Abstract
Current guidelines lack clear recommendations between the implantation of cardiac resynchronization therapy (CRT) with defibrillator (CRT-D) and CRT with pacemaker (CRT-P). We hypothesized that modified model for end-stage liver disease score including albumin (MELD-Albumin score), could be used to select patients who may not benefit from CRT-D. We consecutively included patients with CRT-P or CRT-D implantation between 2010 and 2022. The primary endpoint was the composite of all-cause mortality or worsening heart failure. We performed multivariable-adjusted Cox proportional hazard regression. We assessed the interaction between the MELD-Albumin score and the effect of adding a defibrillator with CRT.A total of 752 patients were included in this study, with 291 implanted CRT-P. During a median follow-up of 880 days, 205 patients reached the primary endpoint. MELD-Albumin score was significantly associated with the primary endpoint in the CRT-D group [HR 1.16 (1.09–1.24); P < 0.001] but not in the CRT-P group [HR 1.03 (0.95–1.12); P = 0.49]. There was a significant interaction between the MELD-Albumin score and the effect of CRTD (P = 0.013). The optimal cut-off value of the MELD-Albumin score was 12. For patients with MELD-Albumin ≥ 12, CRT-D was associated with a higher occurrence of the primary endpoint [HR 1.99 (1.10–3.58); P = 0.02], whereas not in patients with MELD-Albumin < 12 [HR 1.19 (0.83–1.70); P = 0.35). Our findings suggest that CRT-D is associated with an excess risk of composite clinical endpoints in HF patients with higher MELD-Albumin score.
Keywords: Cardiac resynchronization therapy with pacemaker, Cardiac resynchronization therapy with defibrillator , MELD-Albumin score, Clinical endpoints
Graphical Abstract
Graphical abstract.
Introduction
Cardiac resynchronization therapy (CRT) and implantable cardioverter defibrillator (ICD) are fundamental therapies that have shown significant mortality and morbidity benefits in specific subgroups of heart failure (HF).1,2 However, there is still a debate on the benefit of adding a defibrillator in patients with the indication for CRT.3–9
The modified Model for End-stage Liver Disease (MELD) score, which replaces international normalized ratio with serum albumin (MELD-Albumin),10 was an independent predictor of all-cause mortality in patients with HF.11 We hypothesized that the MELD-Albumin score could be a valuable indicator to predict the treatment effect of adding ICD to CRT on HF patients with the indication for CRT.
Methods
This study enrolled patients with CRT with pacemaker (CRT-P) or CRT with defibrillator (CRT-D) implantation between January 2010 and October 2022 at Fuwai Hospital. In brief, we included patients with left ventricular ejection fraction (LVEF) ≤ 35% and had indications for CRT. For patients with CRT-D, those with secondary prophylactic implantation were excluded. The study was approved by the institutional review boards.
The MELD-Albumin score was calculated according to formulas in a previous study.10 In order to avoid negative values, the lower limit of total bilirubin and creatinine is set at 1.0 mg/dL. The MELD-Albumin was calculated as follows: 11.2 × ln (1) + (3.78 × ln bilirubin) + (9.57 × ln creatinine) + 6.43 when serum albumin was ≥4.1 g/dL. When serum albumin was <4.1 g/dL, MELD-Albumin was calculated as follows: 11.2 × ln [1 + (4.1 − albumin)] + (3.78 × ln bilirubin) + (9.57 × ln creatinine) + 6.43.
The primary outcome was the composite of all-cause mortality or worsening HF. The secondary outcome included the individual components of the primary outcome. Time-to-event data were analysed with the use of Kaplan–Meier estimates and the Cox proportional hazards models. The differential prognosis values of the MELD-Albumin score in different subgroups were tested via the introduction of the interaction terms. The optimal cut-off value of the MELD-Albumin score was determined by maximally selected rank statistics. We performed a subgroup analysis in patients with non-ischaemic cardiomyopathy (NICM). All statistical analyses were performed using R version 4.2.1.
Results
In total, 752 patients were included in the analysis. Among these, 291 (38.7%) were CRT-P patients and 461 (61.3%) were CRT-D patients. The mean age was 59.4 ± 11.0 years, and 69.1% of patients were male. The mean LVEF was 27.7 ± 5.0%. A total of 18.6% of patients had ischaemic cardiomyopathy. During a median follow-up of 880 days (771–1006 days), 205 (27.3%) patients reached the composite endpoint. Among those who reached the primary endpoint, 78 were in the CRT-P group and 127 were in the CRT-D group.
In multivariable Cox analysis, there was a significant interaction between the device type and MELD-Albumin score (Pinteraction = 0.013). In the CRT-D group, the MELD-Albumin score was an independent predictor of the composite endpoint in multivariable Cox analysis [HR 1.16 (1.09–1.24); P < 0.001], while this was not present in the CRT-P group [HR 1.03 (0.95–1.12); P = 0.49] (Table 1).
Table 1.
Prediction of clinical outcomes in the CRT-D and CRT-P groups
| CRT-D group | CRT-P group | |||
|---|---|---|---|---|
| (n = 461) | (n = 291) | |||
| MELD-Albumin | Hazard ratio | P value | Hazard ratio | P value |
| (95%CI) | (95%CI) | |||
| Composite endpoint | 1.16 (1.09–1.24) | <0.001 | 1.03 (0.95–1.12) | 0.49 |
| All-cause mortality | 1.16 (1.07–1.26) | <0.001 | 1.08 (0.98–1.19) | 0.11 |
| Worsening HF | 1.12 (1.05–1.20) | <0.001 | 0.93 (0.84–1.04) | 0.21 |
CRT-D, cardiac resynchronization therapy with defibrillator; CRT-P, cardiac resynchronization therapy with pacemaker; MELD, modified Model for End-stage Liver Disease.
The relationship between the MELD-Albumin score and the effect of CRT-D compared with CRT-P is presented in the Graphical Abstract. With a low MELD-Albumin score, there was no significant difference between CRT-D and CRT-P regarding the composite endpoint. However, as the MELD-Albumin score increased, CRT-D was associated with a higher risk of the composite endpoint. The optimal cut-off of the MELD-Albumin score was 12. The implantation of CRT-D was associated with an approximate two-fold higher risk of the composite endpoint [HR 1.99 (1.10–3.58); P = 0.02] in patients with a MELD-Albumin score ≥ 12. In contrast, in patients with MELD-Albumin score < 12, there was no significant difference between the CRT-D group and the CRT-P group [HR 1.19 (0.83–1.70); P = 0.35].
The subgroup analysis of the patients with NICM showed similar results. The MELD-Albumin score was significantly associated with the composite endpoint in the CRT-D group [HR 1.17 (1.09–1.25); P = 0.03], but not in the CRT-P group [HR 0.99 (0.91–1.09); P = 0.87; Pinteraction = 0.03].
Discussion
The most valuable of this study was the MELD-Albumin score could be a useful marker to identify HF with reduced ejection fraction patients who might not benefit from the addition of ICD to CRT. Compared to CRT-P, CRT-D may further improve survival by reducing sudden cardiac death (SCD). Nevertheless, CRT-P per se reduces the risk of SCD and there has been a gradual decrease in SCD rates since the early 2000s.12
The MELD-Albumin score not only eliminates the confounding effects of the anticoagulation but also provides additional prognosis information since albumin is another prominent individual prognostic variable of liver function tests. In the analysis of the PARADIGM-HF study, albumin and total bilirubin showed a distinct temporal profile in patients who suffered SCD.13 Moreover, an albumin level < 4 g/dL was associated with a differential risk of sudden vs. non-sudden cardiovascular deaths (CVD), which meant that albumin < 4 g/dL was distinctively associated with a higher risk for non-sudden CVD. And according to the formula of the MELD-Albumin score, a conditional formula was used based on the difference between albumin and 4.1 g/dL. For patients with albumin < 4.1 g/dL, the lower the albumin, the higher the MELD-Albumin score, while for patients with albumin ≥ 4.1 g/dL, the number 1 was used in the formula. In this study, patients with a higher MELD-Albumin score might have a higher risk of non-sudden death, which could not be attenuated by CRT-D. Besides, CRT-D added specific risks, such as inappropriate shocks, which were associated with poor health outcomes.14 This could partly explain the increased risk of CRT-D in patients with a MELD-Albumin score ≥ 12.
Our study should be interpreted in the context of the limitations of observational single-centre analysis. Furthermore, the optimal cut-off of MELD-Albumin score ≥ 12 needs to be prospectively evaluated. Finally, further studies are needed to confirm our results in patients with ischaemic cardiomyopathy, given that the majority of patients in our study had NICM (81.4%).
Conclusion
Our findings suggest that the implantation of CRT-D is associated with an excess risk of all-cause mortality and worsening HF in HF patients with a higher MELD-Albumin score compared with that of CRT-P.
Contributor Information
Sijing Cheng, The Cardiac Arrhythmia Center, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.167 North Lishi Road, Beijing 100037, China.
Yu Deng, The Cardiac Arrhythmia Center, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.167 North Lishi Road, Beijing 100037, China.
Hao Huang, The Cardiac Arrhythmia Center, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.167 North Lishi Road, Beijing 100037, China.
Yu Yu, The Cardiac Arrhythmia Center, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.167 North Lishi Road, Beijing 100037, China.
Hongxia Niu, The Cardiac Arrhythmia Center, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.167 North Lishi Road, Beijing 100037, China.
Wei Hua, The Cardiac Arrhythmia Center, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.167 North Lishi Road, Beijing 100037, China.
Funding
This study was supported by high-level hospital clinical research funding of Fuwai Hospital, Chinese Academy of Medical Sciences (No.2022-GSP-GG-11).
Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.