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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 9  |  Issue : 4  |  Page : 249-254

Comparison of the effects of bosentan and sildenafil in the treatment of persistent pulmonary arterial hypertension in infants


1 Neonatal ICU, Ali Asghar Children Hospital, Iran University of Medical Sciences, Tehran, Iran
2 Neonatal ICU, Ali Asghar Hospital, Iran University of Medical Sciences, Tehran, Iran
3 Neonatal ICU, Shahid Akbarabadi Clinical Research Development Unit, Iran University of Medical Sciences, Tehran, Iran

Date of Submission12-Mar-2020
Date of Decision10-Jul-2020
Date of Acceptance27-Jul-2020
Date of Web Publication01-Oct-2020

Correspondence Address:
Prof. Semira Mehralizadeh
Pediatric Cardiologist, Ali Asghar Children's Hospital, Iran University of Medical Sciences, Tehran
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcn.JCN_5_20

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  Abstract 


Background: Persistent pulmonary hypertension (PPHN) is a life-threatening condition in neonates. In developing countries, mortality is estimated to be around 10%–20% due to lack of access to the main drug, inhaled nitric oxide. Bosentan as an endothelin type A and B receptor antagonist and sildenafil as a phosphodiesterase inhibitor type 5 are effective in reducing pulmonary vascular resistance and pulmonary artery pressure (PAP). Materials and Methods: A double-blind clinical trial was conducted at the intensive care unit of Akbarabadi Hospital Tehran between October 2017 and September 2019. The efficacy, safety, and possible side effects of bosentan and sildenafil were evaluated in neonates suffering from PPHN. Echocardiographic findings, duration of oxygen dependency, invasive ventilation support requirement, duration of medication, short-term outcomes including blood pressure, white blood cell, and hemoglobin counts were compared between the two groups. Results: Bosentan is as effective as sildenafil in reducing PAP and improving cardiac output. The duration of treatment with bosentan was significantly shorter than that of sildenafil (P = 0.002). The time of oxygen demand was similar between both the groups, ranging from 15 to 17 days (P = 0.198). The need for invasive ventilation support was similar in both the groups (P = 0.989). Although PAP and the severity of tricuspid valve insufficiency were higher before treatment, the third echocardiographic findings such as pulmonic insufficiency (P = 0.194), tricuspid regurgitation (P = 0.368), and ejection fraction (P = 0.160) were similar in bosentan and sildenafil groups. The need for supportive inotropic drugs was similar in both the groups. There was no statistically significant difference in the mean of blood pressure, white blood cell, and hemoglobin counts between the two groups.Conclusion: Bosentan is effective in the treatment of PPHN in neonates and reduces it over a shorter period of time. It is more efficient in reducing PAP and decreases the severity of tricuspid valve insufficiency in a shorter time compared to sildenafil.

Keywords: Bosentan, persistent pulmonary hypertension, pulmonary artery pressure, sildenafil


How to cite this article:
Farhangdoust S, Mehralizadeh S, Bordbar A. Comparison of the effects of bosentan and sildenafil in the treatment of persistent pulmonary arterial hypertension in infants. J Clin Neonatol 2020;9:249-54

How to cite this URL:
Farhangdoust S, Mehralizadeh S, Bordbar A. Comparison of the effects of bosentan and sildenafil in the treatment of persistent pulmonary arterial hypertension in infants. J Clin Neonatol [serial online] 2020 [cited 2020 Nov 28];9:249-54. Available from: https://www.jcnonweb.com/text.asp?2020/9/4/249/297004




  Introduction Top


Persistent pulmonary hypertension (PPHN) has been known for more than 30 years; however, the etiology of the disease and its treatment is still debatable.[1] There are limited studies that considered PPHN causes, its associated risk factors, complications, and therapeutic strategies. On the other hand, use of new drugs is only based on experimental evidence or treatment in adults with PPHN.[2] The physiopathology of the disease is because of inadequate responsiveness of the pulmonary artery to increased oxygen, acute hypoxia, and chronic fetal hypoxia which can be associated with increased thickness of pulmonary artery smooth muscle. Furthermore, it can result in partial or complete inability of the lungs for proper dilatation and ventilation which is subsequently associated with pulmonary artery smooth muscle contraction and as a result decreased lumen diameter, increased pulmonary artery resistance, and increased pulmonary artery pressure (PAP).[3],[4]

The etiology of persistent PPHN is often idiopathic. It is mainly seen in term and postterm infants. The incidence of the disease is 1.9 in 1000 live births. The disease symptoms include respiratory distress in the first hours after birth which is associated with tachypnea, grunting, cyanosis, and low arterial oxygen saturation. These symptoms are not normalized even by 100% oxygenation; however, the arterial oxygen saturation level will be normalized upon hyperventilation. Definite diagnosis of the disease is based on echocardiographic data.[5],[6]

The mortality rate of the disease among infants from developing countries is 10%–20%; however, it is higher among patients who have not accessed to important drugs.[7] Inhaled nitric oxide is the main drug for the treatment of this disease that causes pulmonary vascular vasodilation by increasing CGMP (Cyclic GMP) of pulmonary smooth muscle cells. Inotropes such as intravenous dopamine, dobutamine, epinephrine, and norepinephrine are the other common drugs for PPHN. Dopamine has adrenergic effects and increases systemic blood pressure. Dobutamine reduces left ventricular volume and increases cardiac output. Epinephrine and norepinephrine increase cardiac output and increase systemic blood pressure.[5],[6]

Phosphodiesterase inhibitors such as milrinone and sildenafil are the other group of drugs for the treatment of PPHN. Milrinone increases cardiac output by decreasing afterload and causes pulmonary artery vasodilatation and subsequently leads to a reduction in pulmonary artery pressure by increasing CAMP (Cyclic GMP). However, at higher doses, it increases systemic blood pressure. Sildenafil is an oral medication that causes vasodilation of the pulmonary artery by increasing intracellular CGMP, thereby decreases PAP and dilates blood vessels, increases blood flow to specific parts of the body, resulting in complications.[8],[9] Bosentan is an antagonist of the endothelin A and B receptor. Recent studies have shown that it is effective in treatment of pulmonary arterial hypertension; however, its effect on the pulmonary arteries is restricted and specified without serious systemic complications. In some countries, limited research has been conducted on bosentan due to the availability of inhaled nitric oxide. None of these studies have reported any serious systemic complication caused by bosentan.[10],[11]

Therefore, the most important challenge for the treatment of PPHN in countries that do not have access to inhaled nitric oxide is the use of a drug that only affects the pulmonary arteries and has minimal effect on systemic arteries. For this reason, this clinical trial study aimed to evaluate the efficacy, safety, and side effects of bosentan compared to sildenafil.


  Materials and Methods Top


This double-blind clinical trial was conducted to compare the efficacy, safety, and possible side effects of bosentan and sildenafil on neonates with PPHN who were admitted to the neonatal intensive care unit at Akbarabadi Hospital (Tehran, Iran) from 2017 to 2019. The study was approved by the Ethics Committee of the Iran University of Medical Sciences and registered in the Iranian Registry of Clinical Trials (IRCT number: IRCT20190127042504N1).

Before the patient's selection, echocardiography (USA SonoSite 2010 model) was performed for all newborns with respiratory symptoms, low arterial oxygen saturation, and cyanosis. Patients with PAP of ≥25 mmHg and tricuspid valve insufficiency of ≥30 mmHg with or without the right to left shunt were included in this study. Patients with other cyanotic heart diseases, other cyanosis-related diseases, and PPHN caused by pneumonia or meconium aspiration were excluded from the study. Eventually, all patients with PPHN not related to any secondary cause were included in the study and there was no difference between the two groups regarding the cause of PPHN.

Patients were randomly divided into Group A (bosentan) and Group B (sildenafil) using Excel software. In Group A, patients received 1 mg/kg/dose bosentan (tablet 125 mg Company name: Faran Shimi) per gavage every 12 h, while patients in Group B were prescribed with 0.4 mg/kg/dose of sildenafil (tablet 50 mg Company name: Razak) per gavage every 12 h.[7],[11],[12],[13] Echocardiography was performed again on days 6 and 12, and findings of pulmonary arterial pressure, severity of tricuspid valve insufficiency, and cardiac output were compared between the two groups.

In the course of treatment, hypoxia, hyperventilation, hypercarbia, acidosis, and alkalosis were prohibited and inotropes were used according to neonatologist or pediatric cardiologist suggestions. The treatment was stopped when the arterial oxygen saturation level was >95%, the PAP was <25 mmHg, and the severity of tricuspid valve insufficiency was <30 mmHg.

Arterial oxygen saturation was monitored before and during treatments. The criterion for evaluating the efficacy of the drugs was a response to treatment, a condition in which arterial oxygen saturation level was >95%, PAP was <25 mmHg, and the severity of tricuspid valve insufficiency was <30 mmHg. Furthermore, there should be no evidence of drug insufficiency on decreasing the PAP or any complication leading to discontinuation of the drug. The lack of effectiveness means arterial oxygen saturation level in the neonatal monitoring should not be higher than 95%, and on days 6 and 12, PAP should not be <25 mmHg and the severity of valve tricuspid insufficiency should not be <30 mmHg. Duration of oxygen demand, need for aggressive treatment, and duration of medication were compared between the two groups. To evaluate the safety and tolerability of medications, neonates were examined daily for adverse effects, including hypertension, gastrointestinal tolerance, pulmonary hemorrhage, and edema until the end of the treatment.

Statistical analysis

Statistical analysis was performed using Stata 11 (Stata Corp., College Station, TX, USA) and statistical significance was set at P < 0.05. Normalization of data was evaluated using the Kolmogorov–Smirnov test. Quantitative data were analyzed using the descriptive tests and presented as mean ± standard deviation; the percentages and frequencies of each item between the two groups were compared using crosstabs and Chi-square tests. Paired t-test was used to compare the mean of parametric data before and after study in each group. In this study, P < 0.05 was considered statistically significant.


  Results Top


In this study, 50 neonates with confirmed persistent PPHN based on echocardiographic evaluation were entered into the study. The disease diagnosis was confirmed based on a mean PAP of ≥25 mmHg and the severity of valve tricuspid insufficiency of ≥30 mmHg with or without right-to-left shunts. Patients were then randomly divided into two groups: one group treated with bosentan and the other one treated with sildenafil. Four neonates were excluded from the study due to syndromes and six neonates were excluded due to family dissatisfaction. Finally, 40 neonates were enrolled in this study, 15 neonates in bosentan and 25 neonates in sildenafil groups [Figure 1].
Figure 1: Flowchart of the study participants

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Both the groups were matched in terms of gestational age, APGAR score, weight, gravidity, type of pregnancy, gender, maternal medication, and maternal and neonatal risk factors [Table 1]. Bosentan significantly reduced pulmonary arterial pressure and improved cardiac input, similar to sildenafil. The length of treatment with bosentan was significantly shorter than that of sildenafil (P = 0.002) [Table 1].
Table 1: Comparison of clinical characteristics between the study groups

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The duration for oxygen therapy was similar in both the groups, ranged from 15 to 17 days (P = 0.198). Furthermore, the need for aggressive support was similar in both the groups and there was no statistically significant difference [P = 0.989, [Table 1].

Despite the higher PAP and severity of tricuspid valve insufficiency in neonates before treatment, findings of the third echocardiography in bosentan-treated patients were similar to that in sildenafil group, indicating bosentan was more effective than sildenafil [P value for pulmonic insufficiency, tricuspid regurgitation, ejection fraction in the third echocardiography was P = 0. 160, P = 0.368, and P = 0.194, respectively, [Table 2].
Table 2: Comparison of echocardiography results of between the study groups

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Systolic and diastolic blood pressure changes were not significantly different between the two groups before (P = 0.188 and P = 0.742, respectively), during (P = 0.948 and P = 0.705, respectively), and after treatment (P = 0.116 and P = 0.602), respectively. The mean of systolic blood pressure pre- and posttreatment was not significant between and within groups (P = 0.324, f = 1.24). Furthermore, the mean of pre- and posttreatment diastolic blood pressure between and within groups was not statistically significant (P = 0.792, f = 0.68).

Dopamine and milrinone consumption was equally high in both the groups (71% vs. 69%). The mean of white blood cells count in the bosentan and sildenafil groups was similarly decreased and there was no statistically significant difference in the mean of WBC count before (P = 0.442), during (P = 0.359), and after (P = 0.378) treatment between the groups.

The mean of hemoglobin number was similar between the two groups and there was no statistically significant difference in the mean of hemoglobin number before (P = 0.226), during (P = 0.356), and after (P = 0.446) treatment.


  Discussion Top


In this survey, the therapeutic efficacy, safety, and possible side effects of bosentan and sildenafil in neonates with PPHN were assessed for the first time. Neonates with PPHN who were admitted to the neonatal intensive care unit of Akbarabadi Hospital in Tehran, Iran, were included in the study. Our findings revealed that bosentan, similar to sildenafil, was effective in reducing pulmonary arterial pressure and improving cardiac output. More importantly, we found that the length of treatment in neonates treated with bosentan was significantly shorter than sildenafil-treated neonates. In the course of treatment, the duration of oxygen demand in both the study groups was similar and ranged approximately 15–17 days. Our finding was consistent with the result of a study by Steinhorn et al.[14] who did not report any statistically significant difference in the length of oxygen demand between bosentan and placebo groups. We also observed that the need for aggressive support was relatively similar between both the groups; this is in agreement with the findings of the study conducted by Steinhorn et al.[14] In contrast, Mohamed andIsmail[7] reported a statistically significant difference in the frequency of need for aggressive support between bosentan and placebo groups. In the current survey, the need for aggressive support was compared between bosentan and sildenafil groups, while Mohamed and Ismail[7] investigated this condition between bosentan and placebo groups. This may be a reason for the inconsistency in results between our study and these researchers.

In this study, more than half of the patients in both the groups were preterm (53.33% in bosentan and 60% in sildenafil group). In previous studies, like the study by Steinhorn,[15] pulmonary arterial hypertension in preterm neonates mostly occurred after bronchopulmonary dysplasia (BPD). For this reason, in the present study, we selected age-matched patients in both the groups to decrease the possible effect of age on treatment output.

In our study, despite the higher PAP and severity of tricuspid valve insufficiency in neonates before treatment in bosentan-treated patients, the third echocardiography revealed that both sildenafil and bosentan improved pulmonary arterial pressure and tricuspid valve insufficiency after treatment. This finding indicates that bosentan is effective for the treatment of PPHN and tricuspid valve insufficiency in neonates.

We also found that dopamine use in the bosentan and milrinone use in the sildenafil group was equally high (71% vs. 69%). Our finding is consistent with the results of previous studies conducted by Mohamed and Ismail[7] and Maneenil et al.,[10] which reported an equal amount of inotrope use between bosentan and placebo groups. In contrast, Steinhorn et al.[14] showed that the mean of systemic hypotension at the first 24 and 48 h after treatment was not significantly different between bosentan and placebo groups, but the amount of inotrope use in bosentan was significantly higher than placebo. In this research, we did not observe hypotension, gastrointestinal intolerance, pulmonary hemorrhage, and edema in both the groups.

In this study, due to the improvement of clinical symptoms and cardiac function, bosentan was used for the short term, and the short-term effects during drug use were evaluated, while in the study by Mohamed and Ismail,[7] patients were followed up for up to 6 months after discontinuation of treatment. Long-term treatment outcomes such as changes in liver-specific enzymes, neurological symptoms, developmental disorders, and BPD mortality were evaluated. None of these secondary outcomes were greater in the bosentan group than in the placebo group.

McLaughlin et al.[16] considered the survival rates of patients with PPHN within 2 years and concluded that the survival rate of patients who received bosentan as a first line of treatment was higher than the expected rate. In the current study, bosentan was found to be very effective in the treatment of persistent pulmonary arterial hypertension in infants and reduced pulmonary hypertension in a shorter period. Bosentan decreased the PAP, severity of tricuspid valve insufficiency, and cardiac output more effectively in a shorter period compared to sildenafil. In addition, oxygen demand and the need for aggressive respiratory support were similar in both the groups, without any short-term effects such as systemic hypotension, leukopenia, and anemia.


  Conclusion Top


Low sample size and high number of preterm infants were the limitations of this study; however, both the groups were matched. Another point was related to the use of dopamine and milrinone in the study groups. Despite the results of previous studies on the efficacy of combination therapy for the treatment of PPHN, the use of these combination therapies may be one of the limitations of the study because patients in the bosentan group received dopamine and those in sildenafil group received milrinone. It would be better if patients in both the groups were prescribed with similar inotropes. To compare efficiency of the drugs, it would be well if patients in each study group had been compared with a placebo group as well. Inaccessibility of inhaled nitric oxide was another limitation of this survey because it is the best choice for the treatment of PPHN which is used in many other treatments in combination with other medications.

Therefore, future clinical trial studies with larger sample size and long-term follow-up on term or near-term neonates are recommended. Furthermore, the type of inotropes should be similar between the study groups. To make a better evaluation and comparison, another group treated with inhaled nitric oxide or placebo should be entered into the survey. The mortality rate and long-term output can be considered in future studies.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Acknowledgments

The authors would like to thank Shahid Akbarabadi Clinical Research Development Unit and Ali Asghar Clinical Research Development Center for their support and statistical/search assistance throughout the period of the study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Martin RJ, Fanaroff AA, Walsh MC. Genetic and environmental contributions to congenital heart disease. In: Fanaroff and Martin's Neonatal-Perinatal Medicine E-Book: Diseases of the Fetus and Infant. 10th ed. Philadelphia: Elsevier Health Sciences; 2010. p. 1215-22.  Back to cited text no. 3
    
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