Vardenafil efficacy for the treatment of persistent pulmonary hypertension of the newborn

Abstract

BACKGROUND

Persistent pulmonary hypertension of the newborn (PPHN) remains a challenging condition with high morbidity and mortality despite advancements in management, which implies the need to investigate new therapies. While sildenafil is the drug of choice in resource-limited centers and for patients unresponsive to inhaled nitric oxide, alternative phosphodiesterase-5 inhibitors like vardenafil may offer superior efficacy.

AIM

To assess the efficacy of vardenafil in the management of persistent pulmonary hypertension in newborns.

METHODS

This randomized, double-blind, controlled, parallel clinical trial was conducted at Children’s Hospital, Damascus University. Fifty-five newborns (32 females and 23 males, < 96 hours old) with moderate to severe PPHN were allocated at a 1:2 ratio to receive 2 mg/kg/day oral sildenafil (n = 18) or 0.4 mg/kg/day oral vardenafil (n = 37). Recruitment lasted from May 2023 until September 2024. Clinical and echocardiographic findings were monitored daily from diagnosis until pulmonary pressure normalization.

RESULTS

The vardenafil group showed more rapid improvement. Pulmonary hypertension decreased significantly in the vardenafil group after 1 and 2 days (P = 0.002 and P < 0.001 respectively). Similarly, pulmonary vascular resistance decreased significantly in the vardenafil group after 1 day and 2 days (P = 0.001 and P = 0.015 respectively). Additionally, pulmonary artery flow velocity increased more in the vardenafil group after 1 day and 2 days (P = 0.046 and P = 0.048 respectively) and respiratory distress scores improved more in the vardenafil group after 2 days and 3 days of treatment (P = 0.048 and P = 0.004 respectively). No adverse events were reported in either treatment group.

CONCLUSION

Vardenafil at 0.4 mg/kg/day has superior efficacy compared with sildenafil at 2 mg/kg/day in improving echocardiographic and clinical outcomes in patients with PPHN, with comparable safety profiles. These findings suggest vardenafil may be a valuable option for PPHN management.

Key Words: Persistent pulmonary; Hypertension of the newborn; Vardenafil; Sildenafil; Pulmonary vascular resistance; Phosphodiesterase inhibitors

Core Tip: This is the first randomized controlled trial to evaluate the efficacy of vardenafil in the management of patients with persistent pulmonary hypertension of the newborn (PPHN). The study demonstrated that improvements in pulmonary hypertension, pulmonary vascular resistance, pulmonary artery flow velocity, and respiratory distress were faster in the vardenafil group than in sildenafil group without adverse events. These findings if confirmed in larger clinical trials may position vardenafil as a preferred first-line therapy for PPHN particularly in resource limited settings.

INTRODUCTION

During fetal development, pulmonary vascular resistance remains elevated with minimal pulmonary blood flow. The normal transition at birth involves a rapid decrease in pulmonary vascular resistance and a corresponding increase in pulmonary circulation[1].

Persistent pulmonary hypertension of the newborn (PPHN) is a critical syndrome resulting from failure or delayed circulatory adaptation following birth[2]. It is usually evident shortly after birth as severe respiratory distress, labile hypoxemia, and differential cyanosis if the persistent ductus arteriosus (PDA) is patent[3].

The epidemiologic burden of PPHN is substantial, affecting approximately 2 per 1000 live births[4]. Despite advances in management, mortality rates remain concerning with up to 33% even in some well-resourced centers in the United States and United Kingdom[4,5].

The pathophysiology involves complex alterations in pulmonary vascular structure and function[6], necessitating therapeutic interventions to induce pulmonary vasodilatation, optimize lung recruitment, improve blood oxygenation, and reduce oxidative stress[2].

Current therapeutic approaches include inhaled nitric oxide (iNO)[7], assisted ventilation, extracorporeal membrane oxygenation, surfactant therapy, and phosphodiesterase inhibitors. In addition, supportive care measures such as maintaining normal temperature, glucose, and calcium levels, sedation and analgesia are essential adjuncts to achieve the best outcome[8].

iNO is currently the cornerstone of treatment in resource-rich settings. While in resource-constrained settings, pulmonary vasodilators, particularly sildenafil serve as first-line therapy. However, iNO does not appear to be a solution to this problem, as approximately 40% of patients demonstrate resistance, and mortality reduction of critically ill infants remains limited. Therefore, knowledge of the efficacy and safety of different therapeutic agents might serve as the key to improving outcomes and survival[9].

With the growing preference for oral drugs due to their demonstrated efficacy, ease of administration and acceptable side effect profiles[10], phosphodiesterase 5 inhibitors (PDE5i) are an attractive option.

PDE5i prevent cyclic mononucleotide degradation in pulmonary arterial and cardiac smooth muscles, thereby enhancing smooth muscle relaxation, promoting vasodilatation, and providing cardiac support[6].

Sildenafil, the most studied PDE5i for PPHN, is a potent and selective PDE5i that reduces mortality and improves oxygenation in neonates by supporting the respiratory system (higher oxygenation index) and the circulatory system (higher peripheral blood volume), both of which result in immediate improvement in ventilation perfusion[9]. This leads to the presumption of similar effects with other PDE5i.

Vardenafil is the most potent and selective PDE5i. Its structure and binding interactions resemble those of sildenafil the most, with the following differences: (1) The orientation of the piperazine ring in the active site and in the substitution (methyl in sildenafil vs ethyl in vardenafil); and (2) The heterocyclic ring system which simulates the purine ring of cyclic guanosine monophosphate (cGMP)[11]. However, vardenafil has at least 20 times greater affinity for PDE5 than does sildenafil[12]. Furthermore, recent studies suggest that vardenafil acts directly to reduce calcium influx in the pulmonary artery, in addition to its vasodilatory effects via cGMP[13]; hence, vardenafil exhibits pulmonary selectivity, leading to rapid vasodilation.

Vardenafil is rapidly absorbed after oral administration, reaching its maximum concentration within 40 minutes, and has a half-life of 4-5 hours. The most common side effects are headache, flushing, rhinitis, dyspepsia, sinusitis, flu syndrome, and dizziness[14].

Vardenafil is Food and Drug Administration-approved for treating erectile dysfunction[11], and ongoing clinical trials on its use for the treatment of pulmonary arterial hypertension have reached the third stage for Food and Drug Administration approval[15]. However, limited data exist regarding vardenafil use in children[14,16-18], and its efficacy and safety in treating PPHN have not been reported until now. This study aimed to compare the efficacy of vardenafil vs sildenafil in treating newborns with PPHN.

MATERIALS AND METHODS

Study setting and design

This randomized, double-blind, active-controlled, parallel trial was conducted at the neonatal intensive care unit of Children’s Hospital, Damascus University, Syria, following ethical approval by the review board of Damascus University. Enrollment lasted from May 2023 until September 2024[19]. The flow diagram of the study is shown in Figure 1.

Figure 1 Participant’s flow diagram. sPAP: Pulmonary artery systolic pressure; q24h: Every 24 hourly.

Participants

Inclusion criteria: (1) Neonates with moderate to severe PPHN confirmed by echocardiography; (2) Gestational age ≥ 30 weeks; and (3) Age at diagnosis (enrollment) < 96 hours.

Exclusion criteria: (1) Congenital heart disease other than persistent foramen oval (PFO), PDA, small muscular ventricular septal defect; (2) Inability to use the oral route; (3) Death or transfer within 12 hours from diagnosis (before receiving the 2^nd dose of vardenafil or the 3^rd dose of sildenafil); and (4) Use of any pulmonary vasodilators prior to randomization[19].

Randomization and masking

Neonates fulfilling the selection criteria were randomly assigned via the concealed sealed envelope technique at a 2:1 ratio to either group A (sildenafil treatment, n = 18) or group B (vardenafil treatment, n = 37). Both the cardiologist and guardian were blinded to the treatment given[19].

Outcomes

Primary outcomes of treatment are changes in pulmonary pressure, and pulmonary vascular resistance. Secondary outcomes are possible improvements in respiratory distress, pulmonary artery flow velocity[19], and complications of either line of therapy.

Procedures

Intervention started right after diagnosis; group A received sildenafil 0.5 mg/kg every 6 hours orally or via nasogastric tube. The solution was prepared by crushing and dissolving a 50 mg tablet in 20 mL distilled water, achieving a concentration of 2.5 mg/mL.

Group B received vardenafil 0.2 mg/kg every 12 hours orally or via nasogastric tube. The solution was prepared by crushing and dissolving a 10 mg tablet in 20 mL distilled water, achieving a concentration of 0.5 mg/mL. Notably, there are no data concerning the therapeutic pediatric dose of vardenafil. The administered dose was calculated based on the assumption that a 50 mg tablet of sildenafil is equivalent to a 10 mg tablet of vardenafil, thus the standard pediatric dose of sildenafil 2 mg/kg is equivalent to 0.4 mg/kg of vardenafil.

Other supportive treatments were given to all patients as needed, and inotropes infusion for hemodynamic instability was according to the hospital protocol. Medications were discontinued when the right ventricular systolic pressure (RVSP) normalized, except for intubated patients until extubated.

The complications of sildenafil (systemic hypotension, flushing, vomiting, skin rash, etc.) and of vardenafil (flushing, rhinitis, flu syndrome, etc.) were monitored to assess safety. Echo with real-time Doppler flow imaging was performed on Philips IE33 using an X7 or S8 probes at the time of diagnosis, and the process was repeated every 24 hours until pulmonary pressure normalization was achieved.

Tricuspid regurgitation was assessed by continuous wave Doppler from the apical 4 chamber view mainly, whereas pulmonary artery flow profile was assessed by continuous and pulsed wave Doppler from the parasternal short axis view. RVSP was calculated via the modified Bernoulli equation since all patients in this sample had tricuspid regurgitation.

Pulmonary artery systolic pressure (sPAP) was evaluated on the basis of RVSP considering right atrial pressure 5 mmHg (inferior vena cava collapsibility was > 50%), and categorized into severe (RVSP > 2/3 systolic blood pressure or in presence of predominant right-to-left shunting through PFO, PDA, or ventricular dysfunction), moderate (RVSP 1/2-2/3 systolic blood pressure), mild (sPAP 35 mmHg-1/2 systolic blood pressure with left-to-right shunting through PFO, PDA, and intact ventricular function), and normal (sPAP < 35 mmHg with left-to-right shunting through PFO, PDA, and intact ventricular function)[20,21].

Pulmonary resistance was assessed from the ratio of pulmonary artery acceleration time (PAAT) to the right ventricle ejection time (RVET). The PAAT/RVET score was categorized as high (< 0.23), normal (≥ 0.31), or borderline[22].

Additionally, respiratory distress was categorized as severe, moderate, or mild according to the Silverman–Anderson index. Systemic hypotension was defined as blood pressure below the 10^th percentile according to gestational and postnatal age.

Sample size

SampSize app was used to calculate the sample size based on input: Superiority, parallel design, 2:1 ratio of case to control, power 0.8, significance level 0.05, endpoints normal, 2-sided significance, mean difference (of pulmonary pressure) 10; the minimum total size needed was 45 participants.

Statistical analysis

Data were double-checked for any possible errors, then analyzed with the Statistical Package for Social Science (SPSS 25.0 IBM Corporation, NY, United States). Descriptive statistics are presented as mean (SD) for continuous variables (normally distributed), and as n (%) for categorical variables. Normality of data distribution was verified through the Shapiro-Wilk test in conjunction with histograms and Q-Q plots. Differences between treatment groups were assessed using the Mann-Whitney U test for ordinal variables (pulmonary hypertension severity, pulmonary vascular resistance, respiratory distress scores) and the one-way analysis of variance test for continuous variables (pulmonary artery flow velocity). Confidence interval was set at 95% for all tests, P values < 0.05 were considered statistically significant.

RESULTS

Between May 2023 and September 2024, 55 newborns were enrolled in this study.

Baseline characteristics

The demographic profiles of participants were comparable between groups (Table 1). Follow-up was conducted every 24 hours until pulmonary hypertension resolved or death occurred.

Table 1 Baseline characteristics of enrolled participants, n (%)/mean ± SD.

Characteristic	Vardenafil group (n = 37)	Sildenafil group (n = 18)
Gestational age (week)	37.07 ± 1.95	37.74 ± 1.54
Full term/preterm	26 (70.3)/11 (29.7)	14 (77.8)/4 (22.1)
Maternal age (year)	25.90 ± 6.89	29.62 ± 6.83
Antenatal history
Steroids	1 (2.7)	2 (11.1)
Gestational diabetes	4 (10.81)	0
Gestational hypertension	4 (10.81)	1 (5.5)
Delivery cesarian/vaginal	27 (73)/10 (27)	12 (65)/6 (35)
Birth weight (kg)	2.86 ± 0.54	2.65 ± 0.57
Gender (female:male)	21 (56.8):16 (43.2)	11 (61):7 (39)
Deformities	3 (8.1) trisomy 21; 1 (2.7) omphalocele	2 (11.1) piere robin; 2 (11.1) meningocele
Age at diagnosis (day)	2.38 ± 0.83	2.22 ± 0.55
PDA shunt R-L or bidirectional	8 (21.62)	3 (16.67)
PFO shunt R-L or bidirectional	7 (18.9)	6 (33.33)
Tricuspid regurgitation	37 (100)	18 (100)
Pulmonary mid systolic notch	37 (100)	18 (100)
Secondary PPHN causes	21 (56.7) sepsis	10 (55.5) sepsis
	2 (5.4) erythrocytosis	2 (11.1) MAS
	1 (2.7) asphyxia	1 (5.5) asphyxia
	1 (2.7) CDH	1 (5.5) RDS

PDA: Persistent ductus arteriosus; R-L: Right to left shunt; PFO: Persistent foramen oval; sPAP: Pulmonary artery systolic pressure; MAS: Meconium aspiration syndrome; CDH: Congenital diaphragmatic hernia; RDS: Respiratory distress syndrome; PPHN: Persistent pulmonary hypertension of the newborn.

Outcomes

Outcomes are listed in Table 2. Participants who received vardenafil showed faster improvements across all outcome measures compared with those who received sildenafil.

Table 2 Comparison of intervention outcomes between treatment groups, n (%)/mean ± SD.

Parameter	Vardenafil (n = 37)	Sildenafil (n = 18)
Pulmonary hypertension severity
Baseline
Severe	23 (62.2)	13 (72.2)
Moderate	14 (37.8)	5 (27.8)
After 1 day
Severe	0 (0)	4 (22.2)
Moderate	12 (32.4)	9 (50)
Mild	2 (5.4)	0 (0)
Normal	23 (62.2)	5 (28)
After 2 days
Severe	0/141	1/131
Moderate	1/141	4/131
Mild	2/141	1/131
Normal	10/141	6/131
Dead	1/141	1/131
After 3 days
Mild	0/31	1/61,2
Normal	3/31	4/61
Dead	0/01	1/61
Pulmonary vascular resistance
Baseline
High	37 (100)	18 (100)
After 1 day
High	1 (2.7)	2 (11.1)
Border line	6 (16.2)	10 (55.5)
Normal	30 (81.1)	6 (33.3)
After 2 days
High	0/61	1/111
Borderline	0/61	1/111
Normal	6/61	9/111
Pulmonary artery flow velocity (m/second)
Baseline	0.891 ± 0.125	0.893 ± 0.159
After 1 day	1.11 ± 0.18	1.017 ± 0.20
After 2 days	1.20 ± 0.19	1.037 ± 0.24
After 3 days	1.23 ± 0.18	1.1 ± 0.20
Heart rate (bpm)
Baseline	133.3 ± 9.13	138.8 ± 13.75
After 1 day	128.0 ± 11.4	132.1 ± 10.3
After 2 days	120.98 ± 9.3	116.8 ± 9.3
Blood pressure (mm Hg)
Systolic
Baseline	65.8 ± 3.54	67.0 ± 6.75
After 1 day	67.8 ± 3.92	70.9 ± 4.91
After 2 days	75.0 ± 5.97	76.1 ± 8.94
Diastolic
Baseline	35.0 ± 2.43	36.0 ± 3.9
After 1 day	36.9 ± 4.25	38.2 ± 5.14
After 2 days	41.9 ± 3.72	40.6 ± 5.83

¹The number of cases in each category out of the total sample (i.e., cases that have not been normalized yet).

²Normalized on the following day.

In terms of pulmonary hypertension there was a significant decrease in sPAP within each group. The Mann-Whitney U test was conducted to compare changes between the groups, showing statistically significant improvement in group B after 1 day and 2 days of intervention (0.8%, 1.00 95%CI: 0.00-2.00; P = 0.002 after 1 day and 0.00 95%CI: 0.00-0.00; P < 0.001 after 2 days)[19], (r = -0.42, -0.51 respectively).

Similarly, pulmonary vascular resistance was initially high in all patients before the intervention, it decreased significantly in both groups. However, the Mann-Whitney U test revealed statistically significant differences in group B after 1 day and 2 days (0.8%, 1.00 95%CI: 0.00-1.00 and 0.00 95%CI: 0.00-0.00 respectively; P = 0.001 and 0.015 respectively)[19], (r = -0.44, -0.54 respectively).

Respiratory distress scores improved in both groups as pulmonary pressure decreased. The Mann-Whitney U test revealed a statistically significant improvement in the vardenafil group after 2 days and 3 days of treatment (0.8%, 1.00 95%CI: 0.00-2.00 and 1.00 95%CI: 0.00-1.00 respectively; P = 0.048 and 0.004 respectively)[19], (r = -0.36, -0.43 respectively).

Pulmonary artery flow velocity increased significantly in both groups with treatment. The one-way analysis of variance test revealed a statistically significant difference in group B after 1 day and 2 days (0.8%, 95%CI: 1.040-1.144 and 95%CI: 1.082-1.237 respectively; P = 0.046 and P = 0.048 respectively)[19] with a partial eta squared of 0.08 and 0.14 respectively. There was no statistically significant difference after 3 days (Figure 2). Pulmonary annulus size (mm) differences weren’t statistically significant. In group A the annulus size was 8.32 (1.16), 8.47 (1.00), and 8.66 (0.99), and in group B it was 8.21 (0.93), 8.20 (0.96), and 8.19 (0.98) at diagnosis, and after 1 day, 2 days respectively.

Figure 2  Pulmonary artery flow velocity differences between groups.

Additionally, tricuspid annular plane systolic excursion indexed to weight and gestational age at the time of diagnosis decreased in 7 (38.8%) cases from group A and 11 (27%) cases from group B. It normalized the next day except for one case from group A until the 2^nd follow-up.

No adverse events were reported[19] in either treatment group during admission in this sample. During intervention heart rate and systemic blood pressure remained within normal limits. 3 (16.6%) patients on sildenafil and 3 (8.1%) patients on vardenafil required mechanical ventilation, although the differences did not reach statistical significance in this study. 3 patients died from aspiration during intervention (2 in group A and 1 in group B) and hence cannot be considered a failure of therapy.

DISCUSSION

This randomized controlled trial (RCT) provides preliminary evidence supporting the superior efficacy of vardenafil compared with sildenafil for treating PPHN in newborns. The more rapid improvements observed across multiple echocardiographic and clinical parameters suggest vardenafil may offer meaningful therapeutic advantages. The enhanced efficacy of vardenafil may be attributed to its superior selectivity and potency for PDE5 compared with sildenafil[12]. Vardenafil demonstrates approximately 20-fold greater selectivity for PDE5 over other PDE enzymes, potentially resulting in more targeted pulmonary vasodilation[15] with reduced off-target effects. Alternatively, it could be explained to some extent by the doses used.

The absence of adverse events in both treatment groups is reassuring and consistent with the established safety profile of PDE5i. However, the small sample size of this study limits definitive safety conclusions, and larger trials are needed to comprehensively assess the safety profile of vardenafil in newborns.

If confirmed in larger RCTs, these findings could influence clinical practice guidelines for PPHN management. The superior efficacy of vardenafil, combined with its comparable safety profile, and ease of administration (orally, twice daily) may position it as a preferred first-line therapy especially in resource-limited settings where iNO is unavailable and as a preferred second-line therapy in resource-rich settings.

There are several limitations to this trial; the small sample size limits statistical power and generalizability of findings, preterm infants < 30 weeks of gestation were excluded, vardenafil pediatric therapeutic dose is not yet established, and the study did not compare different doses of each drug. Additionally, long-term follow-up data were not collected precluding evaluation of delayed adverse events.

CONCLUSION

This study demonstrates that vardenafil (0.4 mg/kg/day) is more effective than sildenafil (2 mg/kg/day) in improving echocardiographic and clinical outcomes in newborns with moderate to severe PPHN. Both medications exhibited comparable safety profiles with no reported adverse events. These preliminary findings support the need for larger, multicenter RCTs with long term follow-up to definitively establish vardenafil’s role in PPHN management and potentially inform evidence-based treatment guidelines.

ACKNOWLEDGEMENTS

All pediatricians who informed me about candidates for the study.