Effects of sacubitril‐valsartan in the treatment of chronic heart failure patients with end‐stage renal disease undergoing dialysis

Abstract Background The data on the effects of the angiotensin receptor–neprilysin inhibitor (ARNI) sacubitril‐valsartan (LCZ696) in chronic heart failure (CHF) patients with end‐stage renal disease (ESRD) requiring dialysis are lacking. This study assessed the efficacy and safety of LCZ696 in CHF patients with ESRD on dialysis. Hypothesis LCZ696 treatment can reduce rehospitalization rate for HF, delay the occurrence of rehospitalization for HF, and prolong the survival time. Methods We retrospectively analyzed the clinical data of CHF patients with ESRD on dialysis who were admitted to the Second Hospital of Tianjin Medical University from August 2019 to October 2021. Results Sixty‐five patients had primary outcome during the follow‐up. The incidence of rehospitalization for HF in the control group was significantly higher than that in the LCZ696 group (73.47% vs. 43.28%, p = .001). There was no significant difference in mortality between the two groups (8.96% vs. 10.20%, p = 1.000). Our study included a time‐to‐event analysis through 1 year for the primary outcome—Kaplan–Meier curve showed that the LCZ696 group had significantly longer free‐event survival time than the control group over 1‐year follow‐up (median survival time 139.0 days vs. 116.0 days, p = .037). Conclusions Our study found that LCZ696 treatment was associated with a reduction in HF rehospitalization without significant effects on serum creatinine and serum potassium levels. LCZ696 is effective and safe in CHF patients with ESRD on dialysis.


| Study design and patients
This study is a retrospective cohort study of CHF patients with ESRD on dialysis who were admitted to the Department of Cardiology, Department of Nephrology, and Department of Blood Purification in the Second Hospital of Tianjin Medical University from August 2019 to October 2021. The inclusion criteria were as follows: (1) Patients aged ≥ 18 years were hospitalized for an episode of acute decompensated heart failure (ADHF; due to deterioration of CHF, NYHA II-IV) and well on discharge; (2) received in-hospital LCZ696 for the first time, (the LCZ696 group) or did not receive any RAAS inhibitors (the control group); and (3) the patients were complicated with ESRD, receiving HD or PD.
The patients were admitted for an episode of ADHF and discharged following the completion of treatment. They were divided into the LCZ696 group and the control group (without any RAAS blocker) according to whether or not they were treated with LCZ696 after admission.

| Data collection
We defined clinical outcome as rehospitalization for HF or all-cause death, and recorded whether the patients had clinical outcome within 1 year. Biomarkers of cardiac and renal function were also collected: N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP), serum creatinine (SCr), and Serum potassium. The ECG parameter (Rv 5 + Sv 1 ) was used as an indicator of the degree of left ventricular hypertrophy (LVH) degree. 15 3 | RESULTS between the two groups. The BP in the LCZ696 group was significantly higher than that in the control group. The baseline level of NT-proBNP in the LCZ696 group was higher than that in the control group (p = .030).

| Study cohort and their baseline characteristics
The LCZ696 group has more coronary heart disease patients than the control group (82.1% vs. 63.3%, p = .022).

| Effect of LCZ696 treatment on primary outcome
During follow-up, 65 patients in total met the primary outcome of either rehospitalization for HF or all-cause death (LCZ696 group: n = 29; control group: n = 36). The incidence of rehospitalization for HF in the control group was significantly higher than that in the LCZ696 group (73.47% vs. 43.28%, p = .001) with no significant difference in the mortality (8.96% vs. 10.20%, p = 1.000) ( Table 2). This study included a time-to-event analysis 16 through 1 year for the primary outcome-Kaplan-Meier analysis showed that the free-event survival time of the LCZ696 group
3.4 | Effect of LCZ696 treatment on NT-proBNP, R v5 + S v1 , SCr, and serum potassium levels No significant difference in the changes of NT-proBNP, R v5 + S v1 , SCr, and serum potassium levels was observed between the two groups during the 1-year follow-up (Table 5).
T A B L E 1 Baseline characteristics of the two groups. In a meta-analysis of 27 long-term prospective studies in ESRD patients, the increase of BNP/NT-proBNP was significantly associated with increased all-cause mortality, cardiovascular mortality, and cardiovascular events. 21 NT-proBNP is less affected by ARNI than BNP, so this study chose NT-proBNP as the laboratory index to evaluate cardiac function, but the only way for NT-proBNP clearance is glomerular filtration, and renal insufficiency has a great impact on it, so it is necessary to dynamically evaluate NT-proBNP level changes. 22,23 With the decline of renal function, cardiac structural remodeling will also occur, mainly characterized by LVH, which increases with the decline of eGFR, up to 90% in ESRD patients. 24 The ECG parameter (Rv 5 + Sv 1 ) was included in the study to represent the degree of LVH. The results showed that there was no significant improvement in NT-proBNP level and Rv 5 + Sv 1 amplitude in the LCZ696 group compared with the control group during the 1-year follow-up visit. For the evaluation of cardiac structure and function, ultrasonic cardiogram (UCG) will be more convincing than ECG parameters. However, we could not analyze UCG data due to the limited data in this study, which shall be the focus of our next research study. The above indicators may get meaningful results with the extension of follow-up time, the further improvement of data, and the dynamic evaluation of multiple observation points.
In clinical practice, potential deterioration of renal function is often the biggest limiting factor for prescribing LCZ696 in CKD patients. Thus, the safety of LCZ696 in renal function and electrolytes has also attracted much attention in various studies. In the subgroup analysis of PARADIGM-HF and PARAMOUNT-HF trails, it was found that LCZ696 delayed the deterioration of renal function in patients with HFrEF or HFpEF compared with RAAS inhibitors, but eGFR persisted in 30-60 mL/min/1.73 m 2 . 25,26 The UK HARP-III trial demonstrated that in CKD (GFR 20-60 mL/min/ 1.73 m 2 ) patients that LCZ696 had no additional protective effect on kidney function or albuminuria compared with irbesartan, but it F I G U R E 3 Logistic regression to identify significant predictors of the primary outcome. CHD, coronary heart disease; CI, confidence interval; LCZ696, sacubitril-valsartan; NYHA, New York Heart Association; OR, odds ratio.
lowered BP and cardiac biomarker levels. 27 Therefore, the effects of