Effect of diuretic burden and model for end-stage liver disease-sodium score after isolated tricuspid valve surgery

Introduction

In the last decade, isolated tricuspid valve surgery (ITVS) has been associated with high in-hospital mortality rates of up to 10% and poor long-term survival (1,2). One major reason for this high mortality rate is delayed surgical referral, particularly after advanced organ dysfunction has developed (3). Furthermore, recently developed perioperative risk scores, including the TRI-SCORE, have demonstrated that beyond right ventricular function, factors such as diuretic burden and hepatorenal dysfunction significantly increase perioperative mortality rates (4-6). Therefore, to improve ITVS outcomes, appropriate surgical timing should be considered, particularly in the current era of emerging transcatheter tricuspid interventions.

Patients with isolated tricuspid regurgitation (TR) primarily exhibit right-sided heart failure, which often presents with nonspecific symptoms. Although such patients are managed with progressively increasing doses of diuretics, right ventricular dysfunction and renal impairment continue to progress gradually (7). As a result, many patients undergo surgery while receiving high-dose diuretic therapy and after presenting with advanced organ dysfunction and right-sided heart failure, thus leading to poor surgical outcomes.

In this study, we aimed to clarify the effect of preoperative diuretic burden on midterm outcomes after ITVS and examine the influence of diuretic burden and hepatorenal dysfunction on the prognosis of such patients by using a multicenter registry database. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1-2653/rc).

Methods

Patient selection

This retrospective, multicenter, observational study included patients who underwent tricuspid valve surgery at 16 centers in Japan between January 2015 and December 2024 (N=2,025). Patients were excluded if they met any of the following criteria: concomitant surgery involving other valves or the aorta; congenital heart disease; implantation of a ventricular assist device (N=1,920); and mild or less TR (N=20). A total of 85 patients who underwent ITVS were included in the final analysis (Figure 1). Patients with moderate or greater TR on the immediate preoperative echocardiogram were included, as surgical indication was determined based on overall clinical deterioration (e.g., impaired renal function and/or advanced right-sided heart failure) even when TR was graded as moderate at that time point (n=15).

Figure 1 Patient flow chart. Patients who underwent tricuspid valve surgery at 16 institutions in Japan were screened. Those who underwent concomitant surgery were excluded, and the remaining patients were stratified into two groups (high-dose and low-dose groups) according to the preoperative diuretic dose. TR, tricuspid regurgitation.

Patient data were retrieved from the database of the Osaka Cardiovascular Research Group. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Ethics Committee of Osaka University Hospital, Osaka, Japan (No. 25182; date of approval: September 3, 2025), and informed consent was obtained from all patients.

Data collection and grouping

Preoperative clinical characteristics, including age, sex, comorbidities, echocardiographic and laboratory findings, and diuretic dose, were collected from the institutional medical records of all included patients. For patients who did not receive furosemide, loop and thiazide diuretic doses were converted to furosemide-equivalent doses; 40 mg of furosemide was considered equivalent to 60 mg azosemide, 10 mg torasemide, and 2 mg trichlormethiazide (8-10). Prior studies have reported that furosemide-equivalent doses ≥41 mg/day are associated with higher mortality rates and a worse nutritional status, including in patients with TR (11-13) compared with those associated with doses ≤40 mg/day. Therefore, patients who received >40 mg/day of furosemide-equivalent diuretics were classified as the high-dose group (N=20), and those who received ≤40 mg/day were classified as the low-dose group (N=65) (Figure S1). Laboratory variables, including prothrombin time-international normalized ratio, were obtained from routine preoperative blood testing using the value closest to the day of surgery; in patients receiving anticoagulation therapy, the measured value at that time point was recorded.

Echocardiographic assessment and definitions

All echocardiographic reports obtained before surgery were reviewed, and measurements were retrospectively performed using digitally stored images when necessary. Left ventricular ejection fraction was assessed using either the Teichholz method or the biplane method of discs (modified Simpson method). TR severity was evaluated using a multiparametric approach that included the jet area, vena contracta (VC), proximal isovelocity surface area (PISA) radius, effective regurgitant orifice area measured from PISA, three-dimensional VC area (when available), and hepatic vein flow. The TRI-SCORE was calculated according to a previously published method (4). The model for end-stage liver disease (MELD)-sodium (MELD-Na) scores of all patients were calculated using the following formulae (where ln denotes the natural logarithm) (14):

MELD=3.8×ln⁡(totalbilirubin)+11.2×ln⁡(internationalnormalizedratio)+9.6×ln⁡(creatinine)+6.4[1]

MELD-Na=MELD−(serumNa)−(0.025×MELD×(140−(serumNa)))+140[2]

A MELD-Na score ≥20 has been associated with moderate-to-severe hepatorenal dysfunction in previous studies; therefore, a MELD-Na score ≥20 was used in the current study to define patients at high risk (15). Prolonged ventilation was defined as prolonged postoperative mechanical ventilatory support attributable to pulmonary complications, such as acute respiratory distress syndrome, pulmonary edema, or pneumonia.

Follow-up and endpoints

After surgery, patients were maintained on standard heart failure medications, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, beta-blockers, and diuretics, aldosterone antagonists, angiotensin receptor-neprilysin inhibitors, and sodium-glucose cotransporter-2 inhibitors, as appropriate according to institutional practice and individual patient conditions. Postoperative follow-up data, including the results of clinical evaluations, blood tests, and echocardiographic assessments, were collected at 30 days and annually from 1 to 5 years after surgery depending on their availability at each institution as well as their availability for each patient. Complete follow-up was achieved for all patients through the review of clinical records; the median follow-up duration was 3 years [interquartile range (IQR), 0.9–4.8 years].

Clinical endpoints included 5-year all-cause mortality and the composite adverse outcome, which was defined as the occurrence of cardiac death, heart failure-related hospitalization, and dialysis initiation. TR recurrence with moderate or worse severity was analyzed separately. Subgroup analyses of the following four groups stratified by the preoperative diuretic dose and MELD-Na score were performed: high-dose with MELD-Na scores ≥20; high-dose with MELD-Na scores <20; low-dose with MELD-Na scores ≥20; and low-dose with MELD-Na scores <20.

Statistical analysis

Continuous variables (presented as medians with IQR) were compared using the Mann-Whitney U test. Categorical variables (expressed as counts and percentages) were compared using the chi-square test or Fisher’s exact test. A two-sided P<0.05 was considered statistically significant. Cumulative all-cause mortality and the composite adverse outcome were estimated using the Kaplan-Meier method, and group comparisons were performed using the log-rank test. For TR recurrence, we additionally performed a competing risk analysis using the Fine-Gray method with death treated as a competing event, and group comparisons were performed using Gray’s test. Univariable and multivariable Cox regression analyses (including variables with P<0.05 in univariate analysis) were used to assess the determinants of 5-year all-cause mortality. All analyses were performed using JMP Pro 17.0 (SAS Institute Inc., Cary, NC, USA) or Python 3.12.7 (Python Software Foundation, Wilmington, DE, USA).

Results

Patients

Table 1 shows the baseline characteristics of the high-dose and low-dose groups. The total loop diuretic dose, expressed as furosemide equivalents, was 80 mg/day (IQR, 60–80 mg/day) in the high-dose group and 20 mg/day (IQR, 0–40 mg/day) in the low-dose group. Patients in the high-dose group had a significantly higher prevalence of chronic obstructive pulmonary disease (55% vs. 21%; P=0.004), lower estimated glomerular filtration rate [33 (IQR, 26–39) vs. 49 (IQR, 41–67) mL/min/1.73 m²; P<0.001], lower hemoglobin level [10.8 (IQR, 9.2–13.4) vs. 12.5 (IQR, 10.9–14.0) g/dL; P=0.02], and higher MELD-Na score [21 (IQR, 13–22) vs. 14 (IQR, 11–18); P=0.005] than those of patients in the low-dose group. Additionally, patients in the high-dose group had a greater maximum inferior vena cava diameter [25 (IQR, 22–32) vs. 23 (IQR, 18–25) mm; P=0.02], lower TR velocity [2.0 (IQR, 1.9–2.4) vs. 2.5 (IQR, 2.2–2.8) m/s; P=0.01], and greater TR VC [18.1 (IQR, 16.0–21.3) vs. 12.9 (IQR, 7.8–19.5) mm; P=0.01] than those of patients in the low-dose group. Torrential TR was more common in the high-dose group than in the low-dose group. Interestingly, atrial fibrillation was more prevalent in the low-dose group than in the high-dose group (68% vs. 35%; P=0.009).

Early results

Table 2 presents the operative details. Tricuspid valve procedures (replacement vs. repair) did not differ significantly between the two groups (P=0.30). Thirty-day mortality was not observed in the high-dose group and 3% in the low-dose group (P>0.99). In addition, no significant differences in in-hospital mortality (10% vs. 6%; P=0.62) and major postoperative complications, including pacemaker implantation (15% vs. 14%; P>0.99), were observed between the high-dose and low-dose groups.

Cumulative 5-year all-cause mortality

Figure 2 illustrates cumulative 5-year all-cause mortality in the high-dose and low-dose groups. During follow-up, 10 patients (50%) in the high-dose group and 10 patients (15%) in the low-dose group died. According to the Kaplan-Meier analysis, cumulative mortality in the high-dose group was significantly higher than that in the low-dose group (P<0.001 by log-rank test), with cumulative mortality rates of 30.7% vs. 8.0% at 1 year, 57.8% vs. 14.0% at 3 years, and 57.8% vs. 19.4% at 5 years. The univariable Cox regression analysis identified male sex, left ventricular ejection fraction, hemoglobin level, MELD-Na score, right ventricular fractional area change, and high-dose diuretic use as predictors of 5-year all-cause mortality (Table 3). The multivariable Cox regression analysis showed that the MELD-Na score was an independent determinant of all-cause mortality [hazard ratio (HR) =1.11; 95% confidence interval (CI): 1.00–1.23; P=0.045]. As procedure type (TVr vs. TVR) was expected to influence postoperative TR recurrence, we included procedure type as a covariate in the multivariable Cox model for all-cause mortality to assess whether it also affected survival. Overall, procedure type was not independently associated with all-cause mortality (HR =0.73; 95% CI: 0.22–2.45; P=0.61).

Figure 2 Cumulative 5-year mortality in the high-dose and low-dose diuretics groups. The Kaplan-Meier analysis shows cumulative all-cause mortality over 5 years in the high-dose group (red) and low-dose group (blue). The shaded areas represent 95% confidence intervals.

Cumulative incidence of the composite adverse outcome and TR recurrence

Figure 3 shows the cumulative incidence of the composite adverse outcome and TR recurrence over 5 years in the high-dose and low-dose groups. During follow-up, the composite adverse outcome occurred in 12 patients (60%) in the high-dose group and 17 patients (26%) in the low-dose group. TR recurrence was observed in eight patients (40%) in the high-dose group and 14 patients (22%) in the low-dose group. According to the Kaplan-Meier analysis, the cumulative incidence of the composite adverse outcome in the high-dose group was significantly higher than that in the low-dose group (P<0.001 by log-rank test), with cumulative incidences of 42.1% vs. 14.6% at 1 year, 66.2% vs. 23.0% at 3 years, and 77.5% vs. 31.3% at 5 years. Similarly, the cumulative incidence of TR recurrence in the high-dose group (26.0%, 53.7%, and 69.2% at 1, 3, and 5 years, respectively) was higher than that in the low-dose group (14.6%, 16.8%, and 25.4% at 1, 3, and 5 years, respectively; P=0.01 by log-rank test). In a Fine-Gray competing risk analysis treating death as a competing event, the association for TR recurrence was attenuated and was no longer statistically significant (P=0.054), although the direction remained the same (Figure S2). To facilitate clinical interpretation, we additionally analyzed TR recurrence within the high-dose group stratified by procedure type (TVr vs. TVR). Kaplan-Meier analysis showed that the estimated cumulative incidence of TR recurrence in the TVr subgroup approached 100% during follow-up, whereas no recurrence was observed after TVR (Figure S3). With multivariable Cox regression, the left ventricular ejection fraction (HR =0.97; 95% CI: 0.95–1.00; P=0.046), hemoglobin level (HR =0.78; 95% CI: 0.65–0.94; P=0.007), right ventricular fractional area change (HR =0.94; 95% CI: 0.89–1.00; P=0.04), and use of high-dose diuretics (HR =3.70; 95% CI: 1.43–9.56; P=0.007) were independently associated with the composite adverse outcome (Table S1). As moderate TR occurred only in the low-dose group, we performed sensitivity analyses restricted to patients with severe TR; these yielded results consistent with the main analysis for mortality and composite adverse events (Figure S4). For TR recurrence, the direction of effect was unchanged, although the between-group difference was attenuated in the restricted cohort.

Figure 3 Cumulative incidence of (A) the composite adverse outcome and (B) TR recurrence over 5 years in the high-dose and low-dose diuretics groups. The Kaplan-Meier analysis shows the cumulative incidence in the high-dose group (red) and low-dose group (blue). The shaded areas represent 95% confidence intervals. The composite adverse outcome was defined as a combination of cardiac death, admission for heart failure, and dialysis initiation. TR, tricuspid regurgitation.

Subgroup analysis stratified by the diuretic dose and MELD-Na score

Figure 4 shows the cumulative incidence of all-cause mortality and the composite adverse outcome over 5 years stratified by both the preoperative diuretic dose and MELD-Na score. Patients were divided into the high-dose group with MELD-Na scores ≥20 (red), high-dose group with MELD-Na scores <20 (green), low-dose group with MELD-Na scores ≥20 (blue), and low-dose group with MELD-Na scores <20 (yellow). A Kaplan-Meier analysis demonstrated significant differences in both endpoints across these four groups. Regarding all-cause mortality, the high-dose group with MELD-Na scores ≥20 had the highest cumulative mortality at 5 years (75.8%), followed by the low-dose group with MELD-Na scores ≥20 (52.8%), high-dose group with MELD-Na scores <20 (30.0%), and low-dose group with MELD-Na scores <20 (14.1%; P<0.001 by log-rank test). Regarding the composite adverse outcome, the high-dose group with MELD-Na scores <20 had the highest cumulative incidence at 5 years (100%), followed by the high-dose group with MELD-Na scores ≥20 (72.3%), low-dose group with MELD-Na scores ≥20 (33.3%), and low-dose group with MELD-Na scores <20 (30.0%; P=0.005 by log-rank test); however, the number of patients at risk in the high-dose group with MELD-Na scores <20 was small.

Figure 4 Cumulative incidence of (A) all-cause mortality and (B) the composite adverse outcome over 5 years stratified by the diuretic dose and MELD-Na score. Patients were stratified into the following four groups based on the preoperative diuretic dose and MELD-Na score: high-dose with MELD-Na scores ≥20 (red); high-dose with MELD-Na scores <20 (green); low-dose with MELD-Na scores ≥20 (blue); and low-dose with MELD-Na scores <20 (yellow). The composite adverse outcome was defined as a combination of cardiac death, admission for heart failure, and dialysis initiation. MELD-Na score, the model for end-stage liver disease-sodium score.

Discussion

Patients in the high-dose group exhibited more advanced baseline organ dysfunction characterized by reduced renal function, elevated MELD-Na scores, and higher TRI SCOREs; consequently, they experienced worse midterm outcomes after ITVS. During the 5-year follow-up period, patients in the high-dose group had significantly higher all-cause mortality and a greater cumulative incidence of the composite adverse outcome and TR recurrence compared with those of patients in the low-dose group. Furthermore, a stratified analysis that combined the preoperative diuretic burden and MELD-Na score demonstrated clear risk stratification across four groups (high-dose with high MELD-Na scores, high-dose with low MELD-Na scores, low-dose with high MELD-Na scores, and low-dose with low MELD-Na scores) and showed progressively worse midterm survival and adverse event rates with increasing burden. A higher MELD-Na score was associated with higher risk, even among patients administered low diuretic doses, and the worst outcomes were observed when both diuretic burden and the MELD-Na score were high.

Current guidelines highlight the importance of early surgical intervention and recommend that treatment should be considered for asymptomatic patients with severe isolated TR if right ventricular dilatation or dysfunction is observed (16,17). However, poor outcomes are influenced by multiple factors beyond right ventricular function, including diuretic dose, hepatorenal function, and hemoglobin levels (5,18). Therefore, the TRI-SCORE is valuable because it incorporates these factors to enhance risk prediction (4,19). Although the TRI-SCORE is useful for assessing the perioperative risk and identifying patients at high risk, additional research is necessary to clarify the optimal timing of intervention to improve postoperative outcomes. Specifically, the TRI-SCORE defines a diuretic threshold of ≥125 mg furosemide as a risk factor, but none of the patients in our cohort received furosemide-equivalent doses exceeding 125 mg/day. However, patients who received more than 40 mg had significantly higher mortality rates and a higher cumulative incidence of the composite adverse outcome. This finding suggests that the risk of adverse outcomes may increase with diuretic doses that are lower than previously reported doses, indicating that interventions should be considered before patients require a furosemide-equivalent diuretic dose >40 mg. Consistently, a recent transcatheter tricuspid valve intervention study also reported worse outcomes in patients with higher baseline loop diuretic dose (20).

Although a small subset of patients was graded as having moderate TR on the immediate preoperative echocardiogram, these patients had already developed clinical deterioration, including hepatorenal dysfunction and/or advanced right-sided heart failure features, and were therefore judged to require surgery in routine practice. As TR severity can vary with loading conditions and timing of assessment, the last preoperative TR grade may not fully reflect the degree of clinical decompensation. Importantly, a sensitivity analysis restricted to patients with severe TR preserved the main findings, indicating that the primary conclusions were not driven by inclusion of the moderate-TR subgroup.

Additionally, within the high-dose group, postoperative TR recurrence was observed only after tricuspid valve repair (TVr) and not after tricuspid valve replacement (TVR), suggesting that TVR may provide more durable TR control in patients with advanced disease, including torrential TR. However, procedure type was not independently associated with all-cause mortality in the adjusted analysis, indicating that baseline end-organ dysfunction rather than procedural choice may have contributed more strongly to postoperative survival.

The unfavorable outcomes in the high-dose group may reflect both an advanced baseline status and deleterious effects of aggressive diuretic therapy. Aggressive diuretic therapy can impair renal function and may promote end-organ dysfunction. Accordingly, sustained aggressive diuretic therapy may have contributed to the progression of end-organ dysfunction in the high-dose group with high MELD-Na scores. Patients in this subgroup had the poorest outcomes. Notably, the postoperative outcomes of the high-dose group with low MELD-Na scores were comparable to those of the low-dose group with high MELD-Na scores and worse than those of the low-dose group with low MELD-Na scores. These findings suggest that once escalation to high-dose diuretics becomes necessary, surgical referral should be considered even if significant organ dysfunction has not yet developed.

Furthermore, even among patients receiving a diuretic dose ≤40 mg, those with impaired hepatorenal function showed increased rates of midterm mortality and adverse outcomes. The prognostic utility of the MELD score extends beyond liver transplantation and has been validated in various cardiovascular settings. Elevated MELD scores are associated with adverse outcomes of advanced heart failure, cardiac surgery, and heart transplantation and often provide superior risk stratification in conventional models (21-23). Particularly, operative mortality after tricuspid valve surgery increases stepwise across MELD strata, and outcomes in patients with MELD ≥20 may be worse than those predicted by The Society of Thoracic Surgeons Predicted Risk of Mortality and the European System for Cardiac Operative Risk Evaluation II (24). The MELD-Na score incorporates serum Na levels to account for the fluid status, thereby providing a more comprehensive measure of systemic congestion and end-organ dysfunction (15). These findings suggest that even when patients require a low dose of diuretics, the surgical risk increases with hepatorenal dysfunction, which is better captured by the MELD-Na score, and that transient improvements in MELD-Na scores with dose escalation do not improve outcomes, thus underscoring the need for early surgical referral.

Although the absolute threshold of 40 mg furosemide-equivalent diuretics may not be universally applicable because of differences in body size and clinical practice patterns between Western and Asian populations, the key implication that surgical referral should be considered when a notable increase in the diuretic dose becomes necessary remains valid.

This study has a few limitations. First, owing to institutional variability, a detailed assessment of right ventricular function using echocardiography was not consistently obtainable, thus limiting the completeness of the dataset. Second, as an inherent limitation of retrospective multicenter observational studies, differences in patient selection and treatment approaches among the centers may have introduced selection bias. In addition, atrial functional TR phenotyping and detailed rhythm-related variables were not uniformly available across centers; therefore, we could not determine whether the distribution of atrial functional TR differed between groups, which may partly explain the observed imbalance in atrial fibrillation prevalence. Detailed information on contemporary heart failure medications was also not uniformly available across all participating centers; therefore, these therapies could not be fully incorporated into the present analysis. Finally, the rarity of ITVS resulted in a limited sample size, which may have introduced statistical type II errors, thus underscoring the need for larger prospective cohorts.

Conclusions

Higher preoperative diuretic burden was associated with worse midterm outcomes after ITVS. Increasing the diuretic dose to relieve congestion and mitigate organ dysfunction does not reliably improve outcomes; therefore, surgical referral is best considered during low-dose therapy, before high-dose diuretics become necessary, and before overt organ dysfunction develops. Future studies should include larger prospective cohorts as well as standardized echocardiography assessments, patient selection methods, and treatment protocols to validate the prognostic utility of diuretic burden and the MELD-Na score.

Acknowledgments

We would like to thank the clinical staff at the 16 participating centers for their contributions to data collection and perioperative care. Use of AI-assisted tools: during the preparation of this manuscript, the authors used ChatGPT (OpenAI) in order to assist with English translation of draft text and with minor language editing (grammar and phrasing). The authors verified and edited all AI-assisted text and are responsible for the final content. No AI tools were used for study design, data collection, data processing, statistical analysis, figure/image generation, or interpretation of results.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1-2653/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1-2653/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1-2653/prf

Funding: This work was supported by Edwards Lifesciences Japan LLC. The funder had no role in the study design, data analysis, or manuscript preparation.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1-2653/coif). All authors report that this work was supported by Edwards Lifesciences Japan LLC. The funder had no role in the study design, data analysis, or manuscript preparation. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Ethics Committee of Osaka University Hospital, Osaka, Japan (No. 25182; date of approval: September 3, 2025), and informed consent was obtained from all patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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