1. Introduction

Increased prevalence of cancer and the early detection technologies along with advanced therapies have left a dramatically increasing number of cancer survivors in recent years. In 2022, more than 18 million Americans with cancer were alive, and about half of them have had this diagnosis for more than ten years. It is expected to reach 22.1 million by the start of 2030, and almost two-thirds (67%) of them are 65 years or older aged patients. In mainland China, it is reported that 6.69 million cancer survivors were over 65 years old in 2017, which is going up every year.[1–3]

Heart failure (HF) is an illness that consumes substantial healthcare resources, inflicts considerable morbidity and mortality, and significantly affects the quality of life.[4] Cardiovascular disease (CVD), including HF, is believed to have a high morbidity and mortality among cancer patients.[5–7] Such as cancer therapy-related cardio-dysfunction, occurring in approximately 10% of the patients, has the highest mortality of more than 50%.[8] HF in cancer patients often results from all kinds of cardiotoxicity. Advanced antineoplastic therapy nowadays usually has cardiotoxicity, which is believed to be a risk factor of HF.[5–7] What is worse, this kind of cardiotoxicity can also be irreversible and delayed so that cancer patients will have a significantly higher long-term CVD risk and mortality and a poorer cardiac condition in longtime survivorship.[6,9,10] Besides, cancer itself is believed to have a cardiotoxic effect independent of cancer-related therapy.[11,12] Apart from what was said above, age is also a major risk factor of HF. It is reported that Individuals aged ≥65 years take more than 80% of HF deaths, while the aged population is still growing,[7] which means the aging cancer population may suffer more from HF.

Sacubitril/Valsartan (S/V) is a combined formulation of angiotensin receptor inhibitor and neprilysin inhibitor, which inhibits the degradation of natriuretic peptides by neprilysin and brings cardioprotective effects while counteracting the adverse effects of the overactivated renin-angiotensin-aldosterone system (RAAS) including water and sodium retention and vasoconstriction.[13] S/V has been shown to be able to lower the levels of NT-proBNP, improve cardiac function, reverse left ventricular remodeling, decrease cardiovascular disease-related mortality, and improve the life quality in HF patients. Therefore, S/V is currently a first-line recommendation for chronic HF with reduced ejection fraction.[13–17] S/V is the most promising medicine for HF patients with a history of cancer nowadays. Up to now, there have been 3 finished clinical experiments about the use of S/V within cancer patients.[18–20] However, previous studies only paid attention to HfrEF, while HF with preserved ejection fraction (HfpEF) and HF with mildly reduced ejection fraction (HfmrEF) are also problems in the real world, and there is insufficient evidence about its efficacy in aged cancer population with HF.

Although some studies have demonstrated the positive impact of S/V on HfrEF cancer patients, there is still a lack of evidence regarding the drug’s effect on older cancer patients with HfmrEF and HfpEF. Therefore, we conducted this study to investigate the potential benefits of S/V in all 3 types of HF patients with cancer in the elderly population.

2. Methodology 2.1. Study population

We searched the electronic medical records from January 2016 to February 2022 about aged patients with both cancer and HF diagnoses in our institution. The ones who had received full course treatment with S/V as HF management were selected as the candidates for S/V group, and the ones who had received traditionary HF therapy, including ACEI/ARB or beta-blocker or diuretics without S/V were selected as the control group. The Eligible patients for both groups are those who have received at least 1 echocardiography and the NYHA cardiac function assessment before and 3 months after the initiation of S/V for S/V group or the initiation of traditional HF therapy for the control group; NYHA class should be ≥2 in both groups; age should be ≥65 in both groups; with a history of treated cancer while without current anticancer regimen during the HF therapy period.

2.2. Assessment of HF

In both groups, we used the “Criteria from 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic HF[15]” to judge the validity of the HF diagnosis. According to the guideline, we divided them into 3 kinds of HF subgroups, including HF with reduced ejection fraction (HfrEF), HF with mildly reduced ejection fraction (HfmrEF), and HF with preserved ejection fraction (HfpEF), by LVEF ≤ 40%, 40% < LVEF < 50%, LVEF ≥ 50%, respectively. The symptoms and signs of HF are necessary for all 3 kinds of HF. For HfpEF, NT-proBNP ≥ 125 pg/mL and/or Objective evidence of cardiac structural and/or functional abnormalities is also needed.[15]

2.3. Assessment of cancer

The diagnosis of cancer should be based on pathological evidence.

2.4. Clinical data collection

The institution where the research is conducted is a large general hospital with standard oncology and cardiovascular departments. Doctors in this hospital recorded the patients’ diagnoses according to the ICD-10 code and all the other information in the electric medical record system. By reviewing the records, medical information on S/V group and control group was obtained, which includes demographic information, clinical characteristics (the type of neoplasms and cancer treatment history), NYHA cardiac function class before and after the initiation and the use of other cardiovascular diseases-related drugs. Data about cardiac biomarkers, NT-proBNP, and Physical examination (blood pressure and heart rate) were also collected if available, along with the collection of echocardiography data at baseline and during HF treatment for up to 9 months.

2.5. Statistical analysis

Data are presented as mean ± standard deviation for normal quantitative variables and median [interquartile range] for nonnormal ones. Categorical variables were presented as percentages and compared using the Pearson chi-square test, Wilcoxon signed-rank test, or Fisher precision probability test. Paired sample t test and one-way ANOVA were used for comparing continuous variables. We use ordered multinomial logistic regression analysis to analyze the factors that affect patient’s cardiac function. Statistical tests were 2 sided, and we regard 5% as the significance level. All the statistical analyses were performed with SPSS Version 26.

3. Result 3.1. Basic demographic characteristics

We found 1495 patients from the electronic medical record system from January 2016 to February 2022 with the diagnosis of both cancer and HF. After the screening, we filtered 38 patients valid for S/V group and 50 patients valid for the control group (Fig. 1).

Figure 1.:

The consort flow diagram of our study. A total of 1495 patients have been diagnosed with both HF and cancer. After the screening, 38 of them were involved in S/V group, while 50 of them were involved in the control group.

The baseline characteristics of both groups are summarized in Table 1. For S/V group, 38 patients were included in this research with a median age of 77.61 ± 8.18, and 23 (60.5%) were male. For the control group, 50 patients were included in this research with a median age of 77.92 ± 7.59, and 32 (64.0%) were male. The S/V group and the control group patients had no difference at the baseline as shown in Table 1. The dosage and frequency of the Sacubitril/Valsartan are 25 mg bid (n = 11, 28.95%), 50 mg bid (n = 16, 42.11%), and 100 mg bid (n = 11, 28.95%) at the beginning. During the HF therapy process, 7 patients changed the dosage. Among them, 2 patients changed from 50 mg bid to 100 mg bid, 2 patients changed from 25 mg bid to 100 mg bid, and 3 patients reduced the dosage from 100 mg bid to 50 mg bid because of low blood pressure; however, no patients had ever given up taking S/V within our observation period and no hypotensive shock or hypotension related adverse event was found within our cases. There were no significant differences in the dose and frequency of S/V used among the 3 different types of HF, HfrEF, HfmrEF, and HfpEF, either at baseline or at the end of observation period (P = .344, 0.401).

Table 1 - Patients baseline characteristics. Variables S/V group N = 38 Control group N = 50 P value Demographic characteristics  Mean age, y 77.61 ± 8.18 77.92 ± 7.59 .853  Gender, male 23 (60.5%) 32 (64.0%) .341  Height, cm 159.11 ± 7.15 161.10 ± 5.67 .148  Weight, kg (before) 62.74 ± 10.18 63.83 ± 8.03 .575  BMI, kg/m2 (before) 24.82 ± 4.03 24.61 ± 3.00 .424  Weight, kg (after) 62.34 ± 10.41 62.84 ± 8.57 .806  BMI, kg/m2 (after) 24.65 ± 4.05 24.22 ± 3.17 .575 Cancer category .963  Lung cancer 17 (44.7%) 20 (40.0%)  Esophageal cancer 4 (10.5%) 6 (12.0%)  Hepatic cancer 4 (10.5%) 4 (8.0%)  Colorectal cancer 4 (10.5%) 8 (16.0%)  Gastric cancer 2 (5.3%) 4 (8.0%)  Other 7 (18.4%) 7 (14.0%) HF etiology and risk factors  Hypertension 30 (78.9%) 32 (64.0%) .128  Atrial fibrillation 16 (42.1%) 28 (56.0%) .821  COPD 16 (42.1%) 24 (48.0%) .667  CHD 33 (86.8%) 38 (76.0%) .062  Diabetes 13 (34.2%) 15 (30.0%) .674  Smoking 16 (42.1%) 25 (50%) .462  Drinking 11 (28.9%) 13 (26.0%) .758 Previous cancer treatment  Surgery 19 (50.0%) 34 (58.0%) .087  Chemotherapy 15 (39.5%) 25 (50.0%) .326  Radiotherapy 7 (18.4%) 8 (16.0%) .765  Targeted therapy 4 (10.5%) 7 (14.0%) .751  ICI 2 (5.3%) 3 (6.0%) .629  Anthracycline 2 (5.3%) 1 (2.0%) .576 Basic cardiovascular diseases management  CCB 17 (44.74%) 19 (38.00%) .524  ACEI/ARB – 32 (64.00%)  β-Blocker 29 (76.32%) 37 (74.00%) .804  Cardiotonic 33 (86.68%) 36 (72.00%) .804  Diuretic 38 (100.00%) 50 (100.00%) .094  MRA 36 (94.74%) 45 (90.00%) .459  SGLT2i 4 (10.53%) 3 (6.00%) .694 BP and HR  SBP, mm Hg 130.27 ± 21.57 129.0 ± 17.0 .768  DBP, mm Hg 73.49 ± 12.84 76.2 ± 11.06 .296  HR, bpm 88.70 ± 27.19 86.6 ± 18.84 .676

ARB = angiotensin receptor blocker, BP = blood pressure, ACEI = angiotensin-converting enzyme inhibitors, BMI = body mass index, bpm = beats per minute, CHD = coronary artery heart disease, COPD = chronic obstructive pulmonary disease, DBP = diastolic blood pressure, HR = heart rate, ICI = immune checkpoint inhibitor, MRA = mineralocorticoid receptor antagonist, S/V = Sacubitril/Valsartan, SBP = systolic blood pressure, SGLT2i = sodium-glucose cotransporter-2 inhibitor.

3.2. Echocardiographic parameters

Overall echocardiographic parameters of both groups are shown in Table 2. After treatment, comprised with the control group, S/V group suggested a better cardiac condition; S/V group had higher LVEF in 3rd (P = .003), 6th (P = .005), 9th (P = .000), higher LVFS in 3rd (P = .002), 6th (P = .005), 9th (P = .008) month; the change on LVEF, LVFS is shown in Fig. 2. Through Analysis of Variance, we also found that the S/V group showed an improvement in Echocardiographic parameters between 1st and 3rd, 6th, and 9th month when compared within the group, whose average LVEF was elevated (P = .049, Fig. 2). While the control group showed a deterioration manifested in the reduction of LVEF (P = .03), and LVFS (P = .02).

Table 2 - Echocardiographic parameters at the 1st, 3rd, 6th, and 10th month after the initiation of heart failure management. Variables Sacubitril/Valsartan group Control group P value 1st month  LVFS (%) 24.18 ± 6.41 25.08 ± 5.72 .492  LVEF (%) 47.11 ± 10.45 48.32 ± 9.04 .561  LVEDD (mm) 53.71 ± 6.99 53.04 ± 10.06 .726 LAD (mm) 40.95 ± 7.13 39.96 ± 7.61 .541 3rd month  LVFS (%) 28.26 ± 7.65 22.32 ± 4.01 .002  LVEF (%) 53.65 ± 11.84 44.65 ± 5.91 .003  LVEDD (mm) 50.70 ± 9.98 54.67 ± 9.41 .167  LAD (mm) 39.57 ± 8.86 41.78 ± 6.98 .351 6th month  LVFS (%) 27.33 ± 7.26 20.71 ± 4.24 .005  LVEF (%) 52.88 ± 11.94 42.24 ± 7.71 .005  LVEDD (mm) 52.19 ± 8.38 56.76 ± 13.33 .227  LAD (mm) 39.50 ± 7.49 42.05 ± 8.45 .347 9th month  LVFS (%) 26.44 ± 5.01 21.68 ± 6.54 .008  LVEF (%) 53.67 ± 7.69 42.90 ± 10.95 < .001  LVEDD (mm) 52.83 ± 6.92 54.51 ± 12.65 .589  LAD (mm) 37.89 ± 6.47 40.29 ± 8.82 .303

LAD = left atrium volume diameter, LVEDD = left ventricle end-diastolic diameter, LVEF = left ventricular ejection fraction, LVFS = left ventricular fractional shortening, S/V = Sacubitril/Valsartan.

Figure 2.:

The change in LVEF, NT-proBNP, and LVFS (shown as mean ± SD). After the initiation of HF management, the S/V group showed higher LVFS, LVEF and lower NT-proBNP than control group in 3th, 6th and 9th months. (P < .05).

We then divided our patients by LVEF into 3 stages: Stage I, severe reduction (LVEF ≤ 40%); Stage 2, middle reduction (40% < LVEF < 50%); Stage 3: preserved LVEF (LVEF ≥ 50%). The number of patients in each stage before and after the initiation of HF management shows in Fig. 2. We found that more S/V group patients had a better LVEF stage, while fewer had changed their LVEF stage into a worse 1 (P = .000). Seventeen patients (44.74%) in S/V group and 1 patient (2.00%) in the control group changed from a lower stage into a higher stage. Two patients (5.26%) in S/V group and 19 patients in the control group (38.00%) changed from a higher stage to a lower stage. For S/V group, the most significant elevation in LVEF is 27%, and the greatest decrease decreasing in LVEF is 4%, while in the control group, the most significant elevation in LVEF is 11%, and the greatest reduction in LVEF is 29%. The change in LVEF of both groups shows in Fig. 3.

Figure 3.:

The change in LVEF in the S/V group and control group. After therapy, more patents had a LVEF ≥ 50% and less patients had a LVEF ≤ 40% in S/V group, while in control group more patients had a LVEF ≤ 40%.

Our study used 53 mm for women and 52 mm for men as the upper reference value of LVEDD, 37 mm for women, and 43 mm for men as the upper reference value for LAD, which are set for the east China aged population.[21] Then we divided patients into subgroups by normal and abnormal LVEDD and LAD. If the patients had changed from abnormal to normal, then we regarded it as an improvement. At the same time, if a patient had changed from normal to abnormal, then we regarded it as deterioration. The number of improvements and deterioration of LVEDD and LAD in both groups is shown in Fig. 4. We observed fewer patients had deteriorated in both LVEDD and LAD. In S/V group, only 1 patient deteriorated in LVEDD, compared with the control group, which is 9 (P = .023). In S/V group, no patient showed deterioration in LAD, compared with the control group, which is 6 patients (P = .029).

Figure 4.:

The number of patients with improvement and deterioration on LVEDD and LAD after therapy. After the initiation of HF management, S/V group had less deteriorated LVEDD and LAD cases than control group (P < .05).

3.3. Cardiac biomarker

Most of the patients included in this study underwent testing of cardiac biomarkers, including NT-proBNP, CK-MB, MYO, and c-Tnt. The main outcome is shown in Table 3. Compared between groups, S/V group had a lower NT-proBNP in the 3rd (P = .04), 6th (P = .015), and 9th (P = .000) month (Fig. 2). Other indicators showed no significant difference, whether in vertical comparison (compared within the group between each month) or horizontal comparison (compared between 2 groups at each month). Compared within groups between each month, NT-proBNP decreased (P = .004) in S/V group, while in the control group, NT-proBNP was elevated (P = .009).

Table 3 - Cardiac biomarkers in the 1st, 3rd, 6th, and 9th month after the initiation of heart failure management. Variables S/V group Control group P value 1st month  MYO (ng/mL) 138.83 ± 188.61 77.50 ± 98.17 .128  CK-MB (ng/mL) 7.89 ± 10.89 126.49 ± 129.36 .407  c-Tnt (ng/mL) 0.38 ± 0.99 0.21 ± 0.36 .445  NT-proBNP (pg/mL) 5721.31 ± 8133.29 2963.28 ± 4248.86 .065 3rd month  MYO (ng/mL) 103.77 ± 145.73 99.84 ± 124.48 .928  CK-MB (ng/mL) 4.98 ± 8.64 5.88 ± 6.17 .704  c-Tnt (ng/mL) 0.26 ± 0.56 0.029 ± 0.029 .160  NT-proBNP (pg/mL) 2309.68 ± 2631.66 9394.99 ± 10087.42 .004 6th month  MYO (ng/mL) 113.95 ± 225.01 93.32 ± 102.68 .756  CK-MB (ng/mL) 3.66 ± 102.68 5.26 ± 6.13 .400  c-Tnt (ng/mL) 0.043 ± 0.026 0.078 ± 0.11 .429  NT-proBNP (pg/mL) 1574.90 ± 1937.17 6392.20 ± 7845.78 .015 9th month  MYO (ng/mL) 67.70 ± 97.56 98.14 ± 105.67 .351  CK-MB (ng/mL) 5.41 ± 6.76 21.63 ± 61.01 .282  c-Tnt (ng/mL) 0.20 ± 0.37 0.084 ± 0.12 .198  NT-proBNP (pg/mL) 739.54 ± 640.88 7982.18 ± 1037.00 < .001

CK-MB = creatine kinase-MB, MYO = myoglobin, NT-proBNP = N terminal pro B type natriuretic peptide, S/V = Sacubitril/Valsartan.

3.4. Within-group comparison

We used one-way ANOVA to test the changes of various indicators between the S/V group and the control group before treatment, and at 3, 6, and 9 months after treatment. For the S/V group, MYO, CK-MB, c-Tnt, SBP, DBP, HR, FS, LVEF, LVEDD, and LAD showed no statistical significance (P > .05). The change in NT-proBNP was statistically significant (P = .001), with a significant decrease observed at 6 months (P = .029) and 9 months (P = .004) after treatment compared to before treatment. In the control group, MYO, CK-MB, c-Tnt, SBP, DBP, HR, LVEDD, and LAD showed no statistical significance (P > .05). However, NT-proBNP (P = .003), LVEF (P = .018), and LVFS (P = .005) showed statistical significance. Among them, the NT-proBNP level was significantly increased at 3 months (P = .049) and 9 months (P = .034) compared to before treatment; the LVEF level was significantly decreased at 6 months (P = .036) compared to before treatment. The LVFS level was significantly decreased at 6 months (P = .005) compared to before therapy.

3.5. Clinical manifestation

We use NYHA stages to judge the clinical manifestation of HF. As illustrated in Table 4, the difference is shown between groups after the treatment (P = .001), which was more patients had a lower stage in S/V group and fewer patients had a higher stage. At the same time, it is inverse in the control group. The change in the NYHA stage between groups also showed a difference (P = .001); we can see more patients in the S/V group had improvement in the NYHA stage, and fewer patients had deterioration. There is no statistical difference in BP and HR in the horizontal comparison and vertical comparison of both groups (P > .05).

Table 4 - The NYHA functional classification before and after the initiation of heart failure management. S/V group (n) Control group (n) P value Before  Stage II 4 12 .588  Stage III 26 26  Stage IV 8 12 After .001  Stage II 15 4  Stage III 18 30  Stage IV 5 16 The change of heart function  Deterioration 4 20 .001  Improving 16 7  Stabilization 18 23

NYHA = New York Heart Association function classification, S/V = Sacubitril/Valsartan.

3.6. Factors affecting patient’s cardiac function

We used NYHA classification to define the patient’s cardiac function status. Before and after medication, if a patient’s NYHA stage decreased, it was defined as an improvement in cardiac function; if the NYHA stage increased, it was defined as deterioration, and if the NYHA stage remained the same, it was defined as stabilization. The changes in the patient’s cardiac function are shown in Table 4. We used ordered multinomial logistic regression analysis to analyze the factors that affect the changes in the patient’s cardiac function. The included indicators were NT-proBNP, SBP, DBP, HR, FS, EF, LV, LA before treatment; gender, age, weight, and BMI before and after treatment; whether to use diuretics intravenously, whether there is hypertension, whether there is atrial fibrillation, whether there is diabetes, whether there is coronary heart disease, whether there is COPD, whether there is a history of smoking and drinking, HF management methods, past tumor treatment methods, and cancer types. Among them, LVFS before medication (P = .029, OR [95% CI] = 1.62 [1.05, 2.49]), LVEF before medication (P = .021, OR [95% CI] = 0.73 [0.56, 0.96]), LAD before medication (P = .022, OR [95% CI] = 0.90 [0.82, 0.98]), the use of S/V (P = .022, OR [95% CI]=0.02 [0.00, 0.57]), surgery (P = .028, OR [95% CI] = 4.10 [1.17, 14.39]), and lung cancer (P = .035, OR [95% CI] = 0.07 [0.01, 0.84]) were related to the change of the patient’s cardiac function after treatment (Table 5).

Table 5 - Multinomial logistic regression analysis of the association between factors and the changes in the patient’s cardiac function after therapy. Indicators P OR (95% CI) LVFS .029 1.62 (1.05, 2.49) LVEF .021 0.73 (0.56, 0.96) LAD .022 0.90 (0.82, 0.98) Using S/V .022 0.02 (0.00, 0.57) Surgery .028 4.10 (1.17, 14.39) Lung Cancer .035 0.07 (0.01, 0.84)