Abstract
Background/Aim: Sacubitril/valsartan (SV), a novel pharmacological class of angiotensin receptor neprilysin inhibitors, is effective in treating heart failure (HF) by inhibiting the degradation of natriuretic peptides and the renin–angiotensin–aldosterone system. However, no studies have observed the long-term effects of SV on patients with HF and preserved left ventricular ejection fraction (LVEF) undergoing hemodialysis (HD) over a long period. Patients and Methods: This single-center retrospective study of 21 months duration involved consecutive patients with HF and preserved LVEF undergoing HD, who received 50-200 mg/day. All patients were followed up regularly, and clinical, biochemical, and echocardiographic parameters were recorded at baseline and during follow-up. The efficacy and safety of SV were also analyzed. Results: This longitudinal study included nine patients, with a median age of 76 years. The median HD duration was 7 years. At baseline, the mean brain natriuretic peptide (BNP) was 133±73.6 pg/ml and that of LVEF was 66%±9%. After SV therapy, the systolic blood pressure, diastolic blood pressure, and heart rate decreased, albeit without statistical significance. BNP levels, LVEF, left atrial anteroposterior dimension, and left ventricular mass index did not change, compared to baseline values. No adverse effects were observed in any of the patients. Conclusion: SV tended to decrease blood pressure and heart rate in patients with HF and preserved LVEF undergoing HD but did not alter cardiac function assessments, such as BNP or echocardiography.
- Sacubitril
- valsartan
- chronic kidney disease
- hemodialysis
- brain natriuretic peptide
- left ventricular ejection fraction
Chronic kidney disease (CKD) is a global burden that leads to end-stage renal disease (ESRD). Cardiovascular disease is associated with increased morbidity and mortality in CKD (1). Furthermore, heart failure (HF) with reduced ejection fraction (EF) (HFrEF) is a major contributor to mortality in these patients (2). Among patients with CKD grade 5 or undergoing hemodialysis (HD), up to 58% experience fatalities caused by cardiovascular conditions, with HF being the most prominent cause of death (3). HF is independently associated with a less favorable prognosis in patients undergoing either HD or peritoneal dialysis (PD) (4). Therefore, therapies targeting cardiovascular diseases may improve the prognosis of CKD.
In a large clinical trial [prospective comparison of angiotensin receptor-neprilysin inhibitor (ARNI) with ACE-I to determine impact on global mortality and morbidity in heart failure (PARADIGM-HF)], sacubitril/valsartan (SV) significantly reduced the risk of HF hospitalization and cardiovascular mortality in patients with HFrEF compared with angiotensin-converting enzyme inhibitor (ACE-I) (5). By contrast, the prospective comparison of ARNI with angiotensin-receptor blocker (ARB) global outcomes in HF with preserved ejection fraction (PARAGON-HF) trial of the efficacy in HF with preserved EF (HFpEF) showed that ARNI tended to reduce the primary endpoints of HF hospitalization and cardiovascular death compared with ARB; however, the reduction was not found to be statistically significant (6).
Furthermore, the prospective comparison of ARNI with ARB on management of heart failure with preserved ejection fraction (PARAMOUNT) trial showed a significant reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in patients with HFpEF who were treated with SV in a short observational period. However, this difference was not observed as the period increased (7).
In a previous study, SV was found to effectively lower blood pressure (BP) without exacerbating renal function in patients with hypertension and CKD (G3a-G4) (8, 9). To date, most studies examining the effect of SV on patients undergoing dialysis have focused on HFrEF, and its effect on patients with HFpEF undergoing HD is unknown. To the best of our knowledge, this long-term observational study is the first to investigate the efficacy and safety of long-term SV therapy in patients with HFpEF undergoing HD.
Patients and Methods
Study design and collection of medical data. This study retrospectively reviewed and analyzed patients’ medical records. The patients underwent outpatient HD at the M-alie Clinic (Osaka, Japan). Eligible participants were patients with CKD who were undergoing HD, were ≥20 years old, and had LVEF of ≥40% on echocardiography, blood brain natriuretic peptide (BNP) level of ≥40 pg/ml before dialysis, systolic BP >100 mmHg, and diastolic BP >60 mmHg. Patients with insufficient data that affected the results and those with malignancy, congenital heart disease, tuberculosis, or cardiac resynchronization treatment were excluded. Nine patients were included in the study.
All procedures involving human participants were performed in accordance with the ethical standards of the National Research Committee and the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The study was approved by the ethics committee of the M-alie Clinic (approval no. 2022-001). Written informed consent was obtained from all the patients.
Data were collected and analyzed retrospectively using medical records maintained by the M-alie Clinic. Blood biochemical analyses were performed using a LaboSpect 008 autoanalyzer (Hitachi, Tokyo, Japan). Data on serum potassium, total cholesterol, triglycerides, fasting blood glucose, glycated albumin, and patient characteristics [e.g., medication, age, sex, BP, and body mass index (BMI)] were obtained from the medical records.
Data analysis. Continuous variables are presented as median values. Statistical significance was determined using the Wilcoxon test. All analyses were performed using StatView (SAS Institute, Cary, NC, USA) and Excel (Microsoft, Redmond, WA, USA). Statistical significance was set at p<0.05.
Results
Table I shows the baseline characteristics of the nine patients (four males and five females). The total observation period was 21 months. The median age at onset was 76 [interquartile range (IQR)=59-91] years. The median HD duration was 7 (IQR=3-17) years. Diabetes mellitus was a complication in 7 (78%) patients, and the median duration was 15 (IQR=7.5-26) years. The average baseline systolic BP was 164±23 mmHg, and the mean BMI was 21.9 (IQR=21.3-22.4) kg/m2. The baseline fasting blood glucose level was 142±27 mg/dl; glycated albumin, 22.0%±2.4%; serum potassium, 4.3±0.6 mEq/l; total cholesterol, 145±41 mg/dl; and triglyceride, 159±188 mg/dl. Concomitant medications included calcium channel blockers (44%), α-blockers (33%), αβ-blockers (11%), glinide (11%), α-glucosidase inhibitors (33%), and statins (44%).
Patient characteristics.
Compared with the baseline, the cardiothoracic ratio (CTR) did not change (51.1%±4.6% vs. 50.0%±4.4%, p=0.161; Figure 1A). Blood BNP levels did not change with SV therapy (133±73.6 vs. 254±269 pg/ml, p=0.426; Figure 1B). In the echocardiographic study, no differences were observed in the EF, left atrial dimension (LAD), and left ventricular mass index (LVMI) (66.2%±9.0% vs. 69.0%±11.4%, p=0.326; 36.4±5.8 vs. 37.0±5.6 mm, p=0.365; 79.9±16.6 vs. 81.6±21.9 g/m2, p=0.529, respectively; Figure 1C-E). Furthermore, no difference in dry weight change was observed before and after SV administration (53.2±7.3 vs. 52.1±8.1 kg, p=0.441; Figure 1F). Lastly, SV tended to decrease the systolic and diastolic BPs and heart rate; however, the differences were not statistically significant (163.9±23.3 vs. 146.4±19.7 mmHg, p=0.098; 81.1±7.2 vs. 77.8±11.1 mmHg, p=0.234; 72.1±9.3 vs. 73.0±13.4 beats/min, p=0.678; Figure 2A-C).
Changes in CTR, BNP, EF, LAD, LVMI, or DW before and after SV administration in the experimental group. BNP, B-type natriuretic peptide; CTR, cardiothoracic ratio; DW, dry weight; EF, ejection fraction; LAD, left atrial dimension; LVMI, left ventricular mass index.
Changes in SBP, DBP, or HR in the experimental group. DBP, Diastolic blood pressure; HR, heart rate; SBP, systolic blood pressure.
Discussion
This study shows, for the first time, the effects of SV on patients with HFpEF on HD in a long-term observational study. Our results demonstrated the safety of SV in patients with HFpEF, and a tendency to lower BP, although the difference was not statistically significant. However, similar to the PARAMOUNT study, no effect on EF was observed.
Our results also showed no change in LAD before or after SV administration, which may require a longer observation time, since the PAROMOUNT study showed no change at 12 weeks and a decrease at 36 weeks. Furthermore, SV did not result in a change in LVMI, similar to the lack of change in the LV weight observed in the PARAMOUNT study (7). Although NT-proBNP is not affected by neprilysin inhibition, it is high in patients on dialysis because of renal excretion, making it difficult to use as an HF indicator (10, 11). Therefore, the use of BNP as an HF indicator may be a limitation of this study because it is affected by neprilysin inhibition.
The renin–angiotensin–aldosterone system plays an important role in increasing the extracellular matrix in several organs. Angiotensin-converting enzymes convert angiotensin I to angiotensin II (Ang II), resulting in aldosterone secretion, microvascular constriction, increased sympathetic nerve activity, and activation of inflammation and fibrosis signaling. The activation of the Ang II–protein kinase C (PKC) signaling pathway is associated with processes that increase the extracellular matrix and endothelial dysfunction and activate cytokines or transforming growth factor-β (TGF-β) (12, 13). In addition, our previous studies clearly showed that the Ang II-induced TGF-β/Smad1 signaling pathway increases the extracellular matrix in the glomeruli. Interestingly, ARB decreased Smad1 expression, thereby decreasing the mesangial extracellular matrix in CKD (14, 15). A recent study indicated that SV may reduce the LV weight by inhibiting the TGF-β/Smad pathway and may be stronger than valsartan alone (16). Furthermore, a previous report indicated that SV could decrease cardiac remodeling (17).
Inflammation and oxidative stress play important roles in organ damage progression (18-20) because they promote fibrosis (21, 22). Nuclear factor-kappa-B (NF-κB) stimulates cytokine expression via reactive oxygen species and PKCβ. In addition, tumor necrosis factor-α plays an important role in the development of vascular complications. The therapeutic effect of SV on cardiomyocytes and endothelial cells is that SV suppresses NF-κB-mediated inflammation (23).
Several clinical practice guidelines recommend the use of SV for HF because it significantly decreases morbidity and mortality in patients with HF and is superior to ACE-Is and ARB (24, 25). Few studies have examined the application of SV in patients on HD with HFpEF, although HF is a major complication in these patients. Another study of patients on PD showed that SV relieved the signs and symptoms of HF and reduced NT-proBNP levels but did not significantly change the echocardiographic parameters.
Studies have reported that echocardiographic parameters after SV initiation did not improve; however, the rate of improvement in LVEF was higher in the SV group than in the control group (26, 27). This study has several limitations. Firstly, this study included a cohort from a single-center retrospective trial and not a randomized controlled trial, such as the PARADIGM-HF trial. Secondly, only BNP, not NT-proBNP, was used as a marker of HF. Thirdly, this study included a small number of patients.
Conclusion
In summary, this study showed that SV caused a trend toward lower BP and heart rate but did not improve markers of HF in patients with HFpEF undergoing HD. This study has several limitations, but despite these, it is the first report on the efficacy and safety of long-term SV therapy in patients with HFpEF undergoing HD.
Acknowledgements
We extend our appreciation to Honyaku Center, Inc., for their assistance with English language editing. This work was supported by JSPS KAKENHI Grant Number 22K08368 (to A. Mima).
Footnotes
Authors’ Contributions
A. Mima, H. Gotoda, S. Lee, R. Lee, and T. Hamada contributed to the conception and design of the study. A. Mima, A. Murakami, R. Akai, K. Matsumoto, S. Kidooka, T. Nakamoto, Y. Saito, S. Kido, S. Hishida, and S. Lee helped in material preparation, data collection, and analyses. A. Mima wrote the first draft of this manuscript. All the Authors have read and approved the final version of the manuscript.
Conflicts of Interest
A. Mima received speaker’s honoraria from Kyowa Kirin, Torii, Kowa, Bayer, Eli Lilly, Mochida, Viatris, and Boehringer Ingelheim. A. Mima has received research grants from Kyowa Kirin, Sumitomo Pharma, Chugai, Otsuka, Torii, Kowa, and Boehringer Ingelheim.
- Received December 14, 2023.
- Revision received January 14, 2024.
- Accepted January 25, 2024.
- Copyright © 2024 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).