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Abstract
Objective This study aimed to identify characteristics, spectrum of tricuspid regurgitation (TR) severity and treatment patterns in patients considered for intervention of severe TR at a tertiary centre. The population being considered for TR intervention is currently not well defined and the role of transcatheter interventions is unclear.
Methods The study involved 87 patients with severe TR considered for intervention from 1 March 2016 to 12 November 2018 at Mayo Clinic. Patients receiving medications alone were compared with those receiving intervention to identify patterns in demographics, clinical/echocardiographic associations and survival.
Results Mean age was 80±9 (56% female), 93% had atrial fibrillation and 64% had chronic kidney disease ≥3 a. Follow-up was 331±276 days; 95% were symptomatic with 6 min walk distance of 270±110 m. Loop diuretics were used in 93%; aldosterone antagonists in 35%. Mean tricuspid annular plane systolic excursion was 15.6±3.8 mm, effective regurgitant orifice area (EROA) 82±32 mm2 and stroke volume index 39±11 mL/m2; 48% had at least moderate right ventricular (RV) dysfunction, and 75% did not undergo intervention. Patients receiving intervention showed trends towards larger EROA (93±33 vs 75±31 mm2), better right ventricular function and more severe symptoms. Overall group 30-day and 1-year survival were 100% and 76%, respectively.
Conclusions Patients with severe TR considered for intervention are commonly elderly with atrial fibrillation, advanced TR and RV dysfunction; 75% were treated with medications alone and not offered intervention. Patients with greater EROA, better RV function and more severe symptoms were more likely to receive intervention. These findings have implications for future trial design.
- tricuspid regurgitation
- transcatheter intervention
- TVR
- minimally invasive
- device
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Introduction
Tricuspid regurgitation (TR) is an under-recognised valvular pathology associated with an increase in morbidity and mortality proportional to the severity of TR. Patients with severe TR frequently are elderly, have numerous comorbidities and are often poor surgical candidates. In addition to prognosis, severe TR detrimentally affects quality of life due to symptoms of right heart failure and reduced cardiac output.1 2 Surgical tricuspid repair/replacement is infrequently performed without concomitant left-sided valve surgery given the risk of the procedure, and there are limited long-term data showing benefit beyond symptomatic improvement.3 Therefore, transcatheter procedures that can alleviate symptoms and improve clinical outcomes are of great interest.
There is limited literature characterising patients with severe TR, and the criteria used to decide candidacy for intervention (traditional surgical repair/replacement vs novel transcatheter intervention) versus medical therapy alone are poorly defined. Furthermore, predictors of outcome between medical management alone and intervention have not been explored. The goal of this study was to identify characteristics and predictors of outcome in patients considered for interventional management of severe TR at a tertiary referral centre to help define the role for transcatheter intervention.
Materials and methods
Electronic health records of 87 adult patients with severe TR who were considered for interventional treatment of their TR (either surgery or percutaneous repair) from 1 March 2016 to 12 November 2018 at Mayo Clinic in Rochester, Minnesota, were reviewed. These patients were referred by their healthcare provider or self-referred for further evaluation and management of their TR. Inclusion criteria were being male or female over 18 years old and having severe TR. Exclusion criteria included previous tricuspid valve repair or replacement, flail tricuspid valve and/or severe pulmonary hypertension. Patients who met inclusion and exclusion criteria were consecutively added to the study. The sample size was dictated by the number of patient referrals that met our inclusion/exclusion criteria during this time period. Patients receiving medical management alone (n=65) were compared with those receiving intervention (transcatheter device or surgical repair/replacement; n=13 and n=9, respectively; figure 1).
Division of patient population.
Initial evaluation was performed in the Valve Clinic, and patients were subsequently referred to determine surgical candidacy. Surgical patients were those felt to have an acceptable surgical risk after evaluation by a cardiac surgeon with expertise in tricuspid valve surgery. This involved assessment of comorbidities and frailty in addition to identifying technical impediments that would increase the chance of a poor outcome. Transcatheter repair of the tricuspid valve was performed with either edge-to-edge repair of the tricuspid valve (off-label use of MitraClip; Abbott, Santa Clara, California, USA; n=9) or an investigational spacer device (FORMA, Edwards Lifesciences, Irvine, California, USA; n=4). All patients receiving edge-to-edge repair of the tricuspid valve also underwent edge-to-edge repair for their concomitant MR. The medical management-only group included those who were considered prohibitive risk for surgery, did not qualify for a transcatheter device (typically due to primary TR, unfavourable anatomy on cardiac CT and/or lack of device availability) or preferred to avoid any intervention.
Retrospective chart review provided the demographic information, clinical associations and echocardiographic features reported. Severity of TR was defined utilising effective regurgitant orifice area (EROA) in mm2 to quantify the degree of regurgitation.4 EROA measurement utilising the proximal isovelocity surface area (PISA) method was performed in 20 patients included in the study. Our laboratory follows the American Society of Echocardiography (ASE)-endorsed guidelines for measuring TR parameters during expiration. Angle adjustment for the leaflets was performed as recommended. The regurgitant volume was calculated as a product between EROA and regurgitant time-velocity integral.5 6 Other valve abnormality was defined as the patient previously requiring a valve intervention or having greater than or equal to moderate valve dysfunction of any valve other than the tricuspid valve reported on echocardiography. Right ventricular (RV) dysfunction severity was determined by interpretation of tricuspid annular plane systolic excursion (TAPSE), tricuspid lateral annular systolic velocity (S') and visual assessment following ASE guidelines.7 Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate (GFR) of <60 based on creatinine. Loop diuretic dose was converted to oral furosemide equivalents (from oral bumetanide or torsemide; 40 mg: 1 mg and 40 mg: 20 mg, respectively). New York Heart Association (NYHA) class and presence of ascites were determined by review of history and physical examination documentation. Echocardiographic data were gathered from the most recent transthoracic echocardiogram (TTE) prior to TV intervention. For the medically managed patients, data were collected from the TTE performed at the time of initial presentation to Valve Clinic for consideration of TV intervention. Reported diuretic doses, N-terminal pro B-type natriuretic peptide (NT-proBNP), estimated GFR, haemoglobin and 6 min walk test were obtained at the time of initial presentation for TV intervention consideration. Survival from time of initial screen to last clinical contact was used to calculate the survival analysis reported below. Mayo Clinic Institutional Review Board approved this study and did not require written informed consent for this retrospective study.
Statistical analysis
Data were reported as mean ± SD, median (IQR) or number (percentage). Student’s t-test was used to compare continuous variables, and Fisher’s exact test was used to compare normally distributed categorical variables between groups. Non-parametric tests were used for non-normally distributed data. Kaplan-Meier survival analysis was used to compare all-cause mortality between medical management and intervention groups and to examine clinical predictors of all-cause mortality. Statistical analysis was performed using SPSS (SAS software V.12.0).
Results
Demographics
Severe symptomatic TR patients being considered for intervention were predominantly elderly (mean age 80.1±9.2), female (56%) and Caucasian (89%). Mean body mass index was 27±6 kg/m2, and mean body surface area was 1.9±0.3 m2 (table 1).
Demographics and clinical associations
Clinical associations and features
There was a high prevalence of atrial fibrillation (93%) and CKD (64%) in patients with severe TR. CKD was present in 76% of subjects who received transcatheter repair but only 56% of those who had open surgery (p=0.376). Hypertension was more common in the medically managed group (77% vs 63%, p=0.267), but history of stroke or TIA was more common in those who received intervention (27% vs 8%, p=0.027). Medically managed patients were twice as likely to have a history of radiation exposure compared with those who underwent intervention (18.5% vs 9.1%, p=0.503).
Aetiology of TR in the majority of cases was secondary resulting from tricuspid annulus dilatation with incomplete leaflet coaptation in the setting of atrial fibrillation and right atrial enlargement (93% and 95%, respectively). Pacemaker or defibrillator leads were present in 44% of patients. Moderate or greater MR was present in 48% of patients (including both primary and secondary MR aetiologies). Prior non-TV intervention was more common in the medical management group (52% vs 27%, p=0.05).
The majority of patients were NYHA class 2 or 3 (mean 2.7±0.6) with mean 6 min walk distance of 270±111 m. Most were symptomatic with only four patients NYHA class 1 (surgery=1; medical management=3). There was a trend towards more severe symptoms in patients receiving intervention. Ascites was present in 22% of patients with no difference between groups (medical management=23% vs intervention=19%, p=0.770). The NT-proBNP tended to be higher in the medically managed group compared with those who were selected for intervention (management group 2077.5 (IQR 1020–3933) pg/mL vs intervention group 1645.0 (1047–2452) pg/mL, p=0.424).
Most patients (98%) were prescribed a diuretic at the time of evaluation for potential intervention (loop diuretics in 93% and aldosterone antagonists in 35%). The mean dose of oral furosemide (or equivalent dose of torsemide or bumetanide) was 81±87 mg per day (medical management=82±87 mg vs intervention=77±89 mg, p=0.837; tables 1 and 2).
Patient factors
Concomitant valve pathology
Concomitant valve pathology was common (78% of all patients). MR of some degree was present in 100% of patients with at least moderate MR in 48%. Those receiving intervention were more likely to have moderate or greater MR (59% vs 45%, p=0.324). Of those receiving intervention, 36% had severe MR compared with 8% in the medical management group (p=0.003). Aortic stenosis and aortic regurgitation were present in 9% and 6%, respectively. Prior heart valve intervention (operative or transcatheter) of the mitral and/or aortic valves had been performed in 46% (table 3).
Echocardiographic findings and measurements
Echocardiographic features
Mean EROA was 82±32 mm2. The spectrum of severity for each group is illustrated in figure 2. Patients receiving intervention tended to be more likely to have a larger EROA (93±33 mm2 vs 75±31 mm2, p=0.213). All but one patient receiving intervention had an EROA measuring ≥60 mm2. The medically managed group was split with equal numbers having an EROA 40–59 mm2 and ≥80 mm2 and fewer in the intermediate 60–79 mm2 range.
Spectrum of tricuspid regurgitation severity.
Mean TAPSE was 15.6±3.8 mm. Mean tricuspid annulus diameter for both groups was similar (5.01±0.77 cm for the medically managed group vs 4.94±0.70 cm for the intervention group, p=0.720). Tricuspid lateral annular systolic velocity was greater in the intervention group compared with the medically managed group (0.11±0.04 m/s vs 0.09±0.03 m/s, p=0.013). Mean stroke volume index was 38.79±10.72 mL/m2. Mitral regurgitation was moderate or less in most of the patients in the study (77%). However, TR intervention tended to be more likely to occur in those with greater than moderate MR (50% vs 14%, p=0.001). Additional echocardiographic data are shown in table 3.
Clinical outcomes
Mean follow-up duration was 331±276 days, and the majority of patients did not undergo intervention (75%). Thirty-day survival rate was 100% for both groups (p=1.0). One-year survival was 72.7% for the medical management group and 87.5% for those who underwent intervention (overall 1-year survival 75.6%, p=0.441; figure 3). The overall survival for the severe TR population is significantly less than that of age-matched and gender-matched patients (p<0.001; figure 3).
Survival of study population by group and compared to expected survival. TR, tricuspid regurgitation.
Of those patients not receiving intervention who died during the follow-up period (n=15), 100% had other valve abnormalities, atrial fibrillation and a loop diuretic prescribed; 60% had CKD; 80% had hypertension and 47% had a permanent pacemaker or defibrillator.
Predictors of mortality
The presence of ascites, CKD and RV dysfunction (≥moderate) tended to be associated with lower survival compared with patients without these features, although these differences did not reach statistical significance on survival analysis (figure 4).
Clinical and echocardiographic predictors of mortality in study population . CKD, chronic kidney disease; RV, right ventricle; RVSP, right ventricular systolic pressure.
Discussion
The primary findings of this descriptive cohort study of patients referred for consideration of TR intervention include the following: (1) severe TR patients were commonly elderly with atrial fibrillation, CKD and a high prevalence of loop diuretic use; (2) the majority of patients had an extreme degree of TR with 75% treated with medical therapy alone and an overall 1-year mortality rate of 24%; (3) patients with larger EROA, better RV function and more severe symptoms were more likely to receive TR intervention (surgery or percutaneous repair). Of the patients who received intervention, 87.5% had an EROA ≥60 mm2, while only 58.4% of those in the medical management group had an EROA ≥60 mm2.
Despite ample data showing increased mortality associated with severe TR with an EROA >40 mm2, as shown in the present study, the majority of patients do not receive intervention to correct severe TR. Severe TR patients are often poor surgical candidates given comorbidities and advanced age.1 2 Tricuspid valve repair/replacement is uncommonly performed in the absence of left-sided valve disease, but the frequency of isolated TV repair/replacement has increased in recent years as recognition of the morbidity and mortality associated with severe TR has increased. Unfortunately, the high in-hospital mortality associated with TV surgery (average of 8.8% but reportedly as high as 24%) has been static despite the increase in surgical volume. Furthermore, there are limited data about long-term mortality outcomes after TV surgery. While there may be symptomatic improvement, an appreciable mortality benefit has not been demonstrated after this high-risk procedure.3 Therefore, novel transcatheter approaches are of utmost interest as minimally invasive therapies hold the potential to alleviate symptoms and improve survival. This study adds to the understanding of severe TR management by specifically examining clinical and echocardiographic characteristics in addition to 1-year outcomes of a population of severe TR patients who are potential candidates for intervention.
Several factors must be considered in the management of severe TR. Patients with advanced comorbidities, such as severe pulmonary hypertension and/or end-stage renal disease, positive frailty assessment, expected survival less than 1 year due to other comorbidities and prohibitive surgical risk are all factors that may favour medical management over intervention. Surgical tricuspid valve repair by a surgeon experienced in tricuspid valve operation may be the best option for younger patients who have acceptable surgical risk, symptoms primarily related to TR, preserved RV function and/or device lead adherent to the leaflet. Percutaneous intervention is an attractive option for the majority of patients with severe TR in whom TR is believed to be the major cause of their symptoms, yet comorbidities, frailty and/or RV dysfunction make surgical risk prohibitive.
Current guideline indications for surgical TV intervention include TV repair or replacement at the time of left-sided valve surgery in symptomatic and asymptomatic severe TR patients (class I) and TV repair for patients with tricuspid annular dilation >4 cm in the setting of progressive, functional TR at the time of left-sided valve surgery (class IIa). Interestingly, many patients in the present study had prior aortic valve replacement or mitral valve replacement without intervention on the TV despite the mean tricuspid annulus diameter being 5.0±0.8 cm.8 Data from this study clearly demonstrate that patients are referred for TR management at an advanced stage of the disease, which poses a challenge to improve outcomes given more extreme annular enlargement, RV enlargement and dysfunction, and multiorgan system dysfunction that is associated with advanced stage TR. A new grading scheme for classifying severe TR as severe, massive or torrential utilising quantitative echocardiographic parameters (ie, EROA by PISA where 40–59 mm2=severe, 60–79 mm2=massive and ≥80 mm2=torrential) has been proposed by Hahn and Zamorano. Reduction from torrential to severe TR based on quantitative variables following intervention has implications for future trial design and possibly prognostication.4
Despite high observed 1-year mortality, the majority of patients with severe, symptomatic TR in this study did not receive intervention to repair TR. Potential explanations include the high-risk nature of this population, the paucity of low-risk interventional treatment options (ie, percutaneous repair or surgery), a more extreme disease state limiting interventional options or lack of physician referral for an asymptomatic condition. The population in this study was specifically referred and considered for interventional management of their TR; thus, the most likely reasons for lack of intervention in this group were their high-risk clinical features and the lack of an available treatment option with acceptable operative risk.
Current evidence for novel transcatheter device therapies is limited to small series and early feasibility studies. Perlman et al demonstrated that after 1 year following implantation of the FORMA transcatheter tricuspid spacer device (Edwards Lifesciences), there was a statistically significant increase in 6 min walk test, and Kansas City Cardiomyopathy Questionnaire scores improved by 18 points. Additionally, severity of TR, tricuspid annulus dilation and RV size frequently improved after 1 year of device placement. Procedural success was achieved in 89% of patients, and there were minimal adverse events in this initial compassionate use experience with the tricuspid spacer device.9 The SCOUT (Percutaneous Tricuspid Valve Annuloplasty System for Symptomatic Chronic Functional Tricuspid Regurgitation) trial utilised a novel transcatheter device to plicate the tricuspid annulus. The results showed a reduced tricuspid annulus diameter, increased LV stroke volume and a positive impact on patient quality of life. Of the 15 patients, 12 had successful implantation and no detachment of the pledgets. There were no major adverse events associated with implantation of the device.10 In a study on 64 patients, 97% had successful edge-to-edge clip repair of the tricuspid valve. TR improved by at least one grade in 91%, and they also showed improvement (p≤0.001) in EROA, regurgitant volume, vena contracta width, NYHA class and 6 min walk distance with low procedural morbidity and mortality.11 Outcomes from the recently published TriValve Registry, which includes patients who received one of the novel transcatheter TR interventions, have been favourable with a procedural success rate of 72.8%, 30-day mortality rate of 3.6% and 1.5-year survival at 82.8±4%.12
The findings reported in these early observational studies support transcatheter intervention as a potentially safe and feasible management option. It is reassuring that the overall risk of transcatheter intervention, even in early studies with first generation and off-label devices, appears to be lower than surgery. This approach has shown an encouraging signal for improving quality of life and overall survival for these patients. Continued innovations in device technology and larger studies, including randomised controlled trials, comparing transcatheter repair to medical therapy alone will be necessary to further understand the role of these promising therapies.
Limitations
This study is limited by a relatively small sample size and its observational nature. Furthermore, TR-relevant measures, such as EROA, hepatic vein flow reversal and three-dimensional vena contracta width, were not available in all patients. Many of the patients did not have a 6 min walk test as part of their evaluation (32% of all patients), and those receiving intervention were more likely to have this component of the evaluation compared with the medically managed group (55% vs 25%). The limited availability of percutaneous TR devices resulted in some patients receiving medical management alone when they had not necessarily been declined for a percutaneous intervention.
Conclusions
Patients with severe TR considered for intervention at a tertiary referral practice are commonly elderly with atrial fibrillation, CKD, a high prevalence of loop diuretic use and have an extreme disease state of TR. The majority of patients (75%) were treated with medical therapy alone, with 24% observed 1-year mortality. Larger EROA, better RV function and greater functional impairment were more common in patients receiving TR intervention. These findings have implications for future transcatheter tricuspid repair trial design.
Key messages
What is already known on this subject?
Severe tricuspid regurgitation (TR) is associated with an increase in morbidity and mortality. Patients with severe TR often present with numerous comorbidities making them poor surgical candidates. Surgical tricuspid repair/replacement is infrequently performed without concomitant left-sided valve surgery. Therefore, transcatheter tricuspid repair procedures are of great interest.
What might this study add?
This study contributes to our understanding of characteristics, spectrum of TR severity and treatment patterns in patients considered for intervention of severe TR at a tertiary centre.
How might this impact on clinical practice?
A better understanding of this patient population will help guide TR management and define the role for novel, transcatheter tricuspid interventions.
Footnotes
Contributors BSI and MFE primarily planned and wrote this manuscript. They selected patients, collected and analysed the data and composed the manuscript, tables and figures presented. The other listed authors provided significant contributions to the project drawing from their expertise within their respective fields. Each of the listed authors has contributed significantly to this manuscript’s conception, and no conflict of interest—financial or otherwise—is known to exist between any of the authors and the content presented within the submitted manuscript.
Funding This work was supported by the Department of Cardiovascular Medicine, Mayo Clinic.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Patient consent for publication Not required.