Efficacy and Safety of Sacubitril/Valsartan in Hemodialysis Patients with Chronic Heart Failure: A Retrospective Study at a Single Center

Introduction

Heart failure is a common and major complication of end-stage renal disease (ESRD). Heart failure and ESRD often coexist, and often affect the prognosis of patients with ESRD [1,2]. Especially, the incidence of heart failure in patients on MHD is as high as 42.9% due to renal failure, long-term water and sodium retention, hypertension, and uremic cardiomyopathy [3]. However, there is currently no effective treatment to reduce cardiovascular events in MHD patients [4].

SV is an angiotensin receptor blocker and neprilysin inhibitor (ARNI), which is a combination of valsartan and sacubitril [5]. SV is the first US Food and Drug Administration (FDA)-approved drug for the treatment of patients with chronic heart failure who have a reduced ejection fraction in NYHA classes II, III, or IV [6]. Many studies have demonstrated that SV significantly improves LVEF and left ventricular remodeling in patients with heart failure [7–9]. SV can also reduce re-hospitalization and mortality rates in patients with acute heart failure with reduced ejection fraction [10–12]. However, data on SV treatment in MHD patients with chronic heart failure are lacking, as these patients have been excluded from most clinical studies [8,13,14]. Therefore, treatment of chronic heart failure in MHD patients faces great challenges, but the management of heart failure in these patients is critical to improve their quality of life and outcomes [1,15]. Currently, there is no effective treatment to reduce cardiovascular events in MHD patients. A recent report showed that SV can improve cardiac function in hemodialysis patients [16], but the effects of SV on life quality in MHD patients with heart failure are not fully understood. Therefore, this retrospective study from a single center aimed to evaluate the efficacy and safety of SV in 28 chronic heart failure patients on maintenance hemodialysis. Biochemical and echocardiographic findings were assessed at 12-week follow-up. We sought to provide a theoretical basis for the use of SV in patients receiving MHD and in chronic kidney disease (CKD) patients.

Material and Methods

PATIENT SELECTION:

The inclusion criteria were: (1) Patients on maintenance hemodialysis due to ESRD for more than 3 months (ESRD refers to the inability of kidney function to sustain long-term survival without dialysis or kidney transplantation [17]); (2) Age ≥18 years; (3) New York Heart Association (NYHA) class II–IV; (4) Meeting the diagnostic criteria for chronic heart failure in the 2021 European Society of Cardiology Guidelines for the Management of Heart Failure, including heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), and heart failure with mildly reduced ejection fraction (HFmrEF) [18]; (5) Treated with angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) before treatment, with ACEI/ARB discontinued for at least 48 h before treatment; and (6) Complete clinical data. The exclusion criteria were: (1) Complicated with acute coronary syndrome, renal artery stenosis, malignant tumor, severe infection, or unable to cooperate due to mental illness; (2) Allergic to SV; (3) Poor compliance, unable to cooperate with medication and inspection; (4) Irregular dialysis and overt hypervolemia; (5) Severe heart valve disease, arrhythmias, or uncontrollable hypertension; and (6) Severe hepatic dysfunction, biliary cirrhosis, and cholestasis.

QUALITY ASSESSMENT:

Because using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist [19] can greatly improve the transparency and the quality of research, we elaborated and implemented this study based on the STROBE checklist of 22 items, including title and abstract, introduction, methods, results, discussion, and other information.

STUDY DESIGN:

This was a before-and-after, self-controlled, observational study. We used PASS software to calculate the sample size. According to inclusion and exclusion criteria, 29 MHD patients were enrolled in this study. Patients were treated with SV in addition to conventional therapy, which included regular hemodialysis (2–3 times/week, 4 h each time), medication to improve anemia (recombinant human erythropoietin and iron), regulation of calcium and phosphorus metabolic disorders, and glycemic control in diabetic patients. All patients were treated with ACEI/ARB before treatment. In accordance with the instructions, the initial dose of SV (Beijing Novartis Pharmaceuticals Co., Ltd; approval number: State Drug License J20171054) was 50 mg, 2 times per day. The follow-up dose was adjusted at 100–400 mg per day according to patient tolerance. Data on biochemical indicators, echocardiography, and quality of life scores were collected from all patients before SV treatment, and the same examinations were repeated at 12-week follow-up.

OUTCOMES:

We extracted general clinical information of patients from their medical record, including sex, age, and medical history. Five ml of fasting venous blood was drawn and tested for cardiac biomarkers, included cardiac troponin T (reference range 0–1.0 ng/ml) and creatinine kinase MB (CK-MB, reference range 0–25 U/L). After hemodialysis treatment, Philips EPIQ5 color Doppler ultrasound was used to evaluate the cardiac function of patients, and the main parameters were left ventricular ejection fraction (LVEF), left ventricular diastolic diameter (LVDD), left ventricular systolic diameter (LVDS), interventricular septum thickness (IVST), left atrium (LA), and right ventricular end-diastolic dimension (RVEDD).

The secondary objective in the study was quality of life, which was measured by the short form 36-item (SF-36) scale [20] assessed at baseline and after treatment. The SF-36 scale consists of 8 aspects, which were transformed into Physical Component Summary (PCS) and Mental Component Summary (MCS). The PCS includes physical functioning (PF), role physical (RP), bodily pain (BP), and general health (GH). The MCS includes vitality (VT), social functioning (SF), role emotional (RE), and mental health (MH). Each aspect is numerically coded and then transformed into a score of 0 to 100; the higher the score, the better the quality of life.

We also assessed safety outcomes, including hyperkaliemia (serum potassium >5.5mmol/L), hypotension (systolic pressure <100 mmHg), angioedema (defined as subcutaneous and/or submucosal swelling), headache, nausea, and vomiting. During the course of treatment, blood potassium was monitored monthly, and patients were asked about and observed for adverse effects they come to dialysis.

STATISTICAL ANALYSIS:

All data were statistically analyzed using SPSS version 23.0 software (IBM Corp., Armonk, NY). Categorical data are expressed as percentages (%) and numbers, normally distributed continuous variables are expressed as mean±standard deviation, non-normally distributed continuous data are represented by median (interquartile range) using the Wilcoxon matched-pair signed-rank test. The paired-sample t test was used for comparison of self-matching data and the chi-square test was used for qualitative data analysis. The alpha value was set to 0.05, and P<0.05 was considered statistically significant.

Results

BASELINE DATA:

At the beginning of this study, 29 MHD patients with chronic heart failure were consecutively enrolled from September 2021 to October 2022. Twenty patients had anuria, and 9 patients had 24-h urine volume fluctuation of 100–200 ml. SV was interrupted in 1 patient because of asymptomatic hypotension. Therefore, 28 MHD patients with chronic heart failure completed 3 months of observation. The flow chart for patient selection is shown in Figure 1.

Of the 28 patients, 18 (64.3%) were male and 10 (35.7%) were female. The mean age was 63.25±11.76 years, and the mean hemodialysis duration was 25.50 (16.00–42.75) months. The most common kidney diseases were chronic glomerulonephritis (7, 25.0%), hypertensive/renovascular disease (3, 10.7%), diabetic kidney disease (15, 53.6%), and polycystic kidney (3, 10.7%). Eight patients (28.6%) were in NYHA class II, 17 in NYHA class III (60.7%), and 3 in NYHA class IV (10.7%). The baseline characteristics of the 28 patients are shown in Table 1.

The initial dose of SV was 50 mg, 2 times per day. Depending on the patient’s blood pressure, we gradually increase the dose of SV after 4 weeks of treatment – 16 patients had their doses increased to 200 mg daily, 9 had their doses increased to 150 mg daily, and 3 patients did not have their doses increased. After 8 weeks of treatment, 26 patients were increased to 200 mg daily, 2 patients to 150 mg daily, and after 12 weeks, 27 patients were increased to 200 mg daily, and 1 patient had the dose increased to 150 mg daily. No acute heart failure occurred during treatment. None of the patients gained more than 5% of dry body weight during the inter-dialysis period and none received diuresis.

EFFECTS OF SACUBITRIL/VALSARTAN ON VITAL SIGNS AND BIOCHEMICAL INDICATORS:

Compared with baseline, systolic blood pressure was significantly reduced from 160.39±7.99 to 148.93±12.22 mmHg (P=0.001, Table 2) and diastolic blood pressure was significantly reduced from 84.68±7.25 to 80.07±8.29 mmHg (P=0.006, Table 2). The heart rate also showed a downward trend from 78.32±6.40 to 75.93± 7.80 beats/min, but the difference was not statistically significant (P=0.139, Table 2), probably due to the small sample size. In addition, there were no significant differences in hemoglobin, triglyceride, total cholesterol, high-density lipoprotein-cholesterol (HDL-C), LDL-C (low-density lipoprotein-cholesterol), electrolyte, albumin, uric acid, phosphorus, parathyroid hormone, aspartate transaminase, and alanine transaminase.

EFFECTS OF SACUBITRIL/VALSARTAN ON CARDIAC FUNCTION:

Cardiac function evaluation included NYHA functional class, cardiac biomarkers, and echocardiography. Table 2 and Figure 2 show the effects of SV on cardiac function. At the end of 3-month follow-up, the NYHA function of patients in the NYHA class III group was significantly decreased, from 60.71% to 32.14% (P<0.05, Table 2, Figure 2A), and symptoms of heart failure were obviously alleviated in these patients (Table 2). Compared with baseline levels, LVEF was significantly improved from 44.29±8.92% to 53.32±7.88% (P<0.001, Table 2, Figure 2B). To better understand the effect of SV on LVEF in patients, they were divided into groups according to their EF levels. For patients with LVEF ≤40%, it was significantly improved from 33.75±3.92% to 46.50±4.28% (P<0.001, Table 2). For patients with LVEF between 40% and 50%, it was significantly improved from 44.33±3.20% to 51.42±3.96% (P<0.001, Table 2). For patients with LVEF ≥50%, it was significantly improved from 56.00±5.58% to 63.00±5.50% (P=0.016, Table 2). LVDD was significantly reduced from 57.84±6.36 to 54.19±7.96 mm (P=0.010, Table 2, Figure 2C), LVDS was significantly reduced from 45.24±7.66 to 40.15±6.24 mm (P=0.001, Table 2, Figure 2C), and IVST showed no significant difference after treatment (10.49±1.45 vs 10.09±0.80 mm, P=0.169, Table 2, Figure 2C). There were no significant changes in LA or RVEDD before versus after treatment.

EFFECTS OF SACUBITRIL/VALSARTAN ON QUALITY OF LIFE:

After treatment with SV, a significant improvement on the total SF-36 score was observed. The physical functioning score [45 (30–65) to 67.50 (60–73.75) P=0.003], the role physical score [50 (25–50) to 75 (50–75) P<0.001], the general health score [20 (20–32) to 46(32–47) P<0.001], the vitality score [25 (20–35) to 40 (25–43.75) P=0.005], the social functioning score [37.5 (25–63.75) to 62.5 (37.5–75) P=0.001], the role emotional score [33.3 (33.3–66.6) to 66.6 (33.3–100) P=0.007], and the mental health score [40 (32–44) to 44 (33–56) P=0.028] were significantly improved after treatment (Table 3), but the bodily pain score showed no significant difference after treatment (P=0.063, Table 3). The PCS was significantly improved from 40.0±6.41 to 56.20±9.86 (P<0.001, Table 3, Figure 2D), and the MCS was significantly improved from 39.99±6.14 to 52.59±11.00 (P<0.001, Table 3, Figure 2D).

ADVERSE EVENTS:

In the 29 maintenance hemodialysis patients who were initially recruited, 1 male patient quit the study due to symptomatic hypotension (systolic pressure <100 mmHg, diastolic pressure <60 mmHg). None of the other patients had adverse drug reactions such as hyperkaliemia, angioedema, headache, nausea, or vomiting.

Discussion

LIMITATIONS OF THE STUDY:

The present study has some limitations. First, it was not a randomized controlled trial(RCT), and the lack of randomization introduces the potential for selection bias and confounding variables, which could have affected the results. Second, it was a single-center study and a relatively small number of subjects were included, so our results cannot be extrapolated to other patients, and this limits the generalizability of our findings. Third, the observation period was relatively short, and long-term efficacy and safety were not been fully evaluated. Fourth, although significant improvement in laboratory indicators and quality of life after sacubitril/valsartan treatment were observed in these MHD patients, no correlation factor analysis was performed, mainly because of the small sample size. Therefore, larger prospective, multicenter, long-term, randomized controlled studies are needed to further assess the efficacy and safety of sacubitril/valsartan.

Conclusions

Our study demonstrated that sacubitril/valsartan can improve the LVEF [44.29±8.92% to 53.32±7.88% (P<0.001)], LVDD [57.84±6.36 to 54.19± 7.96 mm (P=0.010)], and LVDS [45.24±7.66 to 40.15±6.24 mm (P=0.001)] of chronic heart failure patients receiving MHD with, and also significantly improves PCS [40.0±6.41 to 56.20±9.86 (P<0.001)] and MCS [39.99±6.14 to 52.59±11.00 (P<0.001)] of these patients.