Effects of combination treatment with alprostadil and statins in patients with refractory heart failure

ABSTRACT

This study was designed to evaluate the effects of alprostadil on patients with refractory heart failure receiving statin treatment. One hundred patients with refractory heart failure were categorized into two groups, control (n = 50) and intervention (n = 50). The control group was treated with statins only, while the intervention group received a combination treatment with alprostadil and statins. Total effective rate, New York Heart Association (NYHA) functional classification, quality of life (QOL) score, ventricular remodeling indices, oxidative stress indices, inflammatory factor index, and the serum levels of B-type natriuretic peptide (BNP), blood lipid, blood glucose, and insulin were compared between the two groups. The total effective rate of the intervention group was significantly higher than that of the control group. Following treatment, the intervention group experienced more significant improvements in terms of NYHA functional class, QOL scores, ventricular remodeling indices, oxidative stress indices, and serum levels of inflammatory factor, BNP, blood lipid, blood glucose, and insulin compared with the control group. Administration of alprostadil to patients with refractory heart failure receiving statin treatment can increase the total effective rate; down-regulate serum levels of inflammatory factor, BNP, blood lipid, and blood glucose; and improve insulin resistance, illustrating its value in this clinical application.

KEYWORDS:

• Refractory heart failure
• statins
• alprostadil
• total effective rate
• prognosis

Introduction

Obstinate heart failure, also known as refractory heart failure, is an uncommon, critical illness in the clinical setting which symptoms are not alleviated after treatment with various therapies (and may worsen in some serious cases) unless the heart function enters the final stage and becomes irreversible. Only 51% of patients with refractory heart failure survive longer than 3 months, while 26% and 6% survive for more than 6 and 12 months, respectively, with a median survival rate of less than 4 months in most cases, regardless of active medications dilating blood vessels and improving urine output and heart function (Bahamonde et al. 2018). The illness seriously affects a patient’s quality of life (QOL). The development of technologies, such as cardiac resynchronization therapy (CRT), left ventricular assist devices (LVADs), and cardiac transplantation (CTx), brings new hope to refractory heart failure treatment. However, at present, medications with angiotensin-converting enzyme inhibitors (ACEIs), digitalis, and diuretics are more dominant in the clinical settings (Quirós-Ganga et al. 2015), with inadequate effects. Therefore, there is a need to find effective medications.

Refractory heart failure develops with reduced ventricular filling or blood pumping function, resulting in the failure to transport sufficient blood to organs and tissues and inducing systemic or pulmonary circulation congestion, which induces the neuroendocrine system to secrete more cell factors to boost activation and start up compensatory mechanisms and accelerate the progress of cardiac remodeling, leading to deformed and further enlarged heart chambers and deteriorating heart function (Vergaro et al. 2015). Studies revealed that statins improve energy metabolism of cardiac muscle cells and contractile function (Allard et al. 2018), support new vessel formation, reduced vascular angiotensin II receptor activity, and recover autonomic nervous functions of the heart. The benefits of statins in patients with heart failure include the inhibition of secretion of inflammatory cell factors to alleviate damage due to heart inflammation (Babbitt et al. 2017; Peller et al. 2017). Nonetheless, improvements in prognosis are limited if statins are administered alone. Alprostadil is a natural prostaglandin substance extensively used in clinical settings to dilate coronary artery vessels and ameliorate oxygen metabolism in cardiac muscle cells by improving the diastole of vascular smooth muscle and hemodynamics (Bahamonde et al. 2018) and reduce the amount of arterenol released from the sympathetic nerve ending (SNE). Moreover, alprostadil produces diuretic effects by increasing the blood flow in kidneys and reducing ventricular load. Alprostadil can also enhance the secretion of atrioventricular natriuretic kinin to reinforce heart function (Ono et al. 2017) and improve the treatment effect in refractory heart failure (Kanashiro-Takeuchi et al. 2015; Andersson et al. 2017). Accordingly, combination treatments with alprostadil and statins for refractory heart failure have been speculated to have synergistic effects. Therefore, this study was designed to verify the advantages of a combination treatment of alprostadil and statins for refractory heart failure.

Materials and methods

General materials

A total of 100 near-consecutive patients with refractory heart failure admitted to our hospital from February 2018 to February 2019 were selected as observation objects. Inclusion criteria: (1) patients diagnosed with refractory heart failure by echocardiography; (2) patients with NYHA functional classification of III–IV; (3) patients with history of heart failure ≥90 days and left ventricular ejection fraction (LVEF) <45%; (4) patients who still had heart failure symptoms at rest following systematic medical treatment; (5) patients who strictly followed the doctor’s advice to rest in bed during the treatment and reduced activities; if necessary, the upright position was taken; patients with diet low in salt, fat, and sugar. Exclusion criteria: (1) patients with acute myocardial infarction and acute myocarditis; (2) patients combined with malignant arrhythmia ([1] bradyarrhythmia, heart rate <50 beats/min; [2] tachyarrhythmia, [a] narrow QRS tachycardia, with a heart rate aaa 100 beats/min and QRS time <0.12s; [b] wide QRS tachycardia with QRS aaaa 0.12 s); (3) patients with hypertrophic heart disease, restrictive heart disease, valvular heart disease, etc.; (4) patients with severe hypotension (systolic blood pressure <90 mm Hg and/or diastolic blood pressure <80 mm Hg); (5) patients combined with malignant tumors, blood and immune system diseases, and liver and kidney dysfunction.

Methods

Both groups received routine treatment for heart failure, including diuretic (daily dose of furosemide 100–200 mg by intravenous drip, combined with spironolactone; patients with severe symptoms of heart failure may be given intravenous injection), cardiotonic (digitalis drugs), ACEI/ARB drugs, β-blocker, mineralocorticoid receptor antagonists, and vasodilator drugs (nitrates via intravenous pumping) and improving renal perfusion (small doses of dopamine via intravenous pumping).

Patients in the control group received oral administration of simvastatin (Hangzhou MSD Pharmaceutical Co., Ltd.) at a dose of 20 mg/time, once daily, according to routine treatment for heart failure. Patients in the intervention group received a combination of alprostadil and statins, among which the dosage of simvastatin was the same as the control group, and 20 μg of prostaglandin injection was dissolved in a 0.9% sodium chloride injection solution (100 ml) for intravenous drip, once daily. Both groups continued medication for two weeks.

Observation indicators

The main observation indicators included (1) clinical treatment effects on patients in the two groups according to the Guidelines for the Diagnosis and Treatment of Chronic Heart Failure and rated as markedly effective for declines in NYHA classification of ≧2 and resolved or significantly improved symptoms and signs; effective for declines in NYHA classification of 1 and improvement in symptoms and signs; and ineffective as no significant decline in NYHA and no significant improvement in symptoms and signs. The total effective rate was calculated as (markedly effective cases + effective cases)/total cases × 100%; (2) heart function before and after treatment compared between the two groups according to the NYHA classification criteria in which Class I refers to the compensation period, Class II to the mild heart failure period, Class III to the moderate heart failure period, and Class IV to the severe heart failure period; (3) QOL compared between the two groups using the Minnesota Living with Heart Failure Questionnaire (MLHFQ), which covered items ranging from socioeconomic limitations and physical strength to psychological emotion and body symptoms, with a full score of 105 and lower scores indicating a better QOL; (4) ventricular remodeling indices. Before and after treatment, echocardiography was performed to determine ventricular remodeling indices of left ventricular end-diastolic volume (LVEDV), left ventricular end-diastolic diameter (LVEDD), and left ventricular end-systolic diameter (LVESD). (5) Oxidative stress indices are compared between groups by measuring the levels of superoxide dismutase (SOD) and malondialdehyde (MDA) before and after treatment; (6) detection of inflammatory factor. Serum levels of hypersensitive C-reactive protein (hs-CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were measured before and after treatment. (7) Detection of serum B-type natriuretic peptide (BNP) levels and blood lipid levels. Before and after treatment, the serum BNP, total cholesterol (TC), and triglyceride (TG) levels were measured; (8) detection of blood sugar and insulin levels. Before and after treatment, fasting blood glucose (FBG) and fasting blood insulin (FIS) were identified, and insulin action index (IAI) was calculated.

Statistical analysis

All study data were analyzed using the IBM SPSS Statistics for Windows, version 22.0. Nominal data, namely, total effective rates, were expressed as percentages and compared by chi-squared tests; measurement data, including NYHA functional classification, QOL score, ventricular remodeling indices, oxidative stress indices, and serum BNP, were expressed as ($\overline{x}\pm SD$) and compared using t-tests. P value <0.05 was considered statistically significant.

Results

Comparison of general data

There was no statistically significant difference observed between the two groups in general data, including sex, age, body mass index (BMI), course of disease, combined hypertension, diabetes, BNP, LVEF, NYHA functional classification, primary heart disease, application of diuretics and spironolactone, and administration of ACEI/ARB and β-blocker (P > 0.05; Table 1).

Table 1. Comparison of general data between the two groups [($\overline{x}\pm s$), n (%)].

Item	Intervention group (n = 50)	Control group (n = 50)	Χ^2/t	P
Sex (%)			0.041	0.839
Male	30 (60.00)	29 (58.00)
Female	20 (40.00)	21 (42.00)
Age (years)	65.52 ± 5.39	65.59 ± 5.38	0.065	0.948
BMI (kg/m^2)	24.48 ± 2.13	24.61 ± 2.14	0.304	0.761
Course of disease (years)	4.58 ± 2.45	4.59 ± 2.42	0.021	0.984
Hypertension (%)	22 (44.00)	21 (42.00)	0.041	0.840
Diabetes (%)	18 (36.00)	19 (38.00)	0.043	0.836
BNP $(\text{mg}/\text{L)}$	4682.20 ± 563.28	4679.10 ± 556.21	0.028	0.978
LVEF (%)	27.86 ± 2.05	28.03 ± 2.09	0.411	0.682
NYHA functional class (%)			0.041	0.840
Class III	28 (56.00)	29 (58.00)
Class IV	22 (44.00)	21 (42.00)
Primary heart disease (%)			0.381	0.827
Ischemic cardiomyopathy	26 (52.00)	27 (54.00)
Dilated cardiomyopathy	17 (34.00)	18 (36.00)
Hypertensive heart disease	7 (14.00)	5 (10.00)
Application of diuretic (%)	46 (92.00)	47 (94.00)	0.154	0.695
Spironolactone (%)	41 (82.00)	40 (80.00)	0.065	0.799
Administration of ACEI/ARB (%)	46 (92.00)	47 (94.00)	0.154	0.695
Administration of β-blocker (%)	42 (84.00)	41 (82.00)	0.071	0.790

Comparisons of total effective rates

The total effective rate of the intervention group (98.00%) significantly differed from the control group (86.00%) (P < 0.05). Thus, alprostadil and statins as a combination treatment in patients with refractory heart failure significantly improved clinical effects, indicating a better efficacy compared with routine treatments, as illustrated in Table 2.

Table 2. Comparisons of total effective rates between the intervention and control groups, n (%).

Group	Markedly effective	Effective	Ineffective	Total effective rate
Intervention group (n = 50)	31 (62.00)	18 (36.00)	1 (2.00)	49 (98.00)
Control group (n = 50)	19 (38.00)	24 (48.00)	7 (14.00)	43 (86.00)
χ^2	–	–	–	4.891
P	–	–	–	0.027

Comparisons of NYHA functional class

No marked difference was observed between the two groups in terms of NYHA functional classification (P > 0.05) before treatment. While both test values were reduced after treatment, the decrease was significantly greater in the intervention group compared with the control group (P < 0.05). Therefore, alprostadil and statins as a combination treatment significantly improved the NYHA functional classification of patients with refractory heart failure, with a better efficacy than routine treatments, as shown in Figure 1.

Figure 1. New York Heart Association functional classification in the control and intervention groups.

Notes: Compared to conditions before treatment, ***P < 0.001, and the control group, ^###P < 0.001.

Comparisons of QOL scores

There was no difference observed in QOL scores between the two groups prior to treatment (P > 0.05). After treatment, while scores decreased in both groups, the reduction was more significant in the intervention group than that in the control group (P < 0.05). Thus, alprostadil and statins, as a combination treatment for refractory heart failure, significantly improved the QOL of patients with refractory heart failure, showing better efficacy compared with the group receiving routine treatments, as shown in Figure 2.

Figure 2. Quality of Life scores in the control and intervention groups.

Notes: Compared to conditions before treatment, ***P < 0.001, and the control group, ^###P < 0.001.

Comparison of ventricular remodeling indices

Before treatment, there was no difference between the two groups in terms of ventricular remodeling indices of LVEDV, LVESD, and LVEDD (P > 0.05). However, after treatment, all of them increased, and the increase degree of the intervention group was more significant than that of the control group, showing statistically significant difference (P < 0.05) illustrated in Table 3.

Table 3. Comparison of levels of ventricular remodeling indices between the two groups $(\overline{\mathbf{\text{x}}}\pm \mathbf{\text{s}})$.

	LVEDD (mm)		LVESD (mm)		LVEDV
Group	Before treatment	After treatment	Before treatment	After treatment	Before treatment	After treatment
Intervention group (n = 50)	61.97 ± 8.60	58.07 ± 7.64	49.78 ± 9.20	42.18 ± 9.03	126.31 ± 59.37	103.22 ± 56.93
Control group (n = 50)	62.02 ± 8.56	62.10 ± 8.71	49.72 ± 9.22	47.73 ± 8.28	126.34 ± 59.17	124.60 ± 63.52
t	0.029	2.459	0.032	3.205	0.003	1.772
P	0.977	0.016	0.974	0.002	0.998	0.079

Comparisons of oxidative stress indices

There was no difference between the two groups in terms of oxidative stress indices of SOD and MDA (P > 0.05) prior to treatment. Following treatment, SOD increased and MDA decreased more significantly in the intervention group compared to the control group (P < 0.05), as shown in Figure 3.

Figure 3. Oxidative Stress Indices in the Control and Intervention Groups.

Notes: ***P < 0.001, compared to conditions before treatment; ^###P < 0.001, compared to the control group.

Comparison of hs-CRP, IL-6, and TNF-α levels

There was no significant difference between the two groups in terms of hs-CRP, IL-6, and TNF-α levels before treatment (P > 0.05). However, after treatment, all of them decreased, and the intervention group was significantly lower than the control group (P < 0.05), as shown in Table 4.

Table 4. Comparison of hs-CRP, IL-6 and TNF-α levels between the two groups $(\overline{\mathbf{\text{x}}}\pm \mathbf{\text{s}})$.

	hs-CRP (mg/L)		IL-6 (ng/L)		TNF-α (mg/L)
Group	Before treatment	After treatment	Before treatment	After treatment	Before treatment	After treatment
Intervention group (n = 50)	3.68 ± 0.54	1.53 ± 0.37*	32.05 ± 4.73	13.20 ± 3.28*	29.42 ± 4.50	13.05 ± 3.17*
Control group (n = 50)	3.64 ± 0.52	2.34 ± 0.44*	33.12 ± 4.82	17.98 ± 3.75*	30.28 ± 4.53	16.59 ± 3.46*
t	0.377	9.963	1.120	6.784	0.952	5.334
P	0.707	0.000	0.265	0.000	0.343	0.000

Compared with that before treatment in the group, *P < 0.05.

Comparison of BNP and blood lipid levels

There was no significant difference between the two groups in terms of BNP, TC, and TG before treatment (P > 0.05). After treatment, all of them decreased, and the intervention group was significantly lower than the control group (P < 0.05), as illustrated in Table 5.

Table 5. Comparison of BNP and blood lipid levels between the two groups $(\overline{\mathbf{\text{x}}}\pm \mathbf{\text{s}})$.

	BNP (pg/mL)		TC (mmol/L)		TG (mmol/L)
Group	Before treatment	After treatment	Before treatment	After treatment	Before treatment	After treatment
Intervention group (n = 50)	4682.20 ± 563.28	2054.30 ± 253.18*	7.35 ± 0.69	4.10 ± 0.47*	3.35 ± 0.62	2.10 ± 0.41*
Control group (n = 50)	4679.10 ± 556.21	2938.47 ± 321.60*	7.32 ± 0.68	5.59 ± 0.60*	3.32 ± 0.60	2.59 ± 0.53*
t	0.028	15.275	0.219	13.824	0.246	5.171
P	0.978	0.000	0.827	0.000	0.806	0.000

Compared with prior treatment in the group, *P < 0.05.

Comparison of FGB, FIS and IAI

There was no significant difference between the two groups in terms of FGB, FIS, and IAI before treatment (P > 0.05). After treatment, FGB and FIS decreased and IAI increased, and the range of change in the intervention group was more significant than that in the control group (P < 0.05), as outlined in Table 6.

Table 6. Comparison of FGB, FIS, and IAI between the two groups $(\overline{\mathbf{\text{x}}}\pm \mathbf{\text{s}})$.

	FBG (mmol/L)		FIS (mU/L)		IAI
Group	Before treatment	After treatment	Before treatment	After treatment	Before treatment	After treatment
Intervention group (n = 50)	5.65 ± 0.68	4.70 ± 0.42*	16.02 ± 2.05	9.64 ± 1.30*	−1.93 ± 0.25	−1.59 ± 0.15*
Control group (n = 50)	5.64 ± 0.66	4.89 ± 0.47*	15.97 ± 2.03	13.01 ± 1.59*	−1.94 ± 0.26	−1.67 ± 0.19*
t	0.075	2.132	0.123	11.603	0.196	2.3367
P	0.941	0.036	0.903	0.000	0.845	0.022

Compared with that before treatment in the group, *P < 0.05.

Discussion

Refractory heart failure is an uncommon, severe cardiac illness that is difficult to cure. Routine treatments for heart failure include ACEI, digitalis, and diuretics (Lage and Gutierrez 2017). However, Class III–IV refractory heart failure is always accompanied by congestion in the systemic venous system and lungs and reduced cardiac output and heart function. The influence of other basic diseases often lead to undesired treatment effects and high mortality. This study of alprostadil and statins as a routine treatment for refractory heart failure proved that the combination treatment increased the total effective rate, improved NYHA functional classification, enhanced QOL, inhibited ventricular remodeling, and ameliorated oxidative stress and serum BNP levels.

The addition of alprostadil in adjunctive therapy for refractory heart failure produces significant treatment effects. The possible mechanisms underlying these effects are as follows: (1) alprostadil smoothens and changes vascular smooth muscle to effectively alleviate cardiac afterload (Müller 2012; Dan et al. 2016). (2) Alprostadil inhibits thromboxane synthesis and prevents the formation of thrombi to reduce pulmonary arterial pressure and improve right heart function. (3) Alprostadil helps dilate vessels in the kidneys, reduce renal vascular resistance (RVR), and correct water–sodium retention. (4) Alprostadil significantly reduces the damage caused by cardiac oxidative stress (Kim et al. 2016; Nunes et al. 2016). (5) Alprostadil reinforces improvements to myocardial oxygen supply and increase patient survival (Wittmer et al. 2015; Wei et al. 2016). (6) Alprostadil blocks the progression of ventricular remodeling and improves heart function and ventricular remodeling. In the present study, the total effective rate (98.00%) in the intervention group was statistically higher compared to that in the control group (86.00%). Furthermore, after treatment, the intervention group achieved more significant improvements in terms of NYHA functional classification and QOL scores. It is important to note that Alprostadil and statins, as a combination treatment of refractory heart failure, effectively improves total effective rate, NYHA functional classification, and QOL.

Serum BNP, a cardiac neurohormone and a quantitative marker of heart failure, reflects the ventricular systole function. Its reduction indicates positive treatment effects (Spevack et al. 2004; Cao et al. 2013). This study used serum BNP level as an indicator of treatment effects, observing significantly reduced serum BNP level with the combination of alprostadil and statins in aged patients with refractory heart failure, which further supports the significant effect of the combination treatment.

As the heart fails, preload and afterload in ventricles increases, resulting to oxidative damage in cardiac muscle cells (Reboul et al. 2017; Ribeiro-Samora et al. 2017), excessive oxygen free radicals, increased apoptosis, imbalance in extracellular matrix, thickened and prolonged cardiac muscle cells, spherical changes of heart chambers, and ventricular remodeling (Merlo et al. 2018; Platt et al. 2018). Oxidative stress damage and imbalance in the extracellular matrix play a vital role in the pathophysiological process of heart failure. In the present study, LVEDD, LVESD, and LVEDV, which are closely related to ventricular remodeling, were considered as evaluation indicators, and changes in the levels of the oxidative stress indices of SOD and MDA were observed. The results showed that, after treatment, the degree of improvement of NYHA functional classification, QOL scores, and levels of ventricular remodeling indices, oxidative stress indices, inflammatory factors, serum BNP, blood lipid, blood glucose, and insulin of the intervention group was more significant than that in the control group, indicating statistical difference (P < 0.05). In the present study, the combination of alprostadil and statins as a treatment for aged patients with refractory heart failure significantly improved treatment effects, which is likely due to improvements in the ventricular remodeling process and alleviation of damage from oxidative stress.

In conclusion, the administration of alprostadil to patients with refractory heart failure receiving statin treatment increased the total effective rate; improved NYHA functional class; enhanced QOL; inhibited ventricular remodeling; ameliorated oxidative stress; down-regulated serum levels of inflammatory factors, BNP, blood lipid, and blood glucose; and improved insulin resistance, demonstrating the efficacy of this drug. However, this preliminary study only included limited patients and short follow-up time. Moreover, there was no statistical analysis performed for subsequent mortality and readmission rates, nor was the long-term efficacy of the combination treatment assessed. Further in-depth investigations are necessary in future studies.

At the same time, there are few limitations in this study. The cases selected in this study were patients taking conventional oral simvastatin as a long-term treatment. It still needs to be discussed and analyzed in the next research.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Due to the nature of this research, participants of this study did not agree for their data to be shared publicly, so supporting data is not available.