient with realistic expectations for the likelihood of improved patient-centered outcomes.
In a meta-analysis, Giannini and co-workers (2018) compared survival outcomes of MitraClip with those of medical therapy in patients with functional MR. These investigators performed a comprehensive literature search of PubMed, Medline, and Google Scholar including studies evaluating MitraClip versus medical therapy with multi-variate adjustment and with greater than 80 % of patients with functional MR. Death from any cause was the primary end-point, while freedom from re-admission was the secondary end-point, evaluated with random effects. These analyses were performed at study level and at patient level including only functional MR when available, evaluating the effect of MitraClip in different subgroups according to age, ischemic etiology, presence of implantable cardioverter defibrillator/cardiac re-synchronization therapy, and LVEF and volumes. They identified 6 eligible observational studies including 2,121 subjects who were treated with MitraClip (n = 833) or conservative therapy (n = 1,288). Clinical follow-up was documented at a median of 400 days. At study-level analysis, MitraClip, when compared with medical therapy (p = 0.005), was associated with significant reduction of death (p = 0.002) and of re-admission due to cardiac disease. At patient-level analysis, including 344 patients, MitraClip confirmed robust survival benefit over medical therapy for all patients with functional MR and among the most important subgroups. The authors concluded that compared with conservative treatment, MitraClip was associated with a significant survival benefit. More importantly, this superiority was especially pronounced among patients with functional MR and across all the main subgroups.
Ailawadi and associates (2019) noted that secondary MR (SMR) occurs in the absence of organic mitral valve disease and may develop as the left ventricle dilates or remodels or as a result of leaflet tethering with impaired coaptation, most commonly from apical and lateral distraction of the sub-valvular apparatus, with late annular dilatation. The optimal therapy for SMR is unclear. These researchers evaluated the 1-year adjudicated outcomes of all patients with SMR undergoing the MitraClip procedure in the EVEREST II (Endovascular Valve Edge-to-Edge Repair Study) Investigational Device Exemption (IDE) program, which is comprised of the randomized clinical trial, the prospective High-Risk Registry, and the REALISM Continued Access Registry (Multicenter Study of the MitraClip System). Patients with 3+/4+ SMR enrolled in EVEREST II were stratified by non-high surgical risk (non-HR) and high surgical risk (HR) status (defined as Society of Thoracic Surgeons risk of mortality greater than or equal to 12 % or pre-defined risk factors). Clinical, echocardiographic, and functional outcomes at 1 year were evaluated. A total of 616 patients (482 HR, 134 non-HR; mean age of 73.3 ± 10.5 years; Society of Thoracic Surgeons risk, 10.2 ± 6.9 %) with SMR underwent the MitraClip procedure. At baseline, 80.5 % of patients were in NYHA class III/IV. Major AEs at 30 days included death (3.6 %), stroke (2.3 %), and renal failure (1.5 %). At discharge, 88.8 % had MR of less than or equal to 2+. At 1 year, there were 139 deaths, and the Kaplan-Meier estimate of freedom from mortality was 76.8 %. The majority of surviving patients (84.7 %) remained with MR of less than or equal to 2+ and NYHA class I/II (83.0 %). Kaplan-Meier survival at 1 year was 74.1 % in HR patients and 86.4 % in non-HR patients (p = 0.0175). At 1 year, both groups achieved comparable MR reduction (MR of less than or equal to 2+, 84.0 % versus 87.0 %) and improvement in left ventricular end-diastolic volume (-8.0 ml versus -12.7 ml), whereas NYHA class I/II was found in 80.1 % versus 91.8 % (p = 0.008) of HR and non-HR patients, respectively. In HR patients, the annualized rate of HF hospitalizations decreased from 0.68 to 0.46 in the 12 months before to 12 months after the procedure (p < 0.0001). The authors concluded that TMVR with the MitraClip in patients with secondary MR was associated with acceptable safety, reduction of MR severity, symptom improvement, and positive ventricular re-modeling.
Arnold and colleagues (2019) stated that in the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) Trial, TMVR led to reduced HF hospitalizations and improved survival in patients with symptomatic HF and 3+ to 4+ secondary MR on maximally-tolerated medical therapy. Given the advanced age and co-morbidities of these patients, improvement in health status is also an important treatment goal. These investigators reported on the health status outcomes of patients with HF and 3+ to 4+ secondary MR treated with TMVR versus standard care. The COAPT Trial randomized patients with HF and 3+ to 4+ secondary MR to TMVR (n = 302) or standard care (n = 312). Health status was assessed at baseline and at 1, 6, 12, and 24 months with the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the SF-36 health status survey. The primary health status end-point was the KCCQ overall summary score (KCCQ-OS; range of 0 to 100; higher = better; minimum clinically important difference = 5 points). At baseline, patients had substantially impaired health status (mean KCCQ-OS 52.4 ± 23.0). While health status was unchanged over time in the standard care arm, patients randomized to TMVR demonstrated substantial improvement in the KCCQ-OS at 1 month (mean between-group difference 15.9 points; 95 % CI: 12.3 to 19.5 points), with only slight attenuation of this benefit through 24 months (mean between-group difference 12.8 points; 95 % CI: 7.5 to 18.2 points). At 24 months, 36.4 % of TMVR patients were alive with a moderately large (greater than or equal to 10-point) improvement versus 16.6 % of standard care patients (p < 0.001), for a number needed to treat of 5.1 patients (95 % CI: 3.6 to 8.7 patients). TMVR patients also reported better generic health status at each time-point (24-month mean difference [MD] in SF-36 summary scores: physical 3.6 points; 95 % CI: 1.4 to 5.8 points; mental 3.6 points; 95 % CI: 0.8 to 6.4 points). The authors concluded that among patients with symptomatic HF and 3+ to 4+ secondary MR receiving maximally-tolerated medical therapy, edge-to-edge TMVR resulted in substantial early and sustained health status improvement compared with medical therapy alone.
On March 14, 2019, the FDA approved the MitraClip NTR/XTR Clip Delivery System for the treatment of secondary/functional MR in select HF patients who remain symptomatic despite guideline-directed medical therapy. The MitraClip therapy is the first commercially available transcatheter mitral valve intervention. Potential AEs from the device and implant procedure include atrial fibrillation, major bleeding, stroke, and death. The MitraClip is contraindicated in patients who cannot tolerate blood thinners during or after the procedure, who have endocarditis of the mitral valve, rheumatic mitral valve disease or evidence of blood clots in the heart or veins leading to the heart.
Trans-Apical Approach (e.g., the NeoChord System and the Permavalve) for Mitral Valve Repair
Dahle and associates (2017) stated that a transcatheter heart valve technique can be used in failed MV repairs with annuloplasty rings, deteriorated bioprostheses and in mitral annular calcification, all serving as “docking stations” for balloon-expandable valves. Specially designed transcatheter MV platforms are used in ongoing studies for native MR. These investigators presented their single-center experience with TMVI trans-apical (TA) approach procedures. A total of 11 patients were treated between 2011 and 2016. They had severe MR due to either failed repair annuloplasty rings (n = 6), failed bioprostheses (n = 2), or in the native valve (n = 3), all at high-risk for open MV surgery. Three different types of transcatheter valves were used: the SAPIEN XT/SAPIEN 3, the Lotus valve, and a Tendyne transcatheter mitral valve. Computed tomography reconstruction, echocardiography, 3D printing and bench tests were carried out in the pre-operative evaluation and procedural planning; TA approach access was performed via a left mini-thoracotomy. Implantation success was 100 % with no LVOT obstruction. Good hemodynamics and improved NYHA class were demonstrated in all patients; 1 patient died before 30 days due to sepsis; 1 patient had a valve thrombosis when switching from Coumadin to new oral anti-coagulant (OAC) and had a 2nd valve implanted into the 1st one as a “valve-in-valve” procedure. The authors concluded that the TA approach was a safe and straight-forward procedure for accessing the MV. These researchers stated that transcatheter aortic valve implantation prostheses may be used in redo surgery due to an already sufficient “docking station”. They noted that these specially designed new prostheses may be beneficial for addressing MR, but are still under evaluation.
Sarkar and colleagues (2017) stated that TMVR is a novel approach for treatment of severe MR. A number of TMVR devices are currently undergoing feasibility trials using both trans-septal (TS) and TA routes for device delivery. Overall experience worldwide was limited to fewer than 200 cases. At present, the 30-day mortality exceeded 30 % and was attributable to both patient- and device-related factors. TMVR has been successfully used to treat patients with degenerative mitral stenosis (DMS) as well as failed mitral bioprosthesis and MV repair using TMViV/ViR repair. These patients are currently treated with devices designed for TAVR. Multi-center registries have been initiated to collect outcomes data on patients currently undergoing TMViV/ViR and TMVR for DMS and have confirmed the feasibility of TMVR in these patients. However, the high peri-procedural and 30-day event rates underscored the need for further improvements in device design and multi-center, randomized studies are needed to delineate the role of these technologies in patients with MV disease.
Rogers and associates (2018) noted that TMVI is a relatively novel intervention that replaces the MV of individuals deemed too high-risk or unsuitable for open surgery. It is associated with a number of specific risks, including LVOT obstruction. These researchers presented the case of a 75-year old man who was unable to undergo redo surgical repair and had a number of risk factors for LVOT obstruction. To minimize this risk, these investigators deployed TMVI within the anterior MV leaflet resulting in mild MR post-operatively and no LVOT obstruction. The authors concluded that the long-term durability of this approach has yet to be determined, but they believed that this intervention adds to the armamentarium of the heart team.
Cheung and co-workers (2018) stated that TMVR may mature to become a therapeutic option for high-risk patients with severe MR, especially in patients at high or prohibitive surgical risk. MR patients with pre-existing aortic valve prosthesis have been excluded from most TMVR trials because of the potential risks of LVOT obstruction or interaction between the TMVR anchoring mechanism and the aortic prosthesis. These researchers described the procedural and short-term outcomes of TA TMVR with the Tiara valve in patients experiencing severe symptomatic MR with previous AVR. A total of 12 consecutive high surgical risk patients (11 men; mean age of 75 ± 6 years) with aortic valve prosthesis and severe MR underwent TMVR with the Tiara valve. Aortic valves were mechanical in 5 and biological in 7 patients, while 1 patient had previously undergone implantation of a transcatheter valve within a failed bioprosthetic surgical valve; 6 patients (50 %) had undergone redo surgical AVR. Clinical characteristics of the group included prior MVR in 2, prior coronary bypass grafting surgery in 5, chronic AF in 7, renal failure in 9, and pacemaker/cardiac resynchronization device in 9 patients. Mean STS score and EuroSCORE II were 10.5 ± 4.4 and 12.4 ± 3.7, respectively. Mean baseline LVEF was 35.5 ± 5.3 % (range of 30 % to 45 %). The Tiara valve was implanted uneventfully in all patients. Device migration or LVOT obstruction was not observed. No patient required conversion to open heart surgery or peri-procedural hemodynamic support. Procedural success was 100 % with no death, MI, stroke, major bleeding, or access site complications at 30 days; MR was eliminated in all 12 patients immediately following implantation. The authors concluded that TA MVR with the Tiara valve in high-risk patients with severe MR and aortic valve prostheses was technically feasible and could be performed safely.
Kiefer and associates (2018) stated that TA, beating heart, off-pump implantation of the NeoChord System for repair of MV prolapse is of increasing interest. These researchers examined the long-term results for MV repair using the NeoChord system (NeoChord, St. Louis Park, MN). A total of 6 patients underwent treatment for severe primary MR with the NeoChord DS1000 system as part of the initial device safety and feasibility of the Transapical Artificial Chordae Tendinae (TACT) Trial at the authors institution. The primary pathology in all patients was isolated posterior leaflet prolapse of the P2 or P3 segment, or both. Successful repair resulting in no or trace MR was achieved in 5 of 6 patients by implantation of 3 NeoChord under TEE guidance and normal left ventricular loading conditions; 1 patient underwent intra-operative conversion to an open MV replacement as a result of leaflet injury. The early post-operative course was uneventful in all remaining patients; 2 patients had to undergo re-operation for recurrent MR at 3 and 16 months post-operatively, respectively. The remaining 3 patients were followed-up for a period of 5 years. These patients were free of cardiac symptoms, and trans-thoracic examination showed trace or mild-to-moderate MR at 1-, 2-, and 5-year follow-up. A trend toward reverse re-modeling of the left ventricle with no increase in mitral annular dilatation over 5 years was observed. The authors concluded that in select patients, MV repair using the NeoChord system resulted in very good long-term results without recurrent prolapse, MR, or annular dilatation. This study reported on long-term results for only 3 patients, further investigation is needed to validate these preliminary findings.
Colli and colleagues (2018) stated that TA off-pump MV intervention with the NeoChord System is a novel, minimally invasive procedure for treatment of degenerative MR. These researchers applied control charts (CUSUM curves) to monitor the performance of NeoChord repair during the initial phase of its adoption. The first 112 consecutive patients who underwent NeoChord repair at the authors’ institution between November 2013 and March 2016 were included in the analysis. Mitral Valve Academic Research Consortium criteria for 1-year patient success was utilized to determine failed procedures. Control charts had pre-determined acceptable and unacceptable failure rates of 5 % and 15 %, respectively. The actual incidence of 1-year-patient failure was 11 % (12 of 112 cases), with a cluster of failures within the first 20 cases. The CUSUM analysis demonstrated an initial learning curve; however, the upper boundary (alarm line) was never crossed. The reassurance line was first crossed after 40 procedures and performance remained stable after 49 procedures. The authors concluded that NeoChord repair was a safe procedure, and the results were maintained through the 1-year follow-up. A relative high number of implants were needed to overcome the learning curve at the authors’ institution due to the concurrent development of patient selection criteria and the technical refinement of the procedure. These investigators stated that future studies are needed to evaluate the evolution of the learning curve after the wide adoption of the procedure across European and North American centers.
Hu and co-workers (2018) noted that TMViV and TMViR implantation for degenerated mitral bioprostheses and failed annuloplasty rings have recently emerged as therapeutic options for patients deemed unsuitable for repeat surgery. In a systematic review and meta-analysis, these investigators evaluated the data regarding the baseline characteristics and clinical outcomes of patients undergoing TMViV and TMViR procedures. A total of 245 patients (172 patients who underwent TMViV surgery and 73 patients who underwent TMViR surgery) were included in the study; 93.5 % of patients experienced successful TMViV or TMViR implantation. The mortality rates at discharge, 30 days, and 6 months were 5.7 %, 8.1 %, and 23.4 %, respectively. The TA access route was used in most procedures (55.2 %). The TA and TS access routes resulted in similar outcomes. No significant differences were observed in the short-term outcomes between the patients who developed mitral stenosis versus MR as the mode of failure. The authors concluded that TMViV and TMViR implantation for degenerated mitral bioprostheses and failed annuloplasty rings were safe and effective. Both procedures, via TA or TS access, could result in excellent short-term clinical outcomes in patients with mitral stenosis or MR, but long-term follow-up data are currently lacking to determine the durability of these procedures. These researchers stated that technical criteria, such as size selection and valve location, have not been established for TMVI; and larger clinical trials are needed to determine the durability and long‐term outcomes of TMViR and TMViV.
The authors stated that this study had 2 main drawbacks. First, this was an observational study and all patients’ data were obtained from published articles collected during a comprehensive and systematic search. Only a few articles reported long‐term follow‐up data; thus, evaluation of long‐term outcomes was not possible. Second, all studies included in this review lacked control groups.
Kurnicka and colleagues (2019) noted that minimally invasive techniques of MV repair have been used increasingly in recent years; and TA implantation of artificial chordae on a beating heart under 2D/3D TEE guidance with the NeoChord DS1000 device is a new surgical treatment of degenerative MR. These researchers examined early results of MV repair with the NeoChord DS1000 device in the first group of consecutive patients operated on in Poland. A total of 21 patients with severe MR due to posterior leaflet prolapse (81 % men; mean age of 60.7 ± 12.7 years) underwent MV repair with the NeoChord DS1000 system. There were 12 (57.1 %) patients with type A (an isolated central prolapse/flail), 8 (38.1 %) patients with type B (multi-segment disease/flail) and 1 (4.8 %) patient with type C (posterior/para-commisural area) MV prolapse. A flail leaflet was present in 12 (57.1 %) patients. The median number of neochords was 3 (2 to 6). These investigators assessed by echocardiography left-sided heart morphology and evaluated MR degree before and 6 months after chords implantation. Early procedural success was achieved in 100 % of patients. At the 6-month follow-up, non-significant MR (trace and mild) was detected in 17 (81.0 %) patients, while moderate MR was detected in 4 (19.0 %) patients; mean values of left-sided heart dimensions and volumes, mitral E and E' velocity of lateral MV annulus significantly decreased. The authors concluded that a novel procedure with the NeoChord DS1000 device was feasible in properly selected patients, and resulted in a significant reduction of MR degree and left ventricle and left atrium reverse re-modeling at the 6-month follow-up. Moreover, these researchers stated that in order to establish definitive safety and efficacy of this novel technique, a long-term follow-up study is needed.
The authors stated that this study had several drawbacks. First, this was an observational, single-center, non-randomized study that included a relatively small number of consecutive patients (n = 21) treated with the NeoChord DS1000 device. Second, the follow-up duration was short (6 months). Third, an echocardiographic limitation may be a difficult quantitative assessment of MR due to complex and eccentric jets. Thus, despite promising positive early experience, further investigation with a longer-term follow-up and a direct comparison with another MV surgery is needed.
Wrobel and co-workers (2019) noted that TA beating heart off-pump MV repair is a novel surgical technique for treating MR caused by degenerative flail/prolapse (DLP). These investigators presented early outcomes of a single-center experience with TA beating heart MV repair with the NeoChord System. A total of 37 patients with severe symptomatic MR were treated with the NeoChord technique between September 2015 and December 2018 (78 % men; mean age of 62.3 ±13.4 years). These researchers examined standard cardiac surgery peri-operative complications as well as those related to the NeoChord technique as well as early surgical success as defined by the reduction of MR to less than moderate by implantation of at least 2 neochordae. During this series, these researchers observed no hemodynamic instability due to bleeding or arrhythmia. There were no TA technique-related AEs such as a leaflet perforation or tear, a major native chord rupture, which would require implantation of a new chord, ventricular apex rupture, or left atrial perforation. There were no major AEs including death, stroke or acute MI; 9 (24 %) patients developed an episode of peri-operative AF. These researchers were able to conclude the operation in 98 % of their patients with less than moderate MR; 1 (2 %) patient had moderate MR at the conclusion of the operation. The authors concluded that TA off-pump MV repair with the NeoChord system was a safe, minimally invasive procedure, with few minor complications. In well-selected candidates it provided successful treatment of degenerative MR; results were anatomy-dependent, so pre-operative patient selection was crucial. These researchers stated that these initial findings showed safety and technique feasibility as well as the potential for restoration of the proper MV function in selected patients; long-term follow-up data are needed to optimally select patients and to determine the durability of this approach.
Furthermore, an UpToDate review on “Transcatheter mitral valve repair” (Armstrong and Foster, 2019) does not mention TA mitral valve repair as a therapeutic option.
Transcatheter Mitral Valve Annuloplasty
Siminiak and co-workers (2012) stated that functional MR (FMR) contributes to morbidity and mortality in patients with HF. The se researchers examined if percutaneous mitral annuloplasty could safely and effectively reduce FMR and yield durable long-term clinical benefit. The impact of mitral annuloplasty (Carillon Mitral Contour System) was evaluated in HF patients with at least moderate FMR. Patients in whom the device was placed then acutely recaptured for clinical reasons served as a comparator group. Quantitative measures of FMR, LV dimensions, NYHA class, 6MWD, and QOL were assessed in both groups up to 12 months. Safety and key functional data were assessed in the implanted cohort up to 24 months. A total of 36 patients received a permanent implant; 17 had the device recaptured. The 30-day major AE rate was 1.9 %. In contrast to the comparison group, the implanted cohort demonstrated significant reductions in FMR as represented by regurgitant volume [baseline 34.5 ± 11.5 ml to 17.4 ± 12.4 ml at 12 months (p < 0.001)]. There was a corresponding reduction in LV diastolic volume [baseline 208.5 ± 62.0 ml to 178.9 ± 48.0 ml at 12 months (p = 0.015)] and systolic volume [baseline 151.8 ± 57.1 ml to 120.7 ± 43.2 ml at 12 months (p = 0.015)], compared with progressive LV dilation in the comparator. The 6MWD markedly improved for the implanted patients by 102.5 ± 164 m at 12 months (p =0.014) and 131.9 ± 80 m at 24 months (p < 0.001). The authors concluded that percutaneous reduction of FMR using a coronary sinus approach was associated with reverse LV re-modelling; and significant clinical improvements persisted up to 24 months. These researchers stated that while this study provided a comparator group with which to evaluate the hemodynamic and clinical significance of treating FMR, the lack of a randomized and blinded comparator also remained the main drawback of this study; thus, a randomized trial comparing intervention with a medically managed control group is needed.
Taramasso and associates (2016) noted that direct mitral valve annuloplasty is a transcatheter MV repair approach that mimics the conventional surgical approach to treat functional MR. The Cardioband system (Valtech Cardio, Inc., Or-Yehuda, Israel) is delivered by a TS approach and the implant is performed on the atrial side of the mitral annulus under echocardiographic and fluoroscopic guidance using multiple anchor elements. The Cardioband system obtained CE mark approval in October 2015, and initial clinical experiences were promising with regard to feasibility, safety and efficacy.
In a prospective, single-arm, multi-center study, Arsalan and colleagues (2016) examined the acute intra-procedural effects of transcatheter direct mitral annuloplasty using the Cardioband device on 3D anatomy of the mitral annulus. Of the 45 patients with functional MR enrolled in this trial, 22 had complete pre- and post-implant 3D TEE images stored in native data format that allowed off-line 3D reconstruction. Images with the highest volume rate and best image quality were selected for analysis. Multiple measurements of annular geometry were compared from baseline to post-implant using paired t-tests with Bonferroni correction to account for multiple comparisons. The device was successfully implanted in all patients, and MR was reduced to moderate in 2 patients, mild in 17 patients, and trace in 3 patients following final device cinching. Compared with pre-procedural TEE, post-procedural TEE showed statistically significantly reductions in annular circumference (137 ± 15 versus 128 ± 17 mm; p = 0.042), inter-commissural distance (42.4 ± 4.3 versus 38.6 ± 4.4 mm; p = 0.029), antero-posterior distance (40.0 ± 5.4 versus 37.0 ± 5.7 mm; p = 0.025), and aortic-mitral angle (117 ± 8° versus 112 ± 8°; p = 0.032). The authors concluded that the findings of this study showed that transcatheter direct mitral annuloplasty with the Cardioband device resulted in acute re-modeling of the mitral annulus with successful reduction of functional MR.
Bail and colleagues (2017) provided a systematic review of currently available data regarding the percutaneous trans-coronary-venous mitral annuloplasty with the Carillon Mitral Contour System. The author carried out a systematic literature search using the common medical and scientific databases. The documented parameters included among others grade of MR, vena contracta (VC), effective regurgitant orifice area (EROA), 6MWT, NYHA-classification, and QOL at baseline, 30 days and in the long-term follow-up. The exact total number of successfully implantations with available data remained unclear because so many publications were either of the same institution or study group, or they presented overlapping results. Reduction of FMR was associated with significant inverse LV) re-modeling, improvement in 6MWT, QOL and NYHA-class during the 12-month follow-up. In almost 50 % of the enrolled subjects, the Carillon System could not be implanted or had to be removed due to coronary compromises; and AE rates ranged between 2.8 to 39 %. The author concluded that results with regard to reduction of MR and inverse LV re-modeling had been remarkable. Indication and selection criteria for suitable patients, the expected complications, and the long-term results with regard to survival and QOL still remained unclear. The available results did not establish superiority of the Carillon Mitral Contour System and supported the lack of a clear benefit. This investigator stated that the approach with the Carillon Mitral Contour System should be limited to participants of prospective and randomized trials.
Patterson and associates (2019) noted that the incidence of MR is approximately 1.7 % in the developed world, and this increases to more than 10 % in patients aged over 75 years. Secondary MR (also known as FMR) is defined as poor leaflet coaptation and tethering secondary to either ischemic or non-ischemic LV dysfunction and dilatation; and FMR is more common than degenerative (or primary) MR and is associated with significantly worse outcomes in patients with HF, post-MI and following coronary artery bypass graft (CABG) surgery. Patients with severe degenerative MR have excellent outcomes with surgical repair, however the benefits of surgery in FMR are less clear. Although annuloplasty is associated with a lower operative mortality compared to replacement, the recurrence rate of MR is high in patients with FMR and neither surgical repair or replacement have been shown to reduce hospitalization or death in FMR. Furthermore, nearly 50 % of patients are deemed too high risk for surgery and therefore most patients are managed conservatively and there remains an unmet clinical need. The authors concluded that TMVI is an emerging alternative for those at high surgical risk. These researchers stated that the objective of transcatheter mitral repair is to balance the increase in peri-procedural safety (reduced risk) with a sufficient reduction in MR for it to be effective. Annuloplasty, both direct and indirect, leaflet repair and chordal repair are all viable options based upon well-established surgical techniques and a combination of these approaches may provide the most effective resolution of MR. Current predictors of MR recurrence following surgical repair include baseline LV end-diastolic diameter of greater than 65 mm, posterior mitral leaflet angle of greater than 45 degrees and mitral coaptation depth of greater than 10 mm. However, the relevance of these for the success of percutaneous interventions remains unknown. Furthermore, there are numerous challenges to effectively treat MR, including anatomical variation and the complexity of the MV apparatus, imaging constraints and currently available technologies. They noted that there remain important considerations when determining suitability for percutaneous MV interventions, including appropriate patient selection (moderate versus severe MR, normal versus impaired LV function) and choice of device based on anatomical characteristics. These researchers stated that although further work is needed to ensure safety and durability of these devices, increased understanding of the true incidence, natural history and pathophysiology of MR, will enable better targeted device therapy in this cohort.
Furthermore, an UpToDate review on “Transcatheter mitral valve repair” (Armstrong and Foster, 2019) states that “While a number of technologies are in clinical development, an edge-to-edge leaflet repair device (the MitraClip) is currently the only US Food and Drug Administration (FDA) approved device for TMVR. The MitraClip, as well as the CARILLON mitral annuloplasty device, has CE Mark approval … Investigational devices for mitral valve repair work by a number of mechanisms include the following: Altering the geometry of the mitral valve annulus via direct or indirect annuloplasty to reduce the severity of MR. The CARILLON Mitral Contour system implants a nitinol device in the coronary sinus that indirectly cinches the mitral annulus; chordal replacement …”.
MitraClip for Hemodynamically Unstable Individuals with Cardiogenic Shock or Refractory Pulmonary Edema and Concomitant Moderate-to-Severe Mitral Regurgitation
Flint and co-workers (2019) stated that patients with severe MR and cardiogenic shock (CS) are typically too high risk for immediate surgery; however, PMVR may be reasonable in select patients. In a single-center, case-series study, these investigators described characteristics and outcomes of patients who underwent PMVR with and without CS. They carried out chart review of all patients who underwent PMVR from November 2013 to October 2018; CS was defined as dependence on an intravenous (IV) inotrope, IV afterload reduction, and/or temporary mechanical circulatory support immediately preceding PMVR. A total of 135 patients were included in this analysis; mean age was 80 ± 12 years, 56 (41 %) were women; and 12 (8.9 %) had shock. All patients had 3+ or 4+ MR at baseline. Post-procedure, all CS patients had 2+ or less MR; 2 (17 %) CS patients and 4 (3 %) non-CS patients died within 30 days of PMVR (p = 0.03); 6 (50 %) CS patients had resolution of shock and discharged home (primary outcome); 5 CS patients had acute MI, 4 of whom met the primary outcome; 4 CS patients had chronic MR (more than 21 days), 3 of whom did not meet the primary outcome. Overall, follow-up time for mortality was median (IQR) 198 (42 to 379) days; CS patients who survived to 30 days post-procedure had significantly shorter time from diagnosis of MR to PMVR compared to those who died (35 ± 68 versus 374 ± 111 days; p = 0.0001). The authors concluded that PMVR may be reasonable in CS patients with acute MR and/or acute MI. These researchers stated that the findings of this case-series study should guide larger studies designed to improve selection of CS patients for PMVR.
Martinez-Gomez and colleagues (2021) noted that very few data exist on PMVR in unstable patients with concomitant moderate-to-severe MR. In a systematic review, these investigators examined baseline characteristics, management and clinical outcomes of critically ill patients undergoing PMVR with the MitraClip device. They reviewed the published data on MitraClip from its first use in 2003 to December 2020. Studies referring to critically ill patients in CS or acute refractory pulmonary edema (PE) were included. A total of 40 publications including 254 patients with significant MR (grade-4 in 91 %) were included. Mean age of subjects was 70 ± 12 years with mean Euroscore II and STS of 21 ± 13 and 20.5 ± 16, respectively. Clinical presentation was with CS and acute MI in 72.8 % and 60.0 % of patients, respectively. Device success was achieved in 238 (93.7 %) patients with a significant reduction in MR (grade less than or equal to 2 in 91.8 %, p < 0.001). The median weaning time from the procedure, to discontinuation of mechanical circulatory or respiratory support, was 2 days (IQR 1 to 4), with an in-hospital mortality and non-fatal complication rate of 12.6 % and 9.1 %, respectively. Kaplan-Meier curves estimated an overall mortality rate of 39.1 % at 12-month follow-up, with persistent reduction in MR severity for survivors (grade less than or equal to 2 in 81.3 %) and 1 case of mitral valve re-intervention. The authors concluded that PMVR with the MitraClip device is a technically feasible and potentially viable management option in high-risk patients with CS or refractory PE and concomitant moderate-to-severe MR. Moreover, these researchers stated that prospective trials are needed to confirm these findings and determine the value of the MitraClip device in hemodynamically unstable patients.
Falasconi and associates (2021) stated that severe MR in the setting of CS is associated with 3 times higher risk of 1-year mortality. In refractory CS, edge-to-edge PMVR can be a potential therapeutic option. In a retrospective, multi-center, observational study, these researchers examined the impact of edge-to-edge PMVR on short- and mid-term clinical outcomes in patients with CS and severe MR. This trial included consecutive patients with refractory CS and concomitant severe MR treated with the MitraClip device. CS was defined according to the criteria used in the SHOCK Trial and procedural success according to Mitral Valve Academic Research Consortium (MVARC) criteria. The 30-day and 6-month mortality were the primary and secondary endpoints, respectively. A total of 31 patients (median age of 73 years [IQR 66 to 78], 25.8 % women), STS mortality score 37.9 [IQR 30.4 to 42.4]), with CS and concomitant severe MR treated with edge-to-edge PMVR were retrospectively enrolled. Procedural success was 87.1 %; 30-day and 6-month survival rates were 78.4 % and 45.2 %, respectively. Univariate Cox Regression Model analysis showed that procedural success was a predictor of both 30-day (hazard ratio = 0.12, 95 % CI: 0.03 to 0.55, p < 0.01) and 6-month survival (hazard ratio = 0.22, 95 % CI: 0.06 to 0.84, p = 0.027). The authors concluded that edge-to-edge PMVR in patients with CS and concomitant severe MR was associated with good procedural safety and success with acceptable short- and mid-term survival rates. It could be considered a bailout option in this setting of patients. The main drawbacks of this study were its retrospective design, small sample size (n = 31), and lack of long-term survival data. These preliminary findings need to be validated by well-designed studies.
Tang et al (2021) noted that edge-to-edge transcatheter mitral valve repair as salvage therapy in high surgical risk patients with severe MR presenting with CS has been described in small case-series studies; however, large clinical results have not been reported. In a retrospective, national database analysis, these researchers examined outcomes of transcatheter mitral valve repair with the MitraClip device in patients with MR and CS. From January 2014 to March 2019, they identified hospitalizations for CS in patients with mitral valve disease using data from Centers for Medicare and Medicaid Services (CMS). Those with a prior surgical or percutaneous mitral valve intervention were excluded. These researchers compared survival between patients who underwent the MitraClip implantation during the index hospitalization and those who did not using propensity-matched analysis. The analysis included 38,166 patients (mean age of 71 ± 11 years, 41.6 % women) of whom 622 (1.6 %) underwent the MitraClip implantation. The MitraClip device was increasingly used during CS hospitalizations over the study period (p < 0.001). After matching, patients receiving the MitraClip device had significantly lower in-hospital mortality (OR, 0.6; 95 % CI: 0.47 to 0.77; p < 0.001) and 1-year mortality (hazard ratio, 0.76; 95 % CI: 0.65 to 0.88; p < 0.001) compared with those without the MitraClip device. The survival benefit associated with the MitraClip device was consistent across subgroups of interest, with the exception of patients requiring acute mechanical circulatory support or hemodialysis at index. The authors concluded that in patients with MR presenting with CS, use of the MitraClip device was increasing and associated with greater in-hospital and 1-year survival. Moreover, these researchers stated that further study is needed to optimize procedural timing and patient selection associated with the improved outcomes, especially in those patients requiring acute mechanical circulatory support and hemodialysis.
The authors stated that this study had several drawbacks. First, these data were derived from an administrative claims database, which lacked granular clinical details such as MR etiology and severity of CS, as well as MitraClip procedural characteristics such as amount of residual MR. However, given the challenges of informed consent and randomization in critically ill patients, administrative claims data provided a viable approach to study the real‐world use of the MitraClip device in a large nationwide cohort of patients with CS. Second, outcomes were not centrally adjudicated in this retrospective observational cohort study; however, the primary endpoint of all‐cause mortality has been widely validated in CMS claims data and has been shown to demonstrate close concordance with trial‐adjudicated mortality. Third, although these investigators attempted to control for all available variables in the propensity matching, as the study was observational residual confounding may be present. More importantly, the clinical decision to carry out a MitraClip procedure on a patient in CS could not be elucidated in a retrospective observational cohort. While the authors’ second sensitivity analysis aimed to account for potential immortal time bias in the matched cohort, it was plausible that patients selected to receive the MitraClip device were those more likely to survive long‐term. Finally, the reported p values were at a nominal alpha level without controlling for the potential inflation of the Type I error rate.
Jung, et al. (2021) conducted a multicenter, collaborative, patient-level analysis to evaluate the outcome of transcatheter mitral valve repair (TMVr) in patients with cardiogenic shock and significant mitral regurgitation (MR). Patients with cardiogenic shock and moderate to severe (3+) or severe (4+) MR who were not surgical candidates were treated with TMVr. The primary outcome was in-hospital mortality. Secondary outcomes included 90-day mortality, heart failure (HF) hospitalization, and the combined event rate of 90-day mortality and HF hospitalization following dichotomization by TMVr device success. Between January 2011 and February 2019, 141 patients across 14 institutions met the inclusion criteria. In-hospital mortality occurred in 22 patients (15.6%), at 90 days in 38 patients (29.5%), and at one year in 55 patients (42.6%). Median length of hospital stay following TMVr was 10 days (interquartile range: 6 to 20 days). HF hospitalization occurred in 26 patients (18.4%) at a median of 73 days (interquartile range: 26 to 546 days). When
stratified by TMVr procedural results, successful TMVr reduced rates of in-hospital mortality (hazard ratio [HR]: 0.36; 95% confidence interval [CI]: 0.13 to 0.98; p = 0.04), 90-day mortality (HR: 0.36; 95% CI: 0.16 to 0.78; p = 0.01), and the composite of 90-day mortality and HF hospitalization (HR: 0.41; 95% CI: 0.19 to 0.90; p = 0.03). The investigators concluded that TMVr may improve short- and intermediate-term mortality in high-risk patients with cardiogenic shock and moderate to severe MR. Randomized studies are needed to definitively establish MR as a therapeutic target in patients with cardiogenic shock.
In an editorial accompanying Jung, et al. (2021), Lurz and Besler (2021) concluded "although we are eagerly waiting for novel therapeutic approaches to improve the often dramatic clinical course and poor prognosis of patients in CS, we need to accept that it is too early to draw any firm conclusion on a potential benefit of transcatheter treatment of MR in CS. For sure, the findings by Jung et al. are encouraging and should stimulate more intense research in the field, but there is still a long way to go."
Percutaneous Closure of Paravalvular Leak of Mitral Valve
Guidelines from the American College of Cardiology (2020) state "Bioprosthetic valve dysfunction may occur because of either degeneration of the valve leaflets or valve thrombosis. Catheter-based treatment for prosthetic valve dysfunction is reasonable in selected patients for bioprosthetic leaflet degeneration or paravalvular leak in the absence of active infection."
Guidelines from the European Association of Cardiology (Vahanian, et al., 2021) state that "Transcatheter closure of a paravalvular leak is feasible, but experience is limited and there is presently no conclusive evidence to show consistent efficacy. Transcatheter closure of paravalvular leaks should be considered for anatomically suitable paravalvular leaks in candidates selected by the Heart Team."
Millan, et al. (2015) reported on a systematic evidence review and metaanalysis of transcatheter closure of paravalvular leaks. The investigators identified 12 clinical studies that compared successful and failed transcatheter PVL reductions in a total of 362 patients. A Bayesian hierarchical meta-analysis was performed using cardiac mortality as a primary end point. The combined occurrence of improvement in New York Heart Association functional class or hemolytic anemia and the need for repeat surgery, were used as secondary end points. The investigators reported that a successful transcatheter PVL reduction was associated with a lower cardiac mortality rate (odds ratio [OR], 0.08; 95% credible interval [CrI], 0.01-0.90) and with a superior improvement in functional class or hemolytic anemia, compared with a failed intervention (OR, 9.95; 95% CrI, 2.10-66.73). Fewer repeat surgeries were also observed after successful procedures (OR, 0.08; 95% CrI, 0.01-0.40). The investigators concluded that a successful transcatheter PVL reduction is associated with reduced all-cause mortality and improved functional class in patients deemed unsuitable for surgical correction.
Transcatheter Tricuspid Valve Repair or Replacement
Tricuspid valve repair or replacement via a transcatheter approach, devices for transcatheter tricuspid valve repair (TTVR) and replacement are in early stages of development for the treatment of TR. There are early studies evaluating use of 2 TTVR devices, the TriClip Delivery System, essentially the same clip delivery used for the mitral valve and the Cardioband Valve System delivery via transfemoral approach (TRI-REPAIR Study). Individual selection criteria for percutaneous tricuspid valve replacement are based on limited data. Currently there are no FDA-approved devices to be delivered in the tricuspid position.
Nickenig and associates (2017) noted that current surgical and medical therapeutic options for severe TR are limited, and additional interventional approaches are needed. In an observational study, these researchers examined the safety and feasibility of transcatheter repair of chronic severe TR with the MitraClip system. In addition, the effects on clinical symptoms were assessed. Patients with HF symptoms and severe TR on optimal medical treatment were treated with the MitraClip system. Safety, defined as peri-procedural AEs such as death, MI, stroke, or cardiac tamponade, and feasibility, defined as successful implantation of 1 or more MitraClip devices and reduction of TR by at least 1 grade, were evaluated before discharge and after 30 days. In addition, functional outcome, defined as changes in NYHA class and 6MWD, were assessed. These researchers included 64 consecutive patients (mean age of 76.6 ± 10 years) deemed unsuitable for surgery who underwent MitraClip treatment for chronic, severe TR for compassionate use. Functional TR was present in 88 %; in addition, 22 patients were also treated with the MitraClip system for MR as a combined procedure. The degree of TR was severe or massive in 88 % of patients before the procedure. The MitraClip device was successfully implanted in the tricuspid valve in 97 % of the cases. After the procedure, TR was reduced by at least 1 grade in 91 % of the patients, thereof 4 % that were reduced from massive to severe. In 13 % of patients, TR remained severe after the procedure. Significant reductions in effective regurgitant orifice area (0.9 ± 0.3cm2 versus 0.4 ± 0.2cm2; p < 0.001), vena contracta width (1.1 ± 0.5 cm versus 0.6 ± 0.3 cm; p = 0.001), and regurgitant volume (57.2 ± 12.8 ml/beat versus 30.8 ± 6.9 ml/beat; p < 0.001) were observed. No intra-procedural deaths, cardiac tamponade, emergency surgery, stroke, MI, or major vascular complications occurred.; 3 (5 %) in-hospital deaths occurred; NYHA class was significantly improved (p < 0.001), and 6MWD increased significantly (165.9 ± 102.5 m versus 193.5 ± 115.9 m; p = 0.007). The authors concluded that transcatheter treatment of TR with the MitraClip system appeared to be safe and feasible in this cohort of pre-selected patients. Initial efficacy analysis showed encouraging reduction of TR, which may potentially resulted in improved clinical outcomes. These researchers stated that because anatomic and echocardiographic feasibility criteria were not well-defined, further research is needed to determine which patients may benefit most from interventional TR repair.
The authors stated that this study had several drawbacks. This was an observational, exploratory study on feasibility of tricuspid valve clipping. This study was not a randomized trial with core laboratory adjudication and pre-defined inclusion criteria. This trial comprised no medically treated control group to compare with. In addition, follow-up was limited, and a relevant amount of follow-up data could not be obtained. Thus, it was unclear whether the presented treatment modality was able to induce sustained clinical benefit or improve prognosis in this severely diseased patients. This task would be addressed in further studies.
Lauten and co-workers (2018) stated that transcatheter caval valve implantation is under evaluation as a therapeutic option for inoperable patients with severe TR. The procedure entailes the catheter-based implantation of bioprosthetic valves in the inferior vena cava and superior vena cava to treat symptoms associated with TR. This study is the first to examine the feasibility, safety, and efficacy of this interventional concept. A total of 25 patients (mean age of 73.9 ± 7.6 years; women, 52.0 %) with severe symptomatic TR despite optimal medical treatment deemed unsuitable for surgery were treated with caval valve implantation under a compassionate clinical use program. Technical feasibility defined as procedural success, hemodynamic effect defined as venous pressure reduction, and safety defined as peri-procedural AEs were evaluated, with clinical follow-up at discharge and up to 12 months. The functional impact was evaluated by assessment of NYHA class at the time of hospital discharge. The total number of valves implanted in the caval position was 31. Patients were treated with single (inferior vena cava-only; n = 19; 76.0 %) or bi-caval valve implantation (inferior vena cava + superior vena cava; n = 6; 24.0 %). Either balloon-expandable valves (Sapien XT/3: n = 18; 72.0 %) or self-expandable valves (TricValve: n = 6; 24.0 %; Directflow: n = 1; 4.0 %) were used. Procedural success was achieved in 96 % (n = 24). Early and late valve migration requiring surgical intervention occurred in 1 patient each; 30-day and in-hospital mortality were 8 % (2 of 25) and 16 % (4 of 25). Causes of in-hospital mortality included respiratory (n = 1) or multiple organ failure (n = 3) and were not linked to the procedure. Mean overall survival in the study cohort was 316 ± 453 days (14 to 1,540 days). The authors concluded that caval valve implantation for the treatment of severe TR and advanced right ventricular failure was associated with a high procedural success rate and appeared safe and feasible in an excessive-risk cohort. The study demonstrated hemodynamic efficacy with consistent elimination of TR-associated venous backflow and initial clinical improvement. These findings encouraged further trials to determine which patients benefit most from this interventional approach. Moreover, these researchers stated that further studies, including randomized trials, are needed to determine which patients benefit most from interventional treatment and to adjust criteria for clinical and anatomic patient selection for different subgroups.
The authors stated that this exploratory study presented observational data on feasibility of CAVI and summarized the current experience with this therapeutic approach. The number of patients was limited, patients were not randomized, and data were acquired without core laboratory adjudication. Because of its exclusive compassionate use, the present clinical experience is currently limited to the most severely ill subgroup of patients with limited clinical follow-up. Thus, it remained unclear whether the presented treatment modality is able to induce a sustained clinical improvement or improve patient prognosis.
Nickenig and co-workers (2019) stated that the aim of the TRILUMINATE trial was to examine the safety and effectiveness of TriClip, a minimally invasive transcatheter tricuspid valve repair system, for reducing TR. The TRILUMINATE trial is a prospective, multi-center, single-arm study in 21 sites in Europe and the U.S. Patients with moderate or greater TR, NYHA class II or higher, and who were adequately treated per applicable standards were eligible for enrolment. Patients were excluded if they had systolic pulmonary artery pressure of more than 60 mm Hg, a previous tricuspid valve procedure, or a cardiovascular implantable electronic device that would inhibit TriClip placement. Participants were treated using a clip-based edge-to-edge repair technique with the TriClip tricuspid valve repair system. Tricuspid regurgitation was graded using a 5-class grading scheme (mild, moderate, severe, massive, and torrential) that expanded on the standard American Society of Echocardiography grading scheme. The primary efficacy end-point was a reduction in TR severity by at least 1 grade at 30 days post-procedure, with a performance goal of 35 %, analyzed in all patients who had an attempted tricuspid valve repair procedure upon femoral vein puncture. The primary safety end-point was a composite of major AEs at 6 months, with a performance goal of 39 %. Patients were excluded from the primary safety analysis if they did not reach 6-month follow-up and did not have a major AE during previous follow-ups. Between August 1, 2017, and November 29, 2018, a total of 85 patients (mean age of 77.8 years [SD 7.9]; 56 [66 %] women) were enrolled and underwent successful TriClip implantation. Tricuspid regurgitation severity was reduced by at least 1 grade at 30 days in 71 (86 %) of 83 patients who had available echocardiogram data and imaging. The 1-sided lower 97.5 % confidence limit was 76 %, which was greater than the pre-specified performance goal of 35 % (p < 0.0001). One patient withdrew before 6-month follow-up without having had a major AE and was excluded from analysis of the primary safety end-point. At 6 months, 3 (4 %) of 84 patients experienced a major AE, which was less than the pre-specified performance goal of 39 % (p < 0·0001). Single leaflet attachment occurred in 5 (7 %) of 72 patients. No peri-procedural deaths, conversions to surgery, device embolization, MI, or strokes occurred. At 6 months, all-cause mortality had occurred in 4 (5 %) of 84 patients. The authors concluded that the TriClip system appeared to be safe and effective in reducing TR by at least 1 grade. This reduction could translate to significant clinical improvement at 6 months post-procedure.
Taramasso and colleagues (2019) developed a large, prospective international registry to examine the initial clinical applications of transcatheter tricuspid valve intervention (TTVI) with different devices. The TriValve Registry included 312 high-risk patients with severe TR (76.4 ± 8.5 years of age; 57 % women; EuroSCORE II 9 ± 8 %) at 18 centers. Interventions included repair at the level of the leaflets (MitraClip, Abbott Vascular, Santa Clara, CA; PASCAL Edwards Lifesciences, Irvine, CA), annulus (Cardioband, Edwards Lifesciences; TriCinch, 4tech, Galway, Ireland; Trialign, Mitraling, Tewksbury, MA), or coaptation (FORMA, Edwards Lifesciences) and replacement (Caval Implants, NaviGate, NaviGate Cardiac Structures, Lake Forest, CA). Clinical outcomes were prospectively determined during mid-term follow-up. A total of 108 patients (34.6 %) had prior left heart valve intervention (84 surgical and 24 transcatheter, respectively). TR etiology was functional in 93 %, and mean annular diameter was 46.9 ± 9 mm. In 75 % of patients the regurgitant jet was central (vena contracta 1.1 ± 0.5; effective regurgitant orifice area 0.78 ± 0.6 cm2). Pre-procedural systolic pulmonary artery pressure (PAP) was 41 ± 14.8 mm Hg. Implanted devices included: MitraClip in 210 cases, Trialign in 18 cases, TriCinch 1st generation in 14 cases, caval valve implantation in 30 cases, FORMA in 24 cases, Cardioband in 13 cases, NaviGate in 6 cases, and PASCAL in 1. In 64 % of the cases, TTVI was performed as a stand-alone procedure. Procedural success (defined as the device successfully implanted and residual TR of less than or equal to 2+) was 72.8 %. Greater coaptation depth (OR: 24.1; p = 0.002) was an independent predictor of reduced device success; 30-day mortality was 3.6 % and was significantly lower among patients with procedural success (1.9 % versus 6.9 %; p = 0.04); actuarial survival at 1.5 years was 82.8 ± 4 % and was significantly higher among patients who had procedural success achieved. The authors concluded that TTVI was feasible with different technologies, had a reasonable overall procedural success rate, and was associated with low mortality and significant clinical improvement. Mid-term survival was favorable in this high-risk population. Greater coaptation depth was associated with reduced procedural success, which was an independent predictor of mortality.
The authors stated that this study had several drawbacks. First, it was a prospective non-randomized study, without a control group. The number of patients with severe TR who were not treated during the same period was not available. Second, this was a real-world registry reporting the clinical practice in different centers and countries; thus, echocardiographic and clinical outcomes had been reported by the different sites and investigators, without core laboratory adjudication. For the same reason, the modalities of follow-up were different within the different centers. Third, due to the different number of patients treated with the different devices, any direct comparisons among the different devices would be inappropriate. Moreover, definitions of procedural success and outcomes had been established by the investigators, because they had not been standardized yet. These researchers stated that long-term outcomes and better patient selection are needed to better understand the clinical role of transcatheter tricuspid valve intervention.
In an observational, first-in-human trial, Fam and associates (2019) examined the feasibility and safety of the PASCAL transcatheter valve repair system and its impact on short-term clinical outcomes in patients with severe TR. A total of 28 patients with severe TR were treated with the PASCAL system in a compassionate use experience at 6 sites. All patients had HF due to severe TR and were deemed at high surgical risk by institutional heart teams. The primary outcome was procedural success, defined as the implantation of at least 1 device with post-procedural TR grade of less than or equal to 2+, without mortality or conversion to surgery. All patients (mean age of 78 ± 6 years, 54 % women) were at high surgical risk (mean European System for Cardiac Operative Risk Evaluation II score 6.2 ± 5.2 %). TR etiology was functional in 92 %, with mean tricuspid annular diameter of 49.5 ± 6 mm and mean coaptation gap of 6.9 ± 3 mm. Procedural success was 86 %, with 1.4 ± 0.6 devices implanted per patient. There were no intra-procedural complications. At 30-day follow-up, mortality was 7.1 %, 88 % of patients were in NYHA functional class I or II, with TR grade of less than or equal to 2+ in 85 %. There were 2 single-leaflet device attachments, which were managed conservatively; 6MWD improved from 240 m (IQR: 172 to 337 m) to 335 m (IQR: 251 to 385 m) (p < 0.001). The authors concluded that this first-in-human experience evaluating transcatheter tricuspid repair with the PASCAL system showed high procedural success, acceptable safety, and significant clinical improvement. Moreover, these researchers stated that larger prospective studies with long-term follow-up are needed to confirm these initial promising results and further define the impact of PASCAL tricuspid repair on clinical outcomes.
Furthermore, an UpToDate review on “Management and prognosis of tricuspid regurgitation” (Otto, 2020) states that “Transcatheter tricuspid valve repair or replacement -- Studies are in progress on the possibility of treating TR with transcatheter approaches similar to those used for mitral valve disease with either a clip on the valve leaflets or an annular remodeling device. However, these approaches are in preclinical or early clinical trials and are not available for general clinical use and require advanced imaging modalities for patient selection and procedural guidance”.
Veen and colleagues (2020) provided a contemporary overview of outcomes after TV surgery for functional TR. The literature was systematically searched for papers published between January 2005 and December 2017 reporting on clinical/echocardiographic outcomes following TV surgery for functional TR. A random effects meta-analysis was conducted for outcome variables, and late outcomes were visualized by pooled Kaplan-Meier curves. Subgroup analyses were performed for studies with a within-study comparison of suture versus ring repair and flexible versus rigid ring repair. A total of 87 publications were included, entailing 13,184 patients (mean age of 62.1 ± 11.8 years, 55 % women). A mitral valve procedure was performed in 92 % of patients. Pooled mean follow-up was 4.0 ± 2.8 years. Pooled early mortality was 3.9 % (95 % CI: 3.2 to 4.6), and late mortality rate was 2.7 %/year (95 % CI: 2.0 to 3.5), of which approximately 50 % was cardiac-related 1.2 %/year (95 % CI: 0.8 to 1.9). Pooled risk of early moderate-to-severe TR at discharge was 9.4 % (95 % CI: 7.0 to 12.1). Late moderate-to-severe TR rate after discharge was 1.9 %/year (95 % CI: 1.0 to 3.5). Late re-intervention rate was 0.3 %/year (95 % CI: 0.2 to 0.4). Mortality and overall (early and late) TR rate were comparable between suture versus ring annuloplasty (14 studies), whereas overall TR rate was higher after flexible ring versus rigid ring annuloplasty (6 studies) (7.5 %/year versus 3.9 %/year, p = 0.002). The authors concluded that the findings of this study showed that patients undergoing surgery for functional TR (FTR) had an acceptable early and late mortality. However, TR remained prevalent following surgery. These investigators stated that the findings of this study could be used to inform patients and clinicians regarding the expected outcome following surgery for FTR and could serve as a benchmark for the performance of emerging transcatheter TV interventions.
Zaccone and associates (2020) stated that TR, either isolated or associated with left-valve disease, has a strong impact on outcome. Surgical treatment of TR has increased in recent years, but in-hospital mortality remains high probably due to the risk profile of the recipients. As a consequence, most of the patients with severe TR, especially if isolated, remain untreated. Transcatheter TV interventions are rapidly spreading as alternative options to open-heart procedures fulfilling this important unmet need. Although patient selection and timing of intervention are unclear, many devices have been developed in recent years for both repair and replacement of TV. Repair tools can be targeted to leaflets or annulus; replacement devices include heterotopic and orthotropic systems.
Kolte and Elmariah (2020) noted that TR is a common valvular heart disease affecting more than 1.6 million people in the U.S. and more than 70 million people worldwide. The age- and sex-adjusted prevalence of more than or equal to moderate TR in the U.S. is estimated to be 0.55 %; 1-year mortality increases with increasing severity of TR. Yet, the majority of patients with severe TR are managed medically in the absence of another indication for cardiac surgery, and isolated TV surgery remains infrequent. To address this unmet clinical need, various transcatheter TV therapies are now being developed as an alternative to surgery in extreme- and high-risk patients with severe FTR. Transcatheter TV repair devices are aimed at improving leaflet coaptation either directly by bringing the leaflets together (leaflet/coaptation devices) or indirectly by repairing the dilated annulus (annuloplasty devices). These researchers described the current state of transcatheter TV repair therapies and summarized the available data on the safety and efficacy of various devices. Procedural and clinical outcomes of transcatheter TV repair therapies are expected to improve in the coming years with technological advancement, newer device iterations, and increased experience in this field. The authors concluded that appropriate patient selection, optimal timing of intervention, and evaluation of long-term outcomes and device durability will be key in ongoing and future studies.
Chang and co-workers (2020) stated that TR is a frequent and complex problem, commonly combined with left-sided heart disease, such as MR. Significant TR is associated with increased mortality if left untreated or recurrent after therapy. Tricuspid regurgitation was historically often disregarded and remained under-treated. Surgery is currently the only Class I guideline recommended therapy for TR, in the form of annuloplasty, leaflet repair, or valve replacement. As growing experience of transcatheter therapy in structural heart disease, many dedicated transcatheter tricuspid repair or replacement devices, which mimic well-established surgical techniques, are currently under development. Nevertheless, many aspects of TR are little understood, including the disease process, surgical or interventional risk stratification, and predictors of successful therapy. The optimal treatment timing and the choice of proper surgical or interventional technique for significant TR remain to be elucidated. In this context, the authors aimed to highlight the current evidence, underline major controversial issues in this field and present a future roadmap for TR therapy.
Otto et al (2020) noted that percutaneous tricuspid repair using the edge-to-edge technique is a novel therapeutic option. More data are needed to better understand which aspects predict a favorable outcome. In an observational, single-center study, a total of 20 high-risk patients (age of 78.6 ± 8.3 years, EuroScore II 9.1 ± 7.7 %, STS score 8.8 ± 4.3) with severe symptomatic TR were treated with the MitraClip device. All patients underwent standardized pre-, peri-, and post-procedural evaluation. Acute success was defined as successful edge-to-edge repair with TR reduction of greater than or equal to 1 grade and survival until hospital discharge. A total of 15 (75 %) patients showed acute success until discharge and 12 (60 %) at 30-day follow-up . In 5 (25 %) patients, repair failed due to either unsuccessful clip implantation (n = 2), single leaflet device attachment (n = 1), TR reduction of less than 1 grade (n = 1), or in-hospital death (n = 1). Comparing patients with successful procedure versus those with failed repair revealed similar co-morbidities but more severe right HF, lower LVEF, worse renal function, and higher diuretic equivalent doses in the failed repair group. No differences in conventional echocardiographic parameters for TR severity but more dilated tricuspid annulus geometry (tricuspid valve annulus, coaptation depth, tenting area) in the failed repair group were observed. The success rate of non-central/non-anteroseptal jet location was only 25 %. The authors concluded that tricuspid annulus geometry assessment may be of crucial importance and appeared to impact procedural outcomes in patients undergoing edge-to-edge tricuspid valve repair. Moreover, these researchers stated that further investigations including advanced imaging are needed to better understand and treat this complex valve disease.
The authors stated that this was a prospective, observational study reporting a single-center experience with a small sample size and multiple comparisons; therefore, patient bias and significances appearing by chance cannot be excluded completely. The findings of this study have to be judged as hypothesis-generating and should be verified by further studies. However, the overall available patient population for isolated TV procedures is limited. In other studies, such as the recently published Triluminate registry, an average of only 4 patients per study site was included during a comparable time-period.
Corpataux et al (2020) described the technical features of the novel Edwards PASCAL transcatheter valve repair system as well as the evidence accumulated so far. These researchers noted that transcatheter mitral and tricuspid valve leaflet approximation enable treatment of patients with MR and TR who are not eligible for surgery. The PASCAL device (Edwards Lifesciences, Irvine, CA) offers an alternative that may allow to overcome some of the limitations of previous systems and open the path for an approach adapted to individual patient's anatomy. Early data showed similar safety and efficacy compared with the MitraClip device. The PASCAL device is a valuable addition to the armamentarium of transcatheter mitral and tricuspid valve repair devices. The authors concluded that randomized, head-to-head comparisons and long-term follow-ups are needed to confirm the promising findings observed so far.
Luedike et al (2021) noted that patients with congenitally corrected transposition of the great arteries (ccTGA) with significant systemic TR and systemic RV dysfunction have prohibitive surgical risk in adulthood. The PASCAL transcatheter valve repair system enables minimally invasive percutaneous tricuspid valve repair in the complex anatomy of patients with ccTGA. These researchers stated that the novel PASCAL technology is available for both mitral/tricuspid valve repair demonstrating the flexibility of the system, while recently a dedicated TriClip system was introduced as an advancement of the existing MitraClip device for meeting the needs of complex steering in the RV. Reports on the TriClip device for the treatment of tricuspid insufficiency in ccTGA do not exist yet. Because no head-to-head comparison of the existing transcatheter leaflet approximation techniques exists and interventional tricuspid valve repair in ccTGA is a rarely performed procedure, it remains speculative whether one technique is superior to the other when treating these complex anatomies. The authors concluded that this was the 1st report of percutaneous tricuspid valve repair using a novel transcatheter percutaneous edge-to-edge repair (TEER) system in a patient with ccTGA. This 1st experience demonstrated that the steering mechanism allowed for optimal maneuvering in complex anatomies and that patients with severe TR in ccTGA can be safely treated with this technology without significant increase of the mean pressure gradient across the valve. Level of Difficulty = Intermediate.
Kitamura et al (2021) stated that transcatheter tricuspid valve repair (TTVr) has rapidly developed and demonstrated favorable acute outcomes; however, longer follow-up data are needed. In an observational, multi-center study, these researchers examined the durability of TR reduction and the clinical outcomes through 12 months after TTVr with the PASCAL Transcatheter Valve Repair System. A total of 30 patients (age of 77 ± 6 years; 57 % women) received PASCAL implantation from September 2017 to May 2019 and completed a clinical follow-up at 12 months. The TR etiology was functional in 25 patients (83 %), degenerative in 3 (10 %), and mixed in 2 (7 %). All patients had TR severe or greater (massive or torrential in 80 %) and HF symptoms (90 % in NYHA III or IV) under optimal medical treatment. Single-leaflet device attachment occurred in 2 patients. Moderate or less TR was achieved in 23/28 patients (82 %) at 30 days, which was sustained at 12 months (86 %); 2 patients underwent repeat TTVr due to residual torrential TR (day 173) and recurrence of severe TR (day 280), respectively. One-year survival rate was 93 %; 6 patients required re-hospitalization due to acute HF. NYHA functional class I or II was achieved in 90 % and 6MWD improved from 275 ± 122 m at baseline to 347 ± 112 m at 12-month (+72 ± 82 m, p < 0.01). There was no stroke, endocarditis, or device embolization during the follow-up. The authors concluded that 12-month outcomes from this multi-center compassionate use experience with the PASCAL device demonstrated high procedural success, acceptable safety, and significant clinical improvement. Moreover, these researchers stated that the pivotal randomized CLASP TR Trial will further define the clinical impact of PASCAL TTVr compared with medical therapy.
The authors stated that despite being designed as an observational, multi-center study, this study had several drawbacks. First, this study was conducted in tertiary care centers, and the procedures were carried out by experienced surgeons; thus, this result might not be translatable to centers with less experience. Second, it appeared likely to choose candidates with large coaptation gaps due to potential advantages from PASCAL's independent clasps and the central spacer, which might have caused a considerable selection bias toward more complex anatomies of severe TR. Indeed, 1/5 of the population had a coaptation gap of greater than or equal to 10 mm, which has been usually excluded from TTVr using conventional edge-to-edge repair devices. Finally, the study population was relatively small (n = 30), and the echocardiographic follow-up was carried out in each participating center without a central echocardiographic laboratory; thus, these results should be verified by future studies with larger cohorts.
Rosch and Lurz (2021) noted that for a long time, severe TR was an under-estimated disease, especially in the elderly and was associated with high morbidity and mortality. Due to the high peri-operative mortality of tricuspid valve surgery, historically only pharmaceutical treatment was a practical therapeutic option. In the first studies, interventional approaches could achieve promising results with an effective reduction of TR with simultaneous proof of a convincing safety profile. Conceptually, the currently available interventional therapeutic options can be divided into 3 categories: coaptation systems (edge-to-edge repair), annuloplasty, and interventional valve replacement . The largest clinical experience and best scientific body of evidence could so far be generated in the field of coaptation systems. Very promising preliminary results with effective reduction of TR and improvement of the clinical symptoms are, however, also available for interventional valve replacement. Meticulous pre-procedural diagnostics with selection of the most suitable therapeutic option for each individual patient is paramount for successful treatment in this critically ill patient cohort. These investigators stated that future prospective randomized studies will examine the net benefit of an interventional treatment of TR in comparison to a purely conservative treatment approach.
Roth et al (2021) reported on the findings of 2 heart transplant patients aged 80 and 83 years with recurrent HF due to severe TR. In view of their high peri-operative risk, both patients underwent percutaneous transcatheter edge-to-edge tricuspid valve repair, and both experienced excellent technical success with favorable 2-year clinical outcome. The authors concluded that in orthotopic heart transplantation patients with severe TR and high surgical risk, percutaneous tricuspid valve repair should be examined as a treatment alternative to tricuspid valve surgery. In patients with favorable anatomy and in the hands of experienced heart teams, percutaneous tricuspid valve repair is feasible and safe, and it can lead to good technical and clinical 2-year outcomes. Follow-up echocardiography revealed persistent reduction of TR and normalization of both RV size and function, and both patients lived an independent life without further hospital stays because of HF. Moreover, these researchers stated that larger studies are needed in this patient population since they are regularly excluded from current trials to increase the understanding of patient selection for different treatment strategies. Level of Difficulty = Advanced.Hahn and Kodali (2022) stated that advanced intra-procedural imaging techniques have been integral to technical and procedural success transcatheter devices. A novel leaflet approximation therapy, the PASCAL Transcatheter Valve Repair System has demonstrated high procedural success, acceptable safety, and significant clinical improvement in patients with severe MR and TR of either primary or secondary etiology; and has Conformite Europeenne (CE) mark approval in Europe with pivotal trials underway in the United States.
In a systematic review and meta-analysis, Bugan et al (2022) examined the feasibility of the orthotopic TTVR devices, echocardiographic, functional improvements, and mortality rates following replacement in patients with significant tricuspid valve regurgitation. These investigators searched for the studies examining the safety and effectiveness of TTVR for significant tricuspid valve regurgitation. The safety and effectiveness outcomes were the improvements in NYHA functional class, 6MWD, all-cause death, and peri-procedural and long-term complications. Furthermore, a random-effect meta-analysis was carried out comparing outcomes before and after TTVR. A total of 9 studies with 321 patients were included. The mean age was 75.8 years, and the mean European System for Cardiac Operative Risk Evaluation II score was 8.2 % (95 % CI: 6.1 to 10.3). Severe, massive, and torrential tricuspid valve regurgitation was diagnosed in 95 % of patients (95 % CI: 89 % to 98 %), and 83 % (95 % CI: 73 % to 90 %) of patients were in NYHA functional class III or IV. At a weighted mean follow-up of 122 days, NUHA functional class (RR = 0.20; 95 % CI: 0.11 to 0.35; p < 0.001) and 6MWD (MD = 91.1 m; 95 % CI: 37.3 to 144.9 m; p < 0.001) significantly improved, and similarly, the prevalence of severe or greater tricuspid valve regurgitation was significantly reduced after TTVR (baseline RR = 0.19; 95 % CI: 0.10 to 0.36; p < 0.001). A total of 28 patients (10 %; 95 % CI: 6 % to 17 %) had died. Pooled analyses showed non-significant differences in hospital and 30-day mortality and greater than 30-day mortality than predicted operative mortality (RR = 1.03; 95 % CI: 0.41 to 2.59; p = 0.95, RR = 1.39; 95 % CI: 0.69 to 2.81; p = 0.35, respectively). The authors concluded that TTVR could be an emerging treatment option for patients with severe TR who are not eligible for transcatheter repair or surgical replacement because of high surgical risk and poor prognosis. Moreover, these researchers stated that findings reported from well-conducted RCTs with “real-world evidence” addressing optimal device and patient selection are needed
The authors stated that this study had several drawbacks. First, this analysis included only single-arm, interventional, case-series studies, and no RCTs were available for inclusion at the time of the study. It should be noted that the studies have more potential for bias regarding excellent treatment effects and significant heterogeneity when they are not randomized or controlled. As a consequence, this analysis comprehended specific devices with different mechanisms of TV replacement alongside favorable outcomes inducing a potential selection bias regarding patient and anatomic features. Second, moderate heterogeneity was found concerning the included studies’ results. Because there were changing degrees of reductions in NYHA functional class and baseline TR severity expanded from moderate-to-torrential even though leave-one-out analysis affirmed the consistency of the results. Third, as there are currently no specific guideline recommendations for patient selection for TTVR, the studies included in this meta-analysis were also limited by the lack of uniformity in the definition of procedural success. However, as observed with the TAVR, outcomes will be reported according to the valve academic research consortium, which clarified specific definitions and expanded the understanding of patient risk stratification and case selection. Additionally, outcomes will improve as each generation of the device can address imperfections in its fore-runner and as operators complete their learning curve performing the procedure.
In a prospective, single-arm, multi-center study (the TRISCEND Trial), Kodali et al (2022) examined the safety and performance of TF TTVR in patients with clinically significant TR and elevated surgical risk. This trial included patients with symptomatic moderate or greater TR, despite medical therapy, who underwent percutaneous TTVR with the EVOQUE system. A composite rate of major AEs, echocardiographic parameters, and clinical, functional, and QOL measures were evaluated at 30 days. A total of 56 patients (mean age of 79.3 years, 76.8 % female, 91.1 % TR severe or greater, 91.1 % AF, and 87.5 % NYHA functional class III or IV) were treated. At 30 days, TR was reduced to mild or less in 98 %. The composite major AE rate was 26.8 % at 30 days caused by 1 cardiovascular death in a patient with a failed procedure, 2 re-interventions following device embolization, 1 major access site or vascular complication, and 15 severe bleeds, of which none were life-threatening or fatal. No MI, stroke, renal failure, major cardiac structural complications, or device-related pulmonary embolism were observed. NYHA significantly improved to functional class I or II (78.8 %; p < 0.001), 6MWD improved 49.8 m (p < 0.001), and Kansas City Cardiomyopathy Questionnaire score improved 19 points (p < 0.001). The authors concluded that early experience with the TF EVOQUE system in patients with clinically significant TR demonstrated technical feasibility, acceptable safety, TR reduction, and symptomatic improvement at 30 days. The TRISCEND II randomized trial is underway.
Webb et al (2022) noted that untreated TR is associated with excess mortality and morbidity. The 1st-in-human experience with the EVOQUE tricuspid valve replacement system (Edwards Lifesciences) reported favorable 30-day outcomes with no mortality in a compassionate use population. These investigators reported the mid-term outcomes at 1 year in the expanded 1st-in-human experience with the TF EVOQUE System for TR. A total of 27 patients with severe TR were treated with the EVOQUE system in a compassionate use experience at 7 centers between May 2019 and July 2020. All patients had clinical right-sided HF and were deemed inoperable and unsuitable for transcatheter edge-to-edge repair by the institutional heart teams. The clinical outcomes collected included all-cause mortality, symptom status, TR severity, HF hospitalization, and major adverse cardiovascular events (MACEs). At baseline, all patients (age of 77 ± 8 years, 89 % female) were at high surgical risk (mean Society of Thoracic Surgeons score: 8.6 % ± 5.5 %), with 89 % NYHA functional class III/IV. TR was predominantly functional in etiology (19/27, 70 %). At 1 year, mortality was 7 % (2/27), 70 % of patients were NYHA functional class I/II, and 96 % and 87 % of patients had a TR grade of 2+ or less and 1+ or less, respectively. Between 30 days and 1 year, 2 patients experienced HF hospitalizations, and 1 patient required a new pace-maker implantation. The authors concluded that in this early, compassionate use experience, the TF transcatheter EVOQUE tricuspid valve replacement system showed durable effectiveness, persistent improvement in symptom status, and low rates of mortality and HF hospitalizations at a 1-year follow-up. These researchers stated that further studies are underway to validate its effectiveness.
Freixa et al (2022) noted that in patients with TR, edge-to-edge TTVR is the strategy with the highest penetration worldwide. A dedicated edge-to-edge TTVR system has recently become available in Europe. In a multi-center study, these investigators described their initial experience with the system in Spain. They collected individual data from the centers accepted for the use of the novel system within an initial limited release. Between June 2020 and March 2021, all subjects undergoing an edge-to-edge TTVR using the Triclip system in Spain were included in the study. The primary endpoint was the achievement of a TR reduction of at least 1 grade at discharge. This trial included 34 patients; most of them reported a previous history of AF (91 %) and only 1 had a pace-maker lead. The primary endpoint (TR reduction of at least 1 grade at discharge) was met in all patients. Most of the patients required 1 (47 %) or 2 clips (44 %) with a clear predominance of XT (87 %) over NT (13 %). The location of the 1st clip was antero-septal in more than 90 % of the patients. Only 1 patient had a partial detachment, which was stabilized with additional clips in the same procedure. At discharge, TR severity was 2 or less in 91 % of patients. At 3 months, mortality was nil. Overall, 88 % of patients were in NYHA functional class 2 or less and 80 % had residual TR of 2 or less. The authors concluded that edge-to-edge TTVR appeared to be safe and effective with a sustained TR reduction at 3 months. Moreover, these researchers stated that further studies are needed to confirm these findings.
References
The above policy is based on the following references:
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Trans-Apical Approach (e.g., the NeoChord System and the Permavalve) for Mitral Valve Repair
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Transcatheter Mitral Valve Annulus Reconstruction
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Transcatheter Tricuspid Valve Repair or Replacement
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