Sildenafil for congenital heart diseases induced pulmonary hypertension, a meta-analysis of randomized controlled trials

Present in a variety of organs, such as blood vessels, corpus cavernosum, liver, and kidney with more than eleven different families defined, phosphodiesterase (PDE) is an enzymes family which controls the activity of secondary messengers, such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) [1]. Thus, each specific family of PDE is specific in treating selective diseases upon acting on specific 2ndary messengers, such as PDEs 5, 6, and 9 which are selective for cGMP. Upon hydrolyzation of cGMP by PDE5, it results in a cascade establishing various cellular effects, including ion transport, endothelial permeability, and smooth muscle relaxation [1]. PDE5 inhibitors (PDE5-Is) manifest their effects by inhibiting the PDE5-dependent cGMP hydrolysis, thus increasing cGMP intracellularly. As cGMP is the main secondary messenger for both nitric oxide and natriuretic peptide systems, thus upon increasing, it results in vascular smooth muscles relaxation and vasodilatation [2].

Therefore, PDE 5 inhibitors, such as sildenafil, were first prescribed for angina pectoris and then further proven their efficacy in the treatment of erectile dysfunction (ED). As both cardiovascular diseases and ED share the same risk factors, such as age, smoking, hypertension, depression, and metabolic syndrome, and the underlying pathophysiology from endothelial dysfunction, inflammation of small blood vessels, and formation of atherosclerotic plaques. Recently, several studies have elaborated on their cardioprotective efficacy and proposed their usage in pulmonary arterial hypertension (PAH) [3, 4]. PAH can result from several congenital heart diseases (CHD), such as septal defects: ASD, VSD, or PDA which results in the right to left shunt. Without being treated, PAH can cause several fatal complications due to the unoxygenated blood presents in the systemic circulation [5]. Whether to use PDE5-Is in congenital heart diseases induced pulmonary hypertension has been a controversy emerging from its ingenious potential side effects on children [5]. Thus, our meta-analysis aimed to further investigate the safety and efficacy of sildenafil in congenital heart diseases induced pulmonary hypertension (CHD-PAH).

This review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [6], and the Cochrane handbook for systematic reviews and meta-analysis [7] and has been registered with https://​doi.​org/​10.​27405/​OSF.​IO/​TQBXA.

We used the Cochrane risk of bias (ROB-2) assessment tool which is described in chapter 8.5 of the Cochrane handbook [6]. This tool can detect five types of bias including selection bias, performance bias, detection bias, attrition bias, and reporting bias. We classified included articles in each domain as low, some concerns, or high bias.

Our manuscript is the most comprehensive meta-analysis done today including 14 studies, with a total of 849 children, comparing the efficacy of using sildenafil in pulmonary hypertension associated with congenital heart diseases. Our meta-analysis showed a significant decrease favoring the sildenafil group in mPAP, sPAP, PO/AO, mechanical ventilation duration, ICU stays, and hospital stays, yet an insignificant decrease in mAOP and rates of mortality. When compared to milrinone, sildenafil showed higher mPAP, PO/AO, sPAP, ICU stay, and hospital stay; nevertheless, when compared to tadalafil, sildenafil showed lower mPAP, sPAP, PO/AO, mechanical ventilation time, and ICU stay with no difference in mortality rates.

Furthermore, studies that have not been included in our analysis yet in our systematic review including Brast et al. whom conducted STARTS-1 [9] and 2 [23] randomized controlled trials. In STARTS-1, they compare the effect of sildenafil in several doses: low, medium, and high orally 3 times daily for 16 weeks versus placebo on patients with pulmonary arterial hypertension (PAH). Congenital anomaly-induced hypertension was found in 39 out of 60 patients in the placebo group and 117 out of 174 patients in the sildenafil group. Overall, sildenafil was well tolerated for pediatric PAH with better exercise capacity and hemodynamics with medium and high dose sildenafil with overall profile favoring medium dose sildenafil. In STARTS-2 [23], a 3-year follow-up showed that all sildenafil dose groups exhibited satisfactory survival for children with PAH, although higher unexplained mortality rates were observed with higher compared with lower sildenafil doses.

Moreover, El-Midany et al. conducted a study enrolling 101 patients randomly assigned to either receiving sildenafil pre- and post-operative correction of a congenital cardiac defect causing PAH (n = 51) versus post-operative only (n = 50). Although a slight difference was observed favoring the pre-post-operative group in terms of mPAP, they found no statistical difference between the two groups in terms of mechanical ventilation time, ICU, and hospital stay time.

Pulmonary arterial hypertension (PAH) is a progressive pathology that can cause various complications without treatment as a right ventricular failure and even death [24]. There are several etiologies for PH, they can be classified into five groups: (1) PAH secondary to congenital heart disease (PAH-CHD); (2) illnesses that emerge from either lung diseases or hypoxia (3) a reaction to left-sided heart disease; (4) a grouping for unclear, unknown, multifactorial mechanisms and (5) chronic thromboembolism [25]. CHD leads to increased blood flow to the pulmonary circulation that results in vascular dilation, endothelial damage, shear stress, impairment in the production of vasodilators such as NO endothelin-1 and prostacyclin, and activation of remodeling pathway that results in smooth muscle hypertrophy and fibrosis due to activation of fibroblasts [26]. Early changes to the vascular bed can be reversible if the underlying congenital heart defect is repaired within months, and the pulmonary vascular resistance (PVR) can return to normal values within 1 year [27].

PAH-CHD results from congenital septal defects such as ASD, VSD, or PDA which is called right to left shunt with the most common cause being ASD [28, 29]. In right to left shunt, there is increased blood flow to pulmonary circulation leading in last to pulmonary vasoconstriction and increased right atrial/ventricular pressure. If systolic pressure between both ventricles is equal, this is Eisenmenger's Syndrome. Reversal of the shunt in Eisenmenger's Syndrome relieves the pressure in the right ventricle but results in cyanosis due to unoxygenated blood entering the systemic circulation and other life-threatening complications. Medical or surgical interventions are to be done before Eisenmenger's Syndrome development where there is established PAH and surgical correction in the meantime can aggravate the condition to "the point of no return” [27, 28].

Zhang et al. [30], in their meta-analysis of 15 studies involved, assessed the efficacy of sildenafil in children with pulmonary arterial hypertension (PAH) caused by either idiopathic, congenital heart diseases, persistent pulmonary hypertension of the newborn, or high altitude heart disease, and they showed that mPAP and length of hospital stay were not statistically different between sildenafil and control groups. On the other hand, our study shows statistically different mPAP and length of hospital stay for the sildenafil group. Moreover, the pooled estimate favored that sildenafil reduced the duration of mechanical ventilation time and length of ICU stay and these findings are consistent with ours. Chinwe Unegbu et al. [31], in their meta-analysis, which included 8 RCTs, assessed the effect of PDE5 inhibitors on pulmonary hypertension. Four of the included studies involved patients with CHD-associated PH. 3 studies reported no significant difference in hospital stay, unlike our study. They reported improvement in mPAP by catheterization measurement between both groups which are consistent with our finding.

Several other phosphodiesterases (PDE) inhibitors have been introduced as a solution to PAH, such as milrinone and tadalafil. Milrinone is a type III PDE-3 inhibitor with vasodilating and inotropic effects; first introduced as a treatment for end-stage heart failure as infusion therapy or bridge to cardiac transplant [32]. Due to its vasodilating effects, it has been proposed for neonates' pulmonary hypertension showing promising results as a comparator for sildenafil. Milrinone has been associated with lower mPAP, ICU stays, and hospital stay [12] which is consistent with our findings, yet higher sPAP, and mAOP when compared to sildenafil. Furthermore, A study conducted by El-Ghandour et al. [33] comparing sildenafil to milrinone in neonates with persistent PAH showed better mPAP, sPAP, and right ventricular function with milrinone over sildenafil, with the best results being associated with dual sildenafil and milrinone therapy.

Tadalafil is a type V PDE-5 inhibitor with vasodilation effects primarily introduced for erectile dysfunction and benign prostatic hyperplasia [34], then proposed for treating PAH caused by congenital heart anomalies [18]. However, it showed no significant improvement over sildenafil in any of the hemodynamics parameters. Moreover, in a recent network meta-analysis [35] conducted on PAH in adults, tadalafil was associated with a low change in 6-min walking distance, besides being associated with high clinical worsening compared to other PDE-inhibitors. Bosentan with Iloprost and Bosentan with Sildenafil was the better combinations associated with the lowest mPAP.

Sildenafil is a safe, inexpensive, and well-tolerated treatment in pulmonary hypertension induced by congenital heart diseases especially VSD, as it has proven its efficacy not only in lowering the mPAP and sPAP but also in reducing the mechanical ventilation time, ICU and hospital stay with no difference observed regarding mortality rates.