Introduction

Cardiac resynchronization therapy (CRT) is an established treatment for patients who have advanced-stage heart failure (HF) with a reduced left ventricular ejection fraction (LVEF) and wide QRS complex.1, 2 However, individual outcomes in CRT recipients vary significantly, and long-term death rates remain high.3 Certain patients, such as those with ischaemic cardiomyopathy, severely dilated ventricles, or right ventricular (RV) dysfunction, have been reported to derive less survival benefit than expected from CRT.4, 5 Therefore, risk stratification of potential CRT candidates on the basis of pre-implantation assessment remains important.

Low cardiac output and systemic venous congestion due to advanced HF are known to cause multiple organ dysfunction or tissue damage, which leads to disease progression and adverse outcomes.6, 7 Traditionally, organ dysfunction is evaluated in isolation, meanwhile in clinical settings, several organs may be caused, which can be a marker of more severe HF.8

The Model for End-stage Liver Disease (MELD) score, which is based on bilirubin, creatinine, and the international normalized ratio, reflects liver and kidney function.9 This score was originally developed for prognostic assessment in patients with advanced liver disease.10 The MELD-XI score is one of the several modified MELD scores, and unlike the standard MELD score, it excludes the international normalized ratio value.11 Recently, several studies reported the prognostic relevance of the MELD-XI score in a variety of patients, including those with advanced HF undergoing left ventricular (LV) assist device implantation, those with severe mitral regurgitation (MR) undergoing percutaneous mitral valve repair, and those with severe aortic valve stenosis undergoing transcatheter aortic valve implantation.12-14 However, the relationship between the severity of hepatorenal dysfunction assessed by the MELD-XI score and the long-term clinical outcomes of HF patients receiving CRT has not been evaluated.

In this real-world, observational study, we examine the potential use of the MELD-XI score as a risk assessment tool for all-cause mortality in HF patients receiving CRT. In addition, we investigated whether the predictive value of the MELD-XI score differed between patients receiving CRT with a pacemaker (CRT-P) or an implantable cardioverter–defibrillator (CRT-D).

Methods Patients and study protocol

This was a single-centre, retrospective, observational cohort study. We screened 285 consecutive patients who underwent CRT implantation at Nihon University Itabashi Hospital between March 2004 and October 2020. Two patients were excluded because of lack of data for one or both of the components of the MELD-XI score (total bilirubin or creatinine), and the remaining 283 patients were investigated. This study was approved by the ethics committee of Nihon University Itabashi Hospital (RK-210209-8). The investigation conformed to the principles outlined in the Declaration of Helsinki.

Laboratory tests and the MELD-XI score

The MELD-XI score was determined based on total bilirubin and creatinine levels obtained before CRT implantation. The MELD-XI score was calculated as previously reported: 11.76 × ln (creatinine [mg/dL]) + 5.11 × ln (total bilirubin [mg/dL]) + 9.44.11 If a patient had a creatinine or total bilirubin level lower than 1.0 mg/dL, a value of 1.0 mg/dL was used to prevent negative logarithmic values in the formula.15 Patients were divided into three groups based on the tertile of the MELD-XI score.

Echocardiographic measurement

Echocardiography was performed by experienced technicians according to the guidelines of the American Society of Echocardiography.16 End-systolic and end-diastolic LV volumes were measured in the apical four-chamber and two-chamber views. LVEF was measured by the modified Simpson's method. The RV end-diastolic diameter (RVDd) was measured at the basal ventricular level of the RV in end-diastole. The RV fractional area change (RVFAC) was obtained by tracing the RV end-diastolic area (RVEDA) and end-systolic area (RVESA) in the apical four-chamber view using the following formula: (RVEDA − RVESA)∕RVEDA × 100. MR and tricuspid regurgitation (TR) were graded on a 4-point scale based on colour-flow Doppler images. The TR pressure gradient (TRPG) was measured using continuous-wave Doppler imaging. From the subcostal view, the diameter of the inferior vena cava (IVC) in its long axis was measured within 3 cm of the IVC–right atrium junction during passive respiration.

Cardiac resynchronization therapy

All patients underwent device implantation under local anaesthesia. As previously described, atrioventricular delay was optimized automatically by each device, but if the QRS duration did not narrow sufficiently, the atrioventricular and interventricular delays were optimized manually based on the QRS duration observed on the electrocardiogram.17 Thereafter, patients were followed up in dedicated device therapy clinics at regular 3–6 month intervals. We evaluated two definitions of CRT response: functional and echocardiographic.17 The functional CRT response was defined as the combination of improvement by at least one New York Heart Association (NYHA) functional class and the absence of death or hospitalization due to HF at 6 months after CRT implantation.17, 18 The echocardiographic CRT response was defined as an improvement in the LVEF of at least 5% or a reduction in the LV end-systolic volume (LVESV) of at least 15% at 6 months after CRT implantation.17

Follow-up and endpoint

The primary endpoint was all-cause mortality, and the secondary endpoint was the incidence of cardiac death. Patients were followed from the date of device implantation to December 2020 or until the endpoint. Follow-up data were collected in a blinded fashion via review of all available medical records.

Statistical analysis

Continuous variables are presented as medians (inter-quartile range) and categorical variables as numbers (percentage). Statistical differences between continuous variables were compared using one-way analysis of variance followed by the post hoc Tukey–Kramer test, or the Kruskal–Wallis test followed by the Steel–Dwass test. Categorical variables were compared by the χ2 test with Bonferroni correction. Correlations between variables were tested by Pearson's correlation coefficient. The Kaplan–Meier method was used to analyse patient survival, and the log-rank test was used to compare group differences.

The associations between pre-CRT implantation characteristics and all-cause mortality were assessed with a Cox proportional hazards regression analysis. Hazard ratios with 95% confidence intervals were calculated. To satisfy the model assumptions, data of N-terminal pro-brain natriuretic peptide (NT-proBNP) were subjected to natural log transformation (ln). Until January 2010, we measured BNP levels instead of NT-proBNP levels, and all BNP data were converted to NT-proBNP data using the following formula: NT-proBNP = BNP1.341 − 15.19

Multivariate Cox proportional hazards regression analysis was used to evaluate the impact of the MELD-XI score. We constructed multivariate models to adjust for the effect of established confounders such as the following: age, sex, diabetes mellitus (DM), ischaemic myopathy, atrial fibrillation, QRS duration >150 ms, LVESV, and moderate or severe MR (Model 1); the effect of a conventional risk score (the VALID-CRT risk score, Model 2); and the effect of echocardiographic parameters related to the severity of right HF (RVDd, RVFAC, TRPG, moderate or severe TR, and maximal IVC diameter) (Model 3). The VALID-CRT risk score was constructed and validated using the following variables: age, sex, implantable cardioverter defibrillator backup, atrial fibrillation, presence or absence of atrioventricular junction ablation in the case of atrial fibrillation, ischaemic aetiology, DM, NYHA class, and LVEF.20 Furthermore, to assess whether the accuracy of predicting all-cause mortality would improve after adding the MELD-XI score to a baseline model consisting of the VALID-CRT risk score, the C-statistics, net reclassification improvement, and integrated discrimination improvement were calculated.

In the sensitive analysis, we classified patients into three groups based on the lowest 20%, middle 60%, and the highest 20% of the MELD-XI score. We then compared the clinical characteristics and clinical outcomes among three groups.

For all analyses, P < 0.05 was considered statistically significant. All statistical analyses were performed using JMP 13.0 (SAS Institute, Cary, NC, USA) and the R Statistics Version 3.5.3 (R Foundation for Statistical Computing, Vienna, Austria).

Results Study population

The distribution of MELD-XI scores among the study patients is shown in Figure 1. The median (inter-quartile range) MELD-XI score was 10.5 (9.4–14.6). The cut-off values used to define the MELD-XI score tertiles were determined to be 9.44 and 13.3, and patients were stratified into three groups accordingly: first tertile (MELD-XI = 9.44, n = 95), second tertile (9.44 < MELD-XI < 13.4, n = 94), and third tertile (MELD-XI ≥ 13.4, n = 94). The baseline clinical characteristics for each group are shown in Table 1. Compared with the other two groups, the third tertile group exhibited the following significant differences: older age; higher prevalence of men; higher prevalence of diabetes mellitus and hypertension; lower administration rates of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker; lower haemoglobin level; and higher levels of total bilirubin, blood urea nitrogen, creatinine, and NT-proBNP (all P < 0.05). The third tertile group also exhibited a higher prevalence of moderate or severe TR, as well as higher TRPG (all P < 0.05). Echocardiographic parameters related to left HF (LV end-diastolic volume, LVESV, LVEF, and MR severity) did not differ significantly between the three groups.

Distribution of MELD-XI scores.

Table 1. Clinical characteristics of patients stratified into three groups according to tertiles of the MELD-XI score Item

First tertile

MELD-XI = 9.44

(n = 95)

Second tertile

9.44 < MELD-XI < 13.4

(n = 94)

Third tertile

MELD-XI ≥ 13.4

(n = 94)

P value Baseline clinical data Age (years) 69 (60–74) 67 (57–76) 72 (64–79)*,† 0.019 Male, n (%) 64 (67.3) 79 (84.0)* 76 (80.8)* 0.016 Body mass index (kg/m2) 21.4 (18.8–24.3) 22.4 (20.4–25.3) 22.3 (19.9–24.8) 0.096 NYHA IV, n (%) 9 (9.4) 11 (11.7) 20 (21.8) 0.052 Diabetes mellitus, n (%) 25 (26.3) 36 (38.3) 44 (46.8)* 0.012 Hypertension, n (%) 38 (40.0) 49 (52.1) 56 (59.5)* 0.024 Ischaemic cardiomyopathy, n (%) 25 (26.3) 36 (38.3) 35 (37.2) 0.15 Atrial fibrillation, n (%) 17 (17.8) 23 (24.4) 27 (28.7) 0.21 QRS duration (ms) 152 (128–172) 150 (123–174) 150 (130–168) 0.89 VALID-CRT risk score 0.80 (−0.08–1.23) 0.76 (0.19–1.35) 0.89 (0.27–1.51) 0.066 Medications ACE-I or ARB, n (%) 65 (68.4) 70 (75.2) 52 (55.3)† 0.013 Beta-blocker, n (%) 85 (89.4) 89 (95.7) 83 (88.3) 0.16 Diuretic, n (%) 86 (90.5) 87 (93.5) 78 (82.9) 0.058 Laboratory data Haemoglobin (g/dL) 12.7 (11.7–13.8) 13.4 (11.2–14.3) 11.7 (10.4–13.0)*,† <0.001 Platelet count (× 103/μL) 201 (169–253) 188 (157–221) 190 (146–220) 0.033 Total bilirubin (mg/dL) 0.6 (0.4–0.8) 0.8 (0.5–1.1)* 0.6 (0.3–1.3) 0.002 AST (U/L) 22 (19–31) 25 (19–34) 23 (17–31) 0.37 ALT (U/L) 18 (13–30) 19 (15–28) 17 (12–28) 0.42 GGT (U/L) 41 (22–84) 49 (27–97) 43 (24–72) 0.58 Sodium (mEq/L) 140 (138–142) 139 (137–141) 139 (136–141) 0.15 BUN (mg/dL) 18 (13–22) 21 (16–26)* 33 (25–47)*,† <0.001 Cr (mg/dL) 0.8 (0.7–0.9) 1.0 (1.0–1.1)* 1.7 (1.4–2.5)*,† <0.001 NT-proBNP (pg/mL) 2310 (1018–5689) 2743 (1417–8029) 7119 (2319–15,461)*,† <0.001 Echocardiographic data LVEDV (mL) 199 (162–259) 215 (163–263) 197 (144–255) 0.46 LVESV (mL) 147 (105–191) 153 (101–201) 134 (90–189) 0.36 LVEF (%) 30 (21–38) 27 (21–36) 30 (23–38) 0.35 Moderate or severe MR, n (%) 17 (17.8) 10 (10.6) 19 (20.2) 0.17 RVDd (mm) 31 (25–35) 34 (30–38) 32 (29–38) 0.13 RVFAC (%) 45 (34–52) 44 (32–50) 42 (35–52) 0.41 Moderate or severe TR, n (%) 11 (14.3) 22 (29.7) 26 (34.2)* 0.009 TRPG (mmHg) 18 (5–30) 22 (5–31) 27 (15–39)*,† 0.019 Maximal IVC diameter (mm) 14 (11–17) 16 (11–19) 15 (13–19) 0.17 ACE-I, angiotensin-converting enzyme inhibitor; ALT, alanine aminotransferase; ARB, angiotensin receptor blocker; AST, aspartate aminotransferase; BUN, blood urea nitrogen; Cr, creatinine; CRT, cardiac resynchronization therapy; GGT, γ-glutamyl transferase; IVC, inferior vena cava; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; MELD-XI, Model for End-stage Liver Disease excluding the International normalized ratio; MR, mitral regurgitation; NT-proBNP, N-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association; RVDd, right ventricular end-diastolic diameter; RVFAC, right ventricular fractional area change; TR, tricuspid regurgitation; TRPG, tricuspid regurgitation pressure gradient. Values are shown as the median (inter-quartile range) or number (%). For multiple comparisons, the ANOVA test was used for symmetrical continuous variables, the Kruskal–Wallis test was used for non-symmetrical continuous variables, and the χ2 test was used for categorical variables. All pair comparisons were performed based on the Tukey–Kramer test for symmetrical continuous variables, the Steel–Dwass test for non-symmetrical continuous variables, and the χ2 test with Bonferroni correction for categorical variables. Hepatorenal function and cardiac resynchronization therapy response

In this study population, 277 patients underwent 6 months of follow-up. Of these patients, 210 (75.8%) were categorized as functional CRT responders. The functional CRT response rates were 79.3% in the first tertile group, 82.9% in the second tertile group, and 64.8% in the third tertile group. The functional CRT response rate was significantly lower in the third tertile group than in the other two groups (P = 0.011). Of 263 patients who underwent follow-up echocardiography 6 months after CRT implantation, 190 (72.2%) were categorized as echocardiographic CRT responders. The echocardiographic CRT response rates were 78.6% in the first tertile group, 73.3% in the second tertile group, and 64.2% in the third tertile group (P = 0.10). The MELD-XI score before CRT implantation was not significantly correlated with the rate of LVEF change from before to after CRT implantation (r = −0.08, P = 0.18).

Hepatorenal function and clinical outcomes

The median (inter-quartile range) follow-up period was 30 (9–67) months, and 105 patients died (58 cardiac deaths and 47 non-cardiac deaths). Kaplan–Meier curves revealed that patients with a higher MELD-XI score had a greater risk of all-cause mortality than those with lower MELD-XI scores (log-rank test: P < 0.001, Figure 2). Furthermore, the rate of cardiac deaths was significantly higher in patients with a higher MELD-XI score (log-rank test: P = 0.002, Figure 3). Univariate Cox proportional hazards regression analysis revealed that a higher MELD-XI score was significantly associated with all-cause mortality, along with lower body mass index, higher NYHA functional class, atrial fibrillation, QRS duration, higher VALID-CRT risk score, lower haemoglobin and sodium levels, and higher blood urea nitrogen and NT-proBNP levels (all P < 0.05, Table 2). Regarding echocardiographic parameters, lower RVFAC, moderate or severe TR, and higher TRPG were significantly associated with all-cause mortality in univariate Cox proportional hazards regression analysis (all P < 0.05, Table 2). Total bilirubin and creatine levels did not separately show a significant association with all-cause mortality. A higher MELD-XI score was significantly associated with all-cause mortality after adjusting for the VALID-CRT risk score, other previously reported clinically relevant factors (age, sex, DM, ischaemic myopathy, atrial fibrillation, QRS duration >150 ms, LVESV, and moderate or severe MR), and echocardiographic parameters related to right HF (RVDd, RVFAC, moderate or severe TR, TRPG, and maximal IVC diameter) (Table 3). Furthermore, adding the MELD-XI score to a baseline model consisting of the VALID-CRT risk score significantly increased the net reclassification improvement and integrated discrimination improvement for predicting all-cause mortality (Table 4).

Kaplan–Meier curves of overall survival for patient groups defined according to the first, second, and third tertiles of the MELD-XI score.

Kaplan–Meier curves of event (cardiac death)-free survival for patient groups defined according to the first, second, and third tertiles of the MELD-XI score.

Table 2. Univariate Cox proportional hazards analysis for risk of all-cause mortality Item Hazard ratio 95% CI P Age (per 1 year increase) 1.00 0.98–1.01 0.69 Male 1.16 0.73–1.94 0.53 Body mass index (per 1 kg/m2 increase) 0.9 0.87–0.936 <0.001 NYHA IV (vs. NYHA II or III) 9.31 5.73–14.9 <0.001 Diabetes mellitus 1.22 0.81–1.80 0.32 Ischaemic cardiomyopathy 1.22 0.81–1.81 0.33 Atrial fibrillation 1.74 1.14–2.61 0.011 QRS duration >150 ms 0.55 0.37–0.82 0.003 VALID-CRT risk score (per 1 increase) 1.40 1.12–1.76 0.002 Haemoglobin (per 1 g/dL increase) 0.80 0.73–0.88 <0.001 Platelet count (per 1 × 103/μL increase) 0.99 0.99–1.00 0.24 Total bilirubin (per 0.1 mg/dL increase) 1.00 0.66–1.45 0.98 AST (per 10 U/L increase) 0.95 0.81–1.00 0.37 ALT (per 10 U/L increase) 0.96 0.85–1.00 0.37 GGT (per 10 U/L increase) 1.00 0.98–1.02 0.40 Sodium (per 1 mmol/L increase) 0.91 0.86–0.96 <0.001 BUN (per 1 mg/dL increase) 1.02 1.00–1.02 <0.001 Cr (per 0.1 mg/dL increase) 1.01 0.99–1.01 0.052 ln [NT-proBNP] (per 1 increase) 1.61 1.38–1.89 <0.001 MELD-XI score (per 1 increase) 1.04 1.01–1.07 0.002 LVEDV (per 10 mL increase) 1.00 0.97–1.02 0.96 LVESV (per 10 mL increase) 1.00 0.97–1.03 0.67 LVEF (per 1% increase) 0.98 0.96–1.00 0.066 Moderate or severe MR 1.26 0.78–1.96 0.32 RVDd (per 1 mm increase) 0.99 0.97–1.02 0.99 RVFAC (per 1% increase) 0.98 0.96–0.99 0.046 Moderate or severe TR 1.74 1.04–2.84 0.032 TRPG (per 1 mmHg increase) 1.02 1.01–1.04 <0.001 Maximal IVC diameter (per 1 mm increase) 1.02 0.98–1.06 0.19 CI, confidence interval. Other abbreviations as in Table 1. Table 3. Multivariate Cox proportional hazards analysis for risk of all-cause mortality Model MELD-XI (per 1 increase) Hazard ratio 95% CI P Model 1 1.04 1.00–1.07 0.014 Model 2 1.04 1.01–1.09 0.005 Model 3 1.04 1.01–1.08 0.020 CI, confidence interval; MELD-XI, Model for End-stage Liver Disease excluding the International normalized ratio. Model 1 = adjusted for age, sex, and clinically relevant factors (diabetes mellitus, ischaemic cardiomyopathy, atrial fibrillation, QRS duration >150 ms, left ventricular end-systolic volume, and moderate or severe mitral regurgitation). Model 2 = adjusted for VALID–cardiac resynchronization therapy risk score. Model 3 = adjusted for age, sex, and factors related to right heart failure (right ventricular end-diastolic diameter, right ventricular fractional area change, tricuspid regurgitation pressure gradient, moderate or severe tricuspid regurgitation, and maximal inferior vena cava diameter). Table 4. Use of the MELD-XI score together with the VALID-CRT risk score improves the prediction of all-cause mortality Risk score C-statistics (95% CI) P NRI (9