Mid-term outcomes of isolated tricuspid valve surgery according to preoperative clinical and functional staging

Abstract

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OBJECTIVES

This study aimed at assessing mid-term outcomes of patients undergoing isolated tricuspid valve (TV) surgery based on a preoperative baseline clinical and functional classification.

METHODS

All patients treated with isolated TV repair or replacement from March 1997 to May 2020 at a single institution were retrospectively reviewed and assessed for mid-term postoperative outcome according to a novel classification [stages 1–5 related to the absence or presence and extent of right heart failure (RHF)]. Kaplan–Meier survival curves were used to estimate mid-term survival. Competing risk analysis for time to cardiac death and hospitalizations for RHF were also carried out.

RESULTS

Among the 172 patients included, 129 (75%) underwent TV replacement and 43 (25%) TV repair. At follow-up (median 4.2 years [2.1–7.5]), there were 23 late deaths. At 5 years, overall survival was 100% in stage 2, 88 ± 4% in stage 3 and 60 ± 8% in stages 4–5 (P = 0.298 and P = 0.001, respectively). Cumulative incidence function of cardiac death at 5 years was 0%, 8.6 ± 3.76% and 13.2 ± 5% for stages 2, 3 and 4 and 5, respectively. At follow-up, cumulative incidence function of re-hospitalizations for RHF was 0% for stage 2, 20 ± 5% for stage 3 and 20 ± 6.7% for stages 4 and 5 (P = 0.118 and P = 0.039, respectively).

CONCLUSIONS

Both short- and mid-term outcomes support early referral for surgery in isolated TV disease, with excellent survival at 5 years and no further hospitalizations for RHF.

INTRODUCTION

Tricuspid regurgitation (TR) has been identified as an independent prognostic factor associated with excess mortality and morbidity, regardless of left ventricular (LV) function and pulmonary hypertension [1–3]. Surgery is mostly performed at the time of left-sided valve surgery, while isolated surgical treatment of tricuspid valve (TV) disease has been avoided for many years due to reported poor short- and long-term outcomes, or usually delayed until severe symptoms or signs of right heart failure (RHF) appear [4, 5].

In the past, ideal timing for surgical treatment has been difficult to determine because patients either tend to be asymptomatic or symptoms can be well tolerated for many years. Medical treatment has always been the gold standard, employed in these patients for many years. Recently, it has been demonstrated that TV interventions result in increased survival and reduced RHF hospitalizations with respect to medical therapy alone [6]. However, despite being a disabling condition, an extremely low percentage of patients are currently being referred for surgical treatment.

In recent years, several studies have highlighted how the reported poor outcomes following isolated TV surgery seem to be related to the baseline characteristics of the patients and their late referral, rather than to the surgical act in itself [7–9]. To facilitate patient screening, a novel clinical and functional staging of TV regurgitation has been recently proposed [10]. This classification that assesses progression of morphological changes to the TV and right ventricle (RV) in association to symptoms onset identifies a number of parameters and factors that may be useful in better stratifying surgical risk. Rather than simply evaluating TR grade, this novel staging mechanism also focuses on symptoms, RV remodelling and function, medical therapy and RHF hospitalizations.

We had previously focused on the short-term (mainly in-hospital) outcomes of patients undergoing isolated TV surgery for severe TR, who were classified according to this preoperative baseline clinical and functional staging [11]. Results showed that a more comprehensive classification reflects the population and in-hospital outcomes of patients affected by isolated TR surgically treated.

The aim of this study was to eventually assess their mid-term outcomes and evaluated the impact of the baseline stage on long-term outcomes.

MATERIALS AND METHODS

Ethics statement

The Ethical Committee of our institution approved the study and waived individual informed consent for this retrospective analysis.

Study population

A retrospective, single-centre study, including patients affected by TV regurgitation and treated with isolated TV surgery from March 1997 to May 2020 at San Raffaele University Hospital, Milan, Italy, was conducted. For a former study, all consecutive patients had previously been individually reviewed and all baseline characteristics were thoroughly analysed.

For completion, a brief description of the study material will be presented, even though it had been previously extensively described. All patients had undergone both preoperative transthoracic echocardiography and transoesophageal echocardiography upon hospitalization. Transoesophageal echocardiography was routinely used to better define the mechanism of TR. Echocardiographic parameters together with all preoperative characteristics and data were inserted within a dedicated database. Symptomatology was defined based on New York Heart Association class, and degree of heart failure was defined based on the presence of peripheral oedema, ascites, repeated previous episodes of hospitalization for RHF and organ damage, defined as altered laboratory values specific for hepato-renal function. TR was graded on a four-grade scale as 1+ (mild), 2+ (moderate), 3+ (moderate to severe) and 4+ (severe). A limited number of patients, in the more recent period of the study, were evaluated and TR grading was based on a multiparametric approach [12, 13]. RV remodelling and function was based on preoperative values, such as RV end-diastolic diameter, tricuspid annular plane systolic excursion, tissue doppler imaging and systolic pulmonary artery pressure. Medical therapy was assessed based on daily diuretic use, dosage and combination therapies [14]. Based on a combination of all these factors, patients had been previously divided according to the 5 stages of the classification (Fig. 1).

All patients underwent transthoracic echocardiography before discharge, to assess biventricular function and outcomes following either TV repair (TVr) or TV replacement (TVR).

Follow-up

Survival and echocardiographic follow-up data were obtained either via regular out-patient clinic visits or querying the informatic hospital system. If follow-up information was not retrieved through the hospital system, patients, or their referring cardiologists, were reached with telephone calls and asked to provide recent laboratory and echocardiographic data (<6 months). Cause of death was determined by death certificates or information from family members or referring physician. Clinical and echocardiographic follow-up was 93% complete; the median follow-up time was 4.2 years [2.1–7.5], with the longest follow-up time of 16.5 years.

Primary end points of the study were overall survival and cardiac mortality at follow-up. Secondary end points were freedom from reintervention, freedom from re-hospitalizations for RHF and symptomatology at long-term follow-up.

Statistical analyses

Statistical analyses were performed using SPSS (IBM, Amonk, New York, USA) and Stata Software (Statacorp, LLC, TX, USA; version 15). Analyses were exploratory in nature. Categorical variables were expressed as absolute number and percentages. Normal distribution of continuous variables was assessed with the Shapiro–Wilk test. Continuous variables normally distributed were expressed as mean ± standard deviation. Continuous variables not normally distributed were reported as median and interquartile range.

Kaplan–Meier survival curves were used for estimating mid-term survival, and log-rank test was used to assess inter-group comparisons. For competing risk analysis, we calculated the cumulative incidence function (CIF) for cardiac death (with non-cardiac death as competing risk), for reintervention (with death as a competing risk) and for re-hospitalizations for RHF (with death as a competing risk). The Fine and Gray model was used for inter-group comparisons. 95% confidence intervals and P-values were not adjusted for multiple comparisons. Due to the limited number of patients classified in stage 5, for better statistical analyses and more straightforward interpretation of results, patients in stages 4 and 5 were grouped.

RESULTS

Patient characteristics and in-hospital results

A total of 172 patients who underwent isolated TV surgery at our institution were reviewed and, based on preoperative characteristics, divided according to the 5 stages. None of our patients fulfilled criteria for stage 1, since by definition TR grade is to be considered less than moderate, and therefore, patients undergoing isolated surgical treatment had at least moderate-to-severe TR. Furthermore, an extremely limited number of patients treated were part of the end-stage disease group (stage 5). We had previously focused on in-hospital outcomes of this study population; therefore, such results will be briefly summarized for the completion of data. Baseline characteristics and in-hospital outcomes are reported in Table 1. Among the total population, 129 (75%) patients underwent isolated TVR (a bioprosthesis was used in 95.4% of cases) and 43 (25%) underwent TVr. The main aetiologies were: functional TR in 75 patients (43.6%), primary TR in 40 patients (23.3%, among whom 2 had carcinoid disease, 4 patients had congenital anomalies, 14 rheumatic disease and 20 degenerative involvement), endocarditis in 15 patients (8.7%), failure of previous TVrs was present in 14 cases (8.1%) and bioprosthesis degeneration in 4 patients (2.3%) and a mix aetiology was seen in 11 patients (6.4%) and traumatic TR in 10 patients (5.8%).

Considering the overall population, the great majority of patients were classified either in stage 3 (46.5%) or in stage 4 (36%). However, when analysing separately patients who underwent either valve repair or replacement, 46.5% of patients who underwent TVr were in stage 2, while more than half of TVR patients were in stage 3 (51.9%). Patients in stage 2 were younger and in less advanced stages of the disease with fewer signs and symptoms of RHF and organ involvement. In this stage, TVr could be performed in most patients, with no in-hospital mortality and lower risk of developing postoperative complications. On the contrary, patients in more advanced stages experienced more postoperative complications, such as acute kidney injury and low cardiac output syndrome with the need of high-dose inotropic support (Table 1).

Mid-term survival

Clinical and echocardiographic follow-up was 93% complete. The median follow-up time was 4.2 years [2.1–7.5], with the longest follow-up time of 16.5 years.

In the first 5 years of follow-up, 23 deaths (15%) occurred. Among these, no patient was in stage 2 (0%), 7 patients were in stage 3 (9.2%) and 16 in stages 4 and 5 (31%). Therefore, at 5-year follow-up, there was a statistically significant difference in survival according to the baseline preoperative classification. More specifically, mid-term survival for patients in stage 2 is 100%, 88.2 ± 4.26%, 95% CI [76.62–94.29] for patients in stage 3, without significant difference with respect to stage 2 (P = 0.298) and 60.4 ± 8.45%, 85% CI [42.00–74.65] for patients in stages 4 and 5 (P = 0.001, versus stage 2) (Fig. 2).

Of the registered long-term deaths, only 11 were reported as being cardiac related (7%). Once again, 0% were in stage 2, 5 patients (6.6%) were in stage 3 and 6 patients (12%) were in stages 4 and 5. The CIF for cardiac death, with death for any cause as competing event, at 5 years was 0% in stage 2, 8.6 ± 3.76%, 95% CI [3.10–17.74] in stage 3 and 13.2 ± 5.14%, 95% CI [5.19–24.91] in stages 4 and 5. Even though the difference was not statistically significant (stage 3 versus stage 2: P = 0.391 and stages 4 and 5 versus stage 2: P = 0.084), as shown in Fig. 3, there was a relevant trend towards an increase in cardiac deaths in more advanced stages of the disease.

Re-hospitalizations for right heart failure

Analyses performed to evaluate reoperation or rehospitalization for RHF aimed at assessing whether, regardless long-term survival, treatment in late stages of the disease would resolve TV disease but would not provide full clinical benefit on the long run due to marked RV dysfunction. At 5-year follow-up, only 4 patients (2.7%) underwent reoperation; among these, 3 were in stage 3 (3.9%) and only 1 in stages 4 and 5 (2.1%). The CIF for reoperation, with death from any cause as competing event, at 5 years was 0% in stage 2, 5.0 ± 2.87%, 95% CI [1.31–12.79] in stage 3 and 4.3 ± 4.15%, 95% CI [0.31–17.85] in stages 4 and 5, with no significant difference among groups (P = 0.392 and P = 0.202, respectively) (Fig. 4).

On the other hand, when considering long-term rehospitalizations, 20 patients (13%) experienced RHF at 5 years. Interestingly enough, RHF occurred in no patient in stage 2; however, patients in stages 3 and 4 and 5 experienced the same rate of rehospitalizations [12/76 (16%) vs 8/51 (16%), respectively]. The CIF for rehospitalization for RHF, with death for any cause as competing event, at 5 years was 0% in stage 2, 20.2 ± 5.31%, 95% CI [10.96–31.34] in stage 3 and 20.0 ± 6.76%, 95% CI [8.81–34.43] in stages 4 and 5 (P = 0.039) (Fig. 5).

Furthermore, at last follow-up, New York Heart Association class I was reported in all patients in stage 2, 20% in stage 3 and only 5% of patients in stages 4 and 5 (P < 0.001). At follow-up, no difference was reported among stages regarding recurrence of at least moderate TR. More specifically, recurrence of ≥moderate TR occurred in 8 patients, among whom 2 had residual moderate TR at discharge. Regarding TVR, all implanted prostheses functioned adequately at last follow-up, with the exception of 8 patients who experienced prostheses degeneration/malfunction (1 patient experienced mechanical prosthesis’ thrombosis). No difference among stages was reported.

DISCUSSION

This retrospective, single-centre study evaluated the mid-term results of patients undergoing isolated TV surgery based on a novel baseline clinical and functional classification of patients with TR [10]. To the best of our knowledge, this is the first study to assess long-term outcomes of isolated TV surgery according to this 5-stage classification.

Management of isolated severe TR still remains strongly influenced by 2 misleading concepts: first, that TR is a benign condition to be treated with diuretics until symptoms occur, and second, that surgical treatment of isolated TR is high-risk surgery, with elevated short- and long-term morbidity and mortality, particularly if performed with signs of RHF [15–17]. Many studies have now demonstrated that the presence of TR is a predictor of negative outcome and worse survival, independently of baseline characteristics or other conditions [18–20]. Poor outcomes following isolated TV surgery, ranging from 10% to 30% mortality [21, 22], come from limited and old series of patients. It was hypothesized that the high rate of complications and postoperative mortality was related to the associated comorbidities or the very advanced clinical presentation of patients. This was further corroborated by a recent multicentric study that showed that in-hospital and mid-term outcomes were predicted by the preoperative presentation of patients [9]. Indeed, TV surgery is relatively simple and well reproducible.

Thus, the aim of our study was to specifically assess mid-term outcomes of patients undergoing isolated TV surgery stratified according to baseline characteristics.

In-hospital results of our experience had been previously reported [11] and showed, not surprisingly, that patients in more advanced stages of the disease experienced higher number of postoperative complications, a longer both intensive care unit and postoperative length of stay, and, therefore, higher in-hospital mortality. However, the other side of the coin of such findings, further supporting our beliefs, was that whenever patients were referred early to surgery and underwent surgical treatment before the development of important symptomatology and organ involvement/damage (stage 2), a smooth and short postoperative course following TVr, as well as no in-hospital mortality, was observed in the majority of cases. However, these data were limited to in-hospital outcomes, not addressing late results at follow-up. In fact, the lack of data reporting positive outcomes following early TV surgery for isolated TR has contributed to the uncertainty as to when and how to treat this pathology. Timing for TV surgery has been controversial, and even though recent updated guidelines promote earlier intervention [23, 24], early referral is not a common practice. Patients are managed with medical therapy for years. However, surgical treatment is, to date, the only curative treatment for severe TR, while medical therapy remains mostly palliative [25].

Our surgical experience underlines how early/timely surgical treatment of TV disease results in both good short- and mid-term results. In fact, patients undergoing isolated TV surgery classified accordingly in stage 2 experienced an excellent in-hospital postoperative course, with 100% survival at 5 years, no further hospitalization for RHF and remained asymptomatic. Therefore, before the development of overt RHF symptomatology, regardless of adequate medical therapy, and RV dysfunction, isolated TV surgery is feasible and safe, with no in-hospital mortality, a very low rate of postoperative complications, a very low reported long-term follow-up mortality and excellent clinical status. Thus, not only does early surgery resolve TV disease, which negatively impacts on survival, but it also provides clinical improvement and benefit to patients. These findings should help in changing the misconception that surgical treatment is associated with excessive morbidity and mortality in all patients. In this regard, a novel dedicated risk score has been made recently available that aims at predicting the outcome of patients following isolated TV surgery, based on echocardiographic parameters and baseline clinical status. This score should help in guiding the clinical decision-making process of patients with severe isolated TR [26].

Transcatheter therapies are becoming readily available, and growing evidence support such interventions in patients deemed high risk for surgical treatment. However, selection and optimal timing are crucial also in these settings, as transcatheter procedures may still result futile in patients with end-stage heart failure, untreated pulmonary hypertension and organ damage. In addition, in most of the cases, their efficacy in decreasing the severity of TR is still limited and not comparable to the one provided by surgery [27].

Therefore, an increased awareness in the community, together with adequate patient monitoring, early referral and timely intervention, is of utmost importance, as demonstrated by our surgical experience. Both TVr and TVR, when performed early on in disease progression (stages 2 and 3), are safe, with excellent in-hospital results and good mid-term follow-up outcomes. Moreover, referral in high-volume centres, with patient evaluation by a multidisciplinary heart team, are fundamental aspects to provide a thorough workup, determine adequate classification and stratification of patients, supply perioperative advanced treatment strategies and whenever necessary circulatory support and offer a broad spectrum of treatment options.

Limitations

Our study has limitations mainly related to a retrospective single-centre study, which may have led to selection bias. The sample size is relatively small due to the few isolated TV interventions performed and also to some extent linked to the lack of sufficiently complete data. Furthermore, follow-up was not 100% complete; therefore, we cannot exclude that patients lost to follow-up died of cardiac causes or experienced re-hospitalizations for RHF.

CONCLUSIONS

Both short- and mid-term outcomes support early referral for surgery in isolated TV disease, with excellent in-hospital results, survival at 5 years and no further hospitalizations for RHF.

Presented at the 35th Annual Meeting of the European Association for Cardio-Thoracic Surgery, Barcelona, Spain, 13–16 October 2021.

ACKNOWLEDGEMENTS

This paper was written with the support of the Alfieri Heart Foundation.

Funding

No funding was received.

Conflict of interest: none declared.

Data Availability Statement

The datasets analysed in the current study are available from the corresponding author on reasonable request.

Author contributions

Alessandra Sala: Conceptualization; Data curation; Writing—original draft. Roberto Lorusso: Supervision; Writing—review & editing. Edoardo Zancanaro: Data curation. Davide Carino: Supervision. Marta Bargagna: Data curation. Arturo Bisogno: Data curation. Elisabetta Lapenna: Supervision. Stefania Ruggeri: Formal analysis. Roberta Meneghin: Data curation. Davide Schiavi: Data curation. Nicola Buzzatti: Supervision. Paolo Denti: Supervision. Fabrizio Monaco: Supervision. Eustachio Agricola: Supervision. Francesco Maisano: Supervision. Ottavio Alfieri: Supervision. Alessandro Castiglioni: Supervision. Michele De Bonis: Supervision; Writing—review & editing.

Reviewer information

European Journal of Cardio-Thoracic Surgery thanks Manuel J. Antunes, Julien Dreyfus, Omidi Negar and the other, anonymous reviewer(s) for their contribution to the peer review process of this article.

REFERENCES

ABBREVIATIONS

ABBREVIATIONS
 
• CIF

  Cumulative incidence function

 
• RHF

  Right heart failure

 
• RV

  Right ventricle

 
• TR

  Tricuspid regurgitation

 
• TV

  Tricuspid valve

 
• TVr

  Tricuspid valve repair

 
• TVR

  Tricuspid valve replacement