Article Text

Paediatric pulmonary hypertension and sildenafil: current practice and controversies
  1. A J Wardle1,
  2. R M R Tulloh1,2
  1. 1University of Bristol, Bristol, UK
  2. 2Department of Paediatric Cardiology, University Hospitals Bristol, Bristol, UK
  1. Correspondence to Professor Robert M R Tulloh, University Hospitals Bristol NHS Foundation Trust, Upper Maudlin Street, Bristol BS2 8BJ, UK; robert.tulloh{at}uhbristol.nhs.uk

Abstract

In recent times, paediatric pulmonary arterial hypertension management has been transformed to focus on disease modifying strategies that improve both quality of life and survival, rather than just symptom palliation. Sildenafil, a phosphodiesterase-V inhibitor, has been at the centre of this. Despite controversial beginnings, its success in treating pulmonary arterial hypertension has led to its consideration for related pathologies such as persistent pulmonary hypertension of the newborn and bronchopulmonary dysplasia, as well as the development of a range of alternative formulations. However, this has caused its own controversy and confusion regarding the use of sildenafil in younger patients. In addition, recent data regarding long-term mortality and the repeal of US drugs approval have complicated the issue. Despite such setbacks, sildenafil continues to be a major component of the contemporary care of paediatric pulmonary hypertension in a variety of contexts, and this does not seem likely to change in the foreseeable future.

Keywords
  • 1. Pulmonary arterial hypertension
  • 2. Paediatric
  • 3. Sildenafil
  • 4. Review
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Keywords

Introduction

Paediatric cardiology is an area of significant research and progress; however, pulmonary arterial hypertension (PAH) remains an important and often incurable cause of morbidity and mortality. There are many causes ranging from the rare idiopathic form (idiopathic PAH (IPAH)) to those associated with congenital heart disease (CHD) or bronchopulmonary dysplasia. Current survival for IPAH averages just 4 years with treatment, although a recent wave of new medicines have helped to improve this. The phosphodiesterase-V inhibitor (PDE-Vi) sildenafil, originally approved for erectile dysfunction as viagra, has been at the heart of these changes.

Viagra's use in ‘blue babies’ has always been controversial, both with parents and clinicians. However, a decade of research and rebranding, including the trade name Revatio, has resulted in it becoming a mainstay of paediatric PAH treatment. That stated, the US Food and Drug Administration (FDA) recently reignited the controversy by denouncing its use in children. Nevertheless, sildenafil remains the sole oral PAH strategy based upon nitrate-linked mechanisms with the approval of European Medicines Agency in children. Furthermore, it continues to be subject to substantial off-license application, including varying formulations, doses and clinical indications. This article explores these issues indepth.

Pulmonary arterial hypertension

Diagnostically, PAH is defined as a resting mean pulmonary arterial pressure exceeding 25 mm Hg at cardiac catheterisation. The usual echocardiographic entry criterion is a peak Doppler velocity of tricuspid regurgitation greater than 2.7 m/s.1 It is also important to remember that pulmonary vascular resistance must be raised to more than 3 units×body surface area (m2). (Note, resistance is indexed by multiplying by the body surface area, not dividing, a common error in published papers and book chapters.) In addition, this is normally in the absence of left atrial hypertension, such that the mean left atrial pressure is less than 15 mm Hg. This excludes left heart failure, which causes pulmonary venous hypertension, from the diagnosis of PAH.

Children can present with PAH from a variety of causes at any age. Most often, it is associated with known CHD, especially in babies with Trisomy 21. Rarely (2 per million) children with IPAH may present with fatigue, syncope, chest pain, cyanosis and dyspnoea. Examination findings include a loud pulmonary second heart sound, a right ventricular heave or, if very late in the disease process, signs of right heart failure.

PAH is subclassified according to aetiology (table 1).2

Table 1

Classification of pulmonary arterial hypertension according to aetiology

Due to the many possible causes of pulmonary hypertension, it is becoming an increasingly diagnosed condition.3 Current prevalence is unknown but probably in excess of 100/million if all causes are considered and at least 60/million if considering just PAH.4 In addition, improvements in the effectiveness of therapy along with increased survival mean that prevalence continues to rise.

WHO has a functional class system that can be adapted for use in PAH (table 2).5 This is used together with aetiological classification when determining treatment strategy using European Society of Cardiology guidelines (figure 1).1

Table 2

WHO functional class system for categorisation of pulmonary arterial hypertension5

Figure 1

An adaptation of current European Society of Cardiology guidelines for the treatment of pulmonary arterial hypertension.1

Assessment

This review is not intended to cover the major aspects of assessment of PAH. For this, see other works.6 However, the usual assessment of PAH includes a detailed family history, examination, echocardiogram, 6-min walk test (or oxygenation index calculation in younger patients), chest radiogram and a cardiac catheterisation with measured oxygen consumption and vasodilator response (can be excluded in very young patients). Blood tests should also rule out autoimmune, genetic and viral causes. Further imaging, including CT, MRI or lung-perfusion scans, may be indicated too. Nowadays, it is rare to undertake a lung biopsy.

Management

Long-term management of PAH requires a team of professionals including consultants, pharmacists, specialist nurses and allied health professionals, including the Pulmonary Hypertension Association. Together they supply the substantial physical and psycho-social support that children with PAH and their families need. Historically, medication is divided into standard and disease modifying agents. The former includes oxygen, diuretics (in right heart failure), digoxin (rarely used now) and calcium channel blockers (indicated in the 5% of PAH children with good vasodilator response at catheterisation). Warfarin is infrequently used in children, except those with IPAH. It should also be noted that infective exacerbations of PAH can have detrimental effects and so pneumococcal and influenza vaccinations are recommended, while there is also support for bronchiolitis prophylaxis (ie, palivizumab).7

Disease modifying therapy is at the centre of current advanced PAH treatment. There is much evidence that as well as reducing pulmonary arterial pressures by causing smooth muscle cell relaxation these agents may have secondary actions in reducing endothelial and smooth muscle cell proliferation, helping to remodel the pulmonary vasculature towards a more normal phenotype. Presently approved strategies include endothelin receptor antagonists (ERA), prostanoids and, significantly for this work, PDE-Vis, as illustrated in figure 1.1

ERA, such as bosentan, work via endothelin receptors (ET-A and ET-B) on smooth muscle cells to elicit vasodilatation. They have a well-proven efficacy in paediatric PAH and are a key part of contemporary PAH treatment regimen, although causing hepatic dysfunction in about 3% of children.8 Newer ERAs, such as ambrisentan, possess greater ET-A selectivity and offer fewer drug–drug interactions and less liver toxicity. That stated, trials of ERA in CHD are limited.

Prostanoids, such as epoprostenol, activate cyclic AMP intracellular signalling to dilate the pulmonary arteries. These agents have been the gold standard of PAH treatments for many years, and despite common side-effects such as headaches and reduced platelet function, and the need for continuous intravenous infusion, prostanoids remain key to paediatric PAH.

The use of PDE-Vis has become significant in recent years. This is normally started as sildenafil monotherapy, but those refractory to this can be considered for combination management using ERAs or prostanoids under specialist guidance. The remainder of this article will concentrate on the current practice and controversies regarding the use of PDE-Vis agents that are quickly becoming the most commonly used drugs in paediatric PAH.

Sildenafil

Approved indications

According to the European Society of Cardiology guidelines,1 and within the National Pulmonary Hypertension Service framework, sildenafil is considered first-line in non-vasoreactive paediatric IPAH and PAH associated with CHD over 1 year of age. This is based on data showing increases in maximum oxygen consumption of 10.2% after 16 weeks of sildenafil monotherapy (vs 0.5% on placebo) and reinforced by the STARTS trial revealing associated 90% 3-year survivals.9 ,10

Sildenafil for PAH is a ‘red drug’, meaning the National Specialist Commissioning Group provides its funding, while prescriptions originate from the National Pulmonary Hypertension Service—a responsibility that cannot be transferred to primary care. Recommended paediatric dosing for body weights <20 kg is 10 mg three times daily, while patients >20 kg should receive 20 mg three times daily. This applies to those above 1 year of age, and for those below this, including neonates, doses should be started at 250–500 µg/kg every 4–8 h up to a maximum of 30 mg per day and adjusted according to response in line with the British National Formulary for Children.

In 2012, an intravenous 0.8 mg/ml formulation of sildenafil gained European approval for adult PAH. This intravenous bolus is given three times daily for the continuation of sildenafil therapy in patients unable to tolerate enteral administration. It has twice the potency of oral sildenafil meaning the 10 mg bolus is equivalent to one 20 mg tablet.11 It should be noted that this license does not yet pertain to children.

Unlicensed applications

Following its success in licensed applications, sildenafil has been subject to substantial off-license applications, some of which have been reported in published literature.

Sildenafil has shown sound efficacy in the relief of transient postoperative PAH associated with CHD surgery. This is a frequent occurrence but a contentious application. It is not yet clear whether sildenafil should be used routinely to assist weaning from inhaled nitric oxide, or as an adjunct to therapy.12 Furthermore, use as prophylaxis in this situation has also been explored.13 Here one-off doses of 0.4 mg/kg have safely led to reductions in intensive care duration and time on mechanical ventilation. Last, sildenafil is often used in combination with extra-corporeal membrane oxygenation, for example, when there is difficulty coming off cardio-pulmonary bypass. In this situation, sildenafil dosing requires reduction to 5–7 mg/kg/day and then down again to 3–5 mg/kg/day after decannulation.14 That stated, information remains limited for this use. It is also important to note that the above situations usually occurs under 1 year of age, commonly involving neonates, and so these applications fall outside of the European Medicines Agency remit in terms of both age group and clinical indication.

The aforementioned lack of licensing below 1 year of age means a significant number of patients are outside of the approved remit. Alongside the above, this includes patients with persistent pulmonary hypertension of the newborn (PPHN), the failure of pulmonary vascular resistance to regress after birth. Its specific characteristics result in medication generally being developed separately from that used to treat PAH; however, a growing body of evidence is supporting the use of sildenafil. Most notably this includes the conclusions of a recent Cochrane review.15 It found increased arterial oxygenation of 16 mm Hg (95% CI 7 mm Hg to 24 mm Hg) and a relative risk of death of 0.2 (95% CI 0.07 to 0.57) associated with sildenafil intervention and therefore supported its use. The review also highlighted that current randomised controlled trial (RCT) evidence, despite being promising, is currently limited in size, and therefore made calls for larger-scale RCTs in a wider variety of settings. Due in part to this work such data are now forthcoming.16 Although there is no official guidance, doses typically range 250–500 µg/kg three times daily before response titration up to 30 mg daily. This situation may change given recent European approval for an investigation plan including PPHN to help form the basis of officially accepted dosing.

PPHN is not the only potential neonatal use for sildenafil. Bronchopulmonary dysplasia has long been an area where a lack of management consensus has led to significant diversity in clinical opinion. Bronchopulmonary dysplasia can cause pulmonary hypertension, but current evidence suggests 8 mg/kg/day sildenafil safely controls this. Contemporary information exists in the form of monotherapy case studies,17 as well as those involving the combination of sildenafil with nitric oxide,18 prostanoids or ERAs.19 ,20 However, due to a lack of high order evidence and formal approval, as well as the propensity of such data for publication bias, the prescription of sildenafil should be restricted to specialists. Further information in this context is detailed in a recent review.21

Finally, in the context of congenital diaphragmatic hernia, a condition associated with pulmonary hypertension directly and via links with bronchopulmonary dysplasia, sildenafil has shown efficacy in improving cardiac output via alleviation of pulmonary artery pressures. Its use in difficult cases has been established;22 however, more powerful data are required as indicated by the currently ongoing RCT.23

Pharmacology

The utility of sildenafil in PAH relies upon the inhibition of PDE-V. This reduces cyclic guanine monophosphate degradation with resultant reductions in pulmonary smooth muscle cytoplasmic calcium levels causing vasodilatation. This relieves the elevated arterial pressures of PAH and reduces the progression of PAH associated pathology.24

Orally, sildenafil can be given as a tablet, suspension or via nasogastric tube. Once administered, enteral absorption takes 30–90 min to reach a peak of 40% bioavailability.25 It has a half-life of 4 h before hepatic cytochrome P450 (CYP3A4 and CYP2C9) demethylation into a reduced action metabolite.26 It is important to note that in neonates this system can be immature and therefore clearance is reduced, increasing risk of toxicity. Therefore, cautious upwards titration of sildenafil towards the minimum effective dose is important, especially in neonates. Furthermore, the P450 system is vulnerable to inhibition and induction by various agents as outlined in box 1.

Box 1

Common agents that interact with sildenafil in pulmonary hypertension

  • α-Blockers: Risk of hypotension

  • β-Blockers: Reduced sildenafil clearance

  • Calcium channel blockers: Risk of hypotension

  • Cytochrome P450 inhibitors (eg, ritonavir): Reduced clearance increases risk of toxicity; use not recommended

  • Cytochrome P450 inducers (eg, carbamazepine): Increased clearance causes subtherapeutic levels; monitor closely as doses may need increasing

  • Endothelin receptor antagonists: Acute use of sildenafil is safe in the context of long-term ongoing bosentan (COMPASS-1); however, insufficient data exist for long-term use of sildenafil in the context of long-term bosentan (awaiting COMPASS 2; results due 2013)

  • Hepatic impairment: In mild/moderate impairment, reduce usual sildenafil doses only if they are not being tolerated; in severe hepatic impairment avoid sildenafil completely

  • Nitrates/phosphodiesterase-V inhibitor: Similar mechanisms of action; increased risk of toxicity

  • Prostanoids: Reduce bioavailability and steady-state concentrations

  • Renal impairment: Reduce usual sildenafil doses if they are not being tolerated

Briefly stated, this means that sildenafil plasma levels can be erratic, especially in neonates and patients on multidrug regimen; however, interactions seem less significant with intravenous formulations due to avoidance of first-pass metabolism.27

Adverse reactions and contra-indications

The most common side-effects experienced in paediatrics are nausea and vomiting, pyrexia, cough and abdominal pain. Headaches, flushing and a stuffy nose can occur due to vasodilator actions. Linked to this, severe hypotension, including volume depletion, left ventricular outflow obstruction and pulmonary veno-occlusive disease are contra-indications to use. Furthermore, insomnia and anaphylaxis have also been noted.

Haematological disorders are a further area requiring note. Epistaxis is a common side-effect, especially in the context of concomitant warfarin. Sickle cell anaemia associated PAH is also a contra-indication for therapy.

Finally, sildenafil can adversely affect vision. Photophobia is a side-effect and PDE-Vis are associated with retinal dysfunction, although this link is unproven.28 Despite this, the withdrawal of sildenafil remains recommended in the context of sudden visual loss, and sildenafil is contra-indicated in ischaemic optic neuropathy and hereditary degenerative retinal disorders.

Pharmaco-economics

Given recent economic conditions and changes to National Health Service (NHS) commissioning, pharmaco-economic evaluation is increasingly important. Sildenafil has a significant advantage over other agents in this viewpoint. The annual outlay per adult patient for oral sildenafil tablets is around £6000. Comparative liquid formulations for children should be expected to be very similar in cost.29 While not low-cost, the incremental cost-effectiveness ratios, the cost per quality-adjusted life year gained if choosing an alternative treatment over sildenafil, are £27 000 and £277 000 for bosentan and epoprostenol, respectively.30 This shows that relatively minor additional benefits associated with other agents comes at a substantial financial cost.

Developments, confusion and controversies

Despite a decade passing since sildenafil's paediatric PAH introduction, there continues to be substantial debate regarding off-license clinical application. In addition, recent data have now led to a trans-Atlantic divide in sildenafil protocol.

Sildenafils licensing in paediatrics includes either the tablets (taken whole or crushed/dispersed in water) or a Revatio 10 mg/ml suspension. However, the latter was slow reaching the market and it is possible that unlicensed oral liquid formulations created in its place are still being supplied. This may cause problems as the safety, efficacy, equivalence and quality of the unlicensed products cannot be guaranteed, costs vary hugely between manufacturers and they are a potential source of error in the clinical environment as they are available in many concentrations not understood by all parents. They should therefore no longer be used. Furthermore, the licenses for oral administration (tablet and suspension) only apply from 1 year of age and the license relating to intravenous routes only exists for those over 18 years of age. This causes gaps in the paediatric use of sildenafil.

Finally, in August 2012, the controversy over the use of sildenafil in paediatrics resurfaced following a formal FDA statement limiting its use in childhood but not adult PAH.e1 This was based upon paediatric 3-year follow-up data showing dose-dependent increases in mortality (mortality ratio 3.5; p=0.015) when using high-doses (80 mg three times daily in bodyweight >45 kg) relative to low-doses (10 mg three times daily in bodyweight >45 kg).e2 That stated, the European Medicines Agency continues to support the use of sildenafil in paediatrics, although many clinicians feel greater caution is required, especially at doses above European agency recommendations. Specialists should however note that these data apply to the long-term use of sildenafil and not to the acute critical care setting where long-term effects and acute risk–benefit balances may differ.e3

Pfizer's patent for Revatio tablets expired in September 2012 and the intravenous formulation patent expires in May 2013. Subsequent generic versions may reduce the cost of sildenafil, helping a fiscally challenged NHS; however, it is also likely to reduce funding for research into other paediatric applications, thus potentially limiting the expansion of its use into other diseases such as PPHN.

Moreover, sildenafil is beginning to face competition from rival PDE-Vis. Tadalafil is the most heavily researched alternative and has proven efficacy at 1 mg/kg doses in paediatric PAH.e4 In addition, its longer half-life enables once daily dosing, improving outpatient compliance. This acknowledged, formal approval has not yet been obtained and the level of evidence supporting its use lags behind that of sildenafil. A further PDE-Vi that may come to practice is vardenafil; data are currently even more limited on its clinical PAH applications, although it provides a novel combination of calcium channel blocker and PDE-Vi activities.e5 Last, there is work currently analysing the utility of inhaled or even intravenous milrinone, a PDE type-III inhibitor, for paediatric PAH.e6

Conclusions

In summary, the past decade of sildenafil in paediatric PAH has been both contentious and revolutionary. It has clear utility to act as a relatively cost-effective PAH agent ensuring it remains embedded into the paediatric armoury. However, with recent data highlighting a potentially increased mortality, with resultant withdrawal of official FDA recommendation, the conclusion for this story remains unclear. Whether current off-licence applications and competitor PDE-Vis will gain clinical approval also remains to be seen. For now though, sildenafil is a key component of the shared-care approach to successful paediatric PAH care in the UK.

Test your knowledge (answers on page 147)

NB: One, none or all answers may be correct.

  1. What is the definition of PAH?

    1. TR jet (tricuspid regurgitation) peak velocity more than 2.7 m/s?

    2. Mean PA pressure >25 mmHg at cardiac catheterisation with a pulmonary vascular resistance (PVR) more than 3 U/m2?

    3. Systolic PA pressure more than half systemic systolic pressure?

    4. Mean PA pressure >25 mmHg at cardiac catheterisation with a pulmonary vascular resistance more than 3 U.m2 and mean LA pressure <15 mmHg?

    5. Response to nitric oxide in the intensive care unit or cardiac catheter laboratory?

  2. How common is PAH?

    1. 2 per million population in IPAH?

    2. Unknown?

    3. At least 60 per million population?

    4. Higher in children than adults?

    5. Common in left heart disease?

  3. What is the dose of sildenafil?

    1. 10 mg tds for children under 20 Kg?

    2. 20 mg tds for children over 20 Kg?

    3. To be reduced in neonates?

    4. 25 mg tds if only Viagra is available?

    5. Half the oral dose, if the IV dose is used?

  4. Concerning the pharmacology of sildenafil,

    1. It inhibits phosphodiesterase type IV?

    2. It has a half-life of 10 hours?

    3. The metabolite is inactive?

    4. It interacts with CYP3A4 so that concurrent use of Bosentan is not recommended?

    5. It reaches peak bioavailability of 80% in 30–90 minutes?

  5. Regarding its use in infants,

    1. It has a licence for use in children less than 1 year?

    2. It is available in liquid form?

    3. It is recommended for use in bronchopulmonary dysplasia?

    4. It is approved for safe use in severe PPHN?

    5. The FDA has recently approved its use in infants?

FDA, Food and Drug Administration; IPAH, idiopathic PAH; IV, intravenous; PA, pulmonary artery pressure; PAH, pulmonary arterial hypertension; PPHN, persistent pulmonary hypertension of the newborn; tds, three times a day.

Answers to the quiz on page 146

  1. D is true

    The definition of PAH includes the high PA pressure, but this must be recorded in the cardiac catheter laboratory. Frequently the clinical signs combined with a high velocity TR jet indicate the need for catheterisation. Left atrial hypertension has to be excluded and the resistance has to be high (>3 U.m2) or else everyone with a large ventricular septal defect would be regarded has having PAH. (Note the resistance PVR is expressed in terms of Units x body surface area m2)

  2. All are true

    The incidence of IPAH is 2/million population, but the overall incidence of PAH includes CHD that is at least 50/million. However, there is no accurate registry of PAH, but only of those referred for treatment to the National Pulmonary Hypertension Service, resulting in a huge under-reporting of cases. Pulmonary Hypertension is indeed common in left heart disease, but it is due to pulmonary venous hypertension and hence excluded unless a high PVR can be shown in addition. There are many children with Trisomy 21 who have PAH who are possibly inadequately treated.

  3. All are true

    The dose of sildenafil is 10 mg tds if under 20 Kg bodyweight and 20 mg if over this. The IV formulation is only used if children cannot tolerate their usual oral dose. Neonates have reduced excretion and hepatic metabolism and so the dose should be reduced to avoid toxicity. Revatio comes in 20 mg white tablets and Viagra (not licenced for PH) comes in 25 mg blue tablets.

  4. None are true

    Sildenafil inhibits PDE type V and has a half-life of 4 hours, reaching 40% bioavailability in 30–90 minutes. The metabolite is partly active, especially in neonates. Sildenafil does interact with CYP3A4 and enhances the levels of Bosentan.

  5. B is true

    A liquid form of Revatio is available. Sildenafil is not licensed for use in infants under one year of age. The data on the long-term use in bronchopulmonary dysplasia is not yet available but it is widely used in PPHN, although without proper trial data. The FDA recently withdrew its recommendations for use in infants and children from 1 to 17 years.

CHD, congenital heart disease; FDA, Food and Drug Administration; IPAH, idiopathic PAH; IV, intravenous; PAH, pulmonary arterial hypertension; PDE, phosphodiesterase; PPHN, persistent pulmonary hypertension of the newborn; PVR, pulmonary vascular resistance; tds, three times a day.

Acknowledgments

The help from Richard Wardle in the early stages of this document is greatly appreciated.

References

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Footnotes

  • Collaborators Richard Wardle.

  • Contributors AJW and RT were both involved in the conception and design, analysis and interpretation of data and of the drafting the article including revising it critically for important intellectual content and final approval of the version to be published.

  • Competing interests RT has received unrestricted educational grants from Pfizer and Encysive as well as the other companies involved in pulmonary hypertension therapy.

  • Provenance and peer review Commissioned; externally peer reviewed.

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