Remembering the "Forgotten Valve"

Further Insight Into Transcatheter Tricuspid Valve Repair for Right Heart Failure

Wayne Batchelor, MD, MHS; JoAnn Lindenfeld, MD

Disclosures

JACC Heart Fail. 2020;8(4):277-279. 

"Progress is what happens when impossibility yields to necessity"
—Arnold Glasow[1]

With an incidence of nearly 1%, tricuspid valve regurgitation (TR) is estimated to afflict more than 3 million Americans. Despite being the most common form of valvular heart disease associated with heart failure,[2] for decades TR has been understudied and undertreated. With recent advances in transcatheter treatments for TR, including leaflet repair devices, annuloplasty devices, heterotopic caval valve implantation, and transcatheter valve replacement, TR is now getting well-deserved attention. Thus far, the investigative path has been led by transcatheter tricuspid valve edge-to-edge repair (TTVR).[3–5] In this issue of JACC: Heart Failure, Orban et al.[6] advance the understanding of the potential for TTVR to reduce hospitalizations for heart failure (HHF) in patients presenting with right-sided heart failure. Using data collected from 4 compassionate use programs in Europe and Canada over a 3-year period (2015 to 2018), Orban et al.[6] examined the impact of TTVR on HHF, functional status/symptoms, and event-free survival. The study sample included 119 patients who underwent isolated TTVR and another 114 patients in whom TTVR was performed with concomitant transcatheter mitral valve repair during the same procedure (TMTVR). The primary outcome measure was a comparison of the rate of HHF in the year prior versus the year following TTVR. This registry, like others[5,7,8] confirmed the feasibility and safety of TTVR. With experienced operators, Orban et al.[6] reported TTVR procedural success rates of 82%. This compares favorably with data reported from the Trivalve Registry,[8] but slightly less than that observed in the TRILUMINATE Early Feasibility Study.[5] At a median follow-up of 360 days post-TTVR, 72% of treated patients had ≤2+ TR, indicating favorable mid-term durability. TTVR was associated with a 22% reduction in the annual rate of HHF and significant improvements in New York Heart Association functional class (patients with New York Heart Association functional class ≤II: 9% to 67%; p < 0.001), 6-minwalk distance (6MWD) (+39 m; p = 0.001), and Minnesota Living with Heart Failure Questionnaire (MLHFQ) (−6 points; p = 0.02). These improvements in symptoms and quality of life are large enough in magnitude to be clinically important and meaningful for patients. Procedural success was also associated with improved 1-year overall survival (79% vs. 60%; p = 0.04) and event-free survival (death and/or first HHF: 67% vs. 40%; p = 0.001), supporting the authors' assertion that the benefits seen in these patients were likely attributable to the TTVR.

What might this mean? At best, if one were to assume the treatment effect size seen in this study, performing TTVR in 100 patients would be expected to prevent 26 hospitalizations in a year. However, it is important to note that these changes were accomplished with a significant escalation in heart failure medications. Doses of diuretic agents increased from a furosemide equivalent of 70 mg in the year preceding TTVR, to 85 mg at the time of the procedure and 83 mg in the year following TTVR. Thus, although this study provides important procedural success and safety data, it does not provide irrefutable evidence that TTVR alone improves HHF or mortality. This requires validation from further studies employing experimental designs. Orban et al.[6] also noted comparable survival and clinical outcomes in the patients who underwent concomitant TMTVR versus isolated TTVR. This runs counter to another recent report from the Trivalve and TRAMI registries,[8] which demonstrated improved survival when TMTVR (both mitral and tricuspid repair) was performed versus isolated TTVR. This is likely attributable to these 2 treatment cohorts being more similar in terms of baseline overall risk in the current study versus the latter registries.

So, what if anything can one glean from this retrospective study and what impact might it have on future treatment and research directions? With a mean age older than 75 years, more than 92% of patients presenting with New York Heart Association functional class >III, a mean 6MWD of only 227 m, an MLHFQ of 39, and a high rate of HHF (1.21 HHF/patient-year) in the year before TTVR, the Orban et al.[6] study enrolled very symptomatic, frail, older adults who were otherwise poor candidates for surgical intervention. In this setting, TTVR was effective and safe in reducing TR in the short- to mid-term timeframe. Consistent with the Trivalve Registry and the TRILUMINATE (Evaluation of Treatment With Abbott Transcatheter Clip Repair System in Patients With Moderate or Greater Tricuspid Regurgitation) Early Feasibility Study, assuming adequately skilled operators, these results are likely generalizable to the typical patients who present with heart failure and concomitant severe TR. One caveat is that, the Orban et al.[6] study cohort had only mild pulmonary hypertension, a mean mid right ventricular diameter of 41 mm, and mean tricuspid annular plane systolic excursion of 16 mm. Therefore, right ventricular size was only modestly dilated and systolic function mildly reduced. One cannot necessarily extrapolate these favorable results to patients with more advanced right ventricular systolic dysfunction, large TR coaptation gaps, marked leaflet tethering, and severe pulmonary hypertension.[7,8] Accordingly, case selection remains a valuable determinant of treatment success.

What about research study design? Admittedly, in this area the Orban et al.[6] study has several limitations, including a small sample size (albeit still fairly large for this arena of investigation), lack of standardization of device and medical treatment regimens, lack of prespecified follow-up visit regimens, and absence of an independent clinical events committee and/or an echocardiographic core laboratory. Missing data, especially related to MLHFQ scores, 6MWD, and N-terminal pro–B-type natriuretic peptide results, presents another limitation. Finally the study's nonrandomized, retrospective design allowed for significant variances in medications that might have created further bias.

What about procedural/operator factors? An interesting common theme in this and other TTVR registries is that one does not necessarily have to achieve marked reductions in TR for a clinical benefit to be appreciated. In the Orban et al.[6] study, 100% of patients started off with severe TR at baseline. At follow-up, most patients with TTVR still had either moderate (43%) or severe (18%) TR, with only 39% reduced to mild TR. A similar relatively modest (1 to 2 grade) reduction in TR was noted with the Trivalve Registry. Despite these lackluster reductions in TR, significant clinical benefits have still been observed. This speaks not only to the technical challenges inherent in achieving major reductions in TR with current TTVR techniques, but also to the fact that the clinical benefit, itself, may not be dependent on such lofty goals. Still, as the worldwide TTVR experience increases and technological advances ensue, more substantial and reproducible reductions in TR should be achievable. Finally, it is also important to note that the 4 compassionate use TTVR sites in the Orban et al.[6] study were truly "centers of excellence" for TTVR. Therefore, one cannot assume that the safety and procedural success rates reported apply broadly.

Although many have referred to the tricuspid valve as the "forgotten valve," thanks to several recent studies including this report from Orban et al.,[6] this is no longer the case. With an anticipated sample size of 450 patients, an experimental study design, and quantitative echocardiographic core laboratory, the TRILUMINATE Pivotal trial[9] should provide more definitive insight into the relative safety and efficacy of TTVR compared with optimal medical therapy. However, TRILUMINATE will not be completed for several years. In the meantime, Orban et al.[6] provide ample reason to be optimistic about TTVR's ability to favorably alter the natural history of severe TR, an important entity that afflicts millions of patients worldwide and 1 in 5 patients with heart failure.[2]

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