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Sildenafil in Term and Premature Infants: A Systematic Review
Clinical Therapeutics/Volume ], Number ], 2015
Sildenafil in Term and Premature Infants: A Systematic Review Krystle M. Perez, MD; and Matthew Laughon, MD, MPH Division of Neonatal-Perinatal Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina ABSTRACT Purpose: Numerous medications are used off-label in term and premature infants, with limited safety or efficacy data. Although sildenafil is approved by the US Food and Drug Administration for the treatment of pulmonary hypertension in adults, it is not approved for use in children. However, sildenafil use in term and premature infants with pulmonary hypertension is increasing. The goal of this study was to review controlled trials evaluating the efficacy of sildenafil use in: (1) term infants with pulmonary hypertension; (2) premature infants at risk for developing bronchopulmonary dysplasia (BPD); and (3) premature infants with BPD-associated pulmonary hypertension. Methods: MEDLINE, PubMed, EMBASE, Cochrane Database of Systematic Reviews, and International Pharmaceutical Abstracts databases were searched for citations related to sildenafil use in term or near-term infants with pulmonary hypertension or premature infants at risk for BPD or with BPDassociated pulmonary hypertension. Randomized and nonrandomized controlled trials were searched for that evaluated sildenafil use in term and premature infants compared with placebo or inhaled nitric oxide alone. Included studies were limited to English or Spanish language. Risk of bias was determined by using the Cochrane risk of bias tool. Findings: Five trials (4 full-text articles and 1 abstract) of the 802 screened citations met the criteria for inclusion. All 5 trials were randomized controlled trials; the largest had 51 participants. Four of the trials (with a total of 137 subjects) evaluated the use of sildenafil versus placebo for term or near-term infants with persistent pulmonary hypertension of the newborn in low-resource settings in which inhaled nitric oxide was unavailable; there were no trials of sildenafil in areas in which inhaled nitric oxide is routinely available. The trials showed improvements in oxygenation index and a reduction in mortality in the
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sildenafil groups (5.9% vs 44%). One trial evaluated early sildenafil use (after day 7 of life) in premature infants for the prevention of BPD (n ¼ 20). More premature infants in the sildenafil group died, were exposed to postnatal steroids, and had higher rightsided ventricular pressures later during hospitalization; these differences were not statistically significant. No trials evaluated sildenafil versus placebo in premature infants with BPD-associated pulmonary hypertension. Implications: There is currently little evidence to support the use of sildenafil in term or near-term infants with persistent pulmonary hypertension of the newborn in areas in which inhaled nitric oxide is available. More data are needed to determine the effectiveness and dosing of sildenafil in improving outcomes for term and premature infants. Sildenafil dosing and safety studies are needed, especially among premature infants, before efficacy trials are performed. (Clin Ther. 2015;]:]]]–]]]) & 2015 Elsevier HS Journals, Inc. All rights reserved. Key words: premature infant, sildenafil, pulmonary hypertension, bronchopulmonary dysplasia.
INTRODUCTION The majority of medications are used off-label in infants, with no available studies to adequately determine the safety profile or effectiveness of these agents.1 Understanding the efficacy and safety of these medications in the pediatric population is a priority.2 Systematic reviews of existing literature and ongoing large trials to assess the safety and efficacy of these medications are needed. Sildenafil is a medication increasingly being used off-label in term and premature infants with pulmonary hypertension Accepted for publication July 23, 2015. http://dx.doi.org/10.1016/j.clinthera.2015.07.019 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.
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Clinical Therapeutics and/or bronchopulmonary dysplasia (BPD) with a lack of systematic studies to support its use.3 Sildenafil is approved by the US Food and Drug Administration (FDA) for the treatment of pulmonary arterial hypertension (World Health Organization Group I) to improve exercise ability and delay clinical worsening in adults.4 Sildenafil is a potent inhibitor of type 5 phosphodiesterase, the predominant isoform in the lung that metabolizes cyclic guanosine monophosphate, and produces pulmonary vasodilation by potentiating the effects of endogenous nitric oxide. Since its approval for the treatment of pulmonary arterial hypertension in adults, the off-label use of sildenafil in infants has increased.3 After noting an increased risk of death at high doses of sildenafil compared with low doses in 1 long-term pediatric clinical trial, the FDA released a black box warning in 2012 recommending against the use of long-term sildenafil use in children aged 1 to 17 years.5,6 In addition to the concerns regarding mortality, numerous other potential adverse effects of sildenafil have been suggested, including severe systemic hypotension, pulmonary hemorrhage, or increased incidence of retinopathy of prematurity, but none has been consistently reported.7–12 Pulmonary hypertension in premature and term infants represents a heterogeneous group of diagnoses that collectively are associated with poor outcomes. Causes of pulmonary hypertension include congenital heart disease, congenital diaphragmatic hernia, and persistent pulmonary hypertension of the newborn (PPHN) secondary to meconium aspiration syndrome or other hypoxic respiratory failure in term infants and premature infants.13–15 Pulmonary hypertension can also occur in premature infants with BPD later during their hospitalization.13,15,16 Despite new technologies and therapies, the estimated mortality of infants diagnosed with pulmonary hypertension remains at 10% to 20%.13,15–18 Infants with pulmonary hypertension may require prolonged mechanical ventilation, need extracorporeal life support, or progress into right-sided heart failure.13,15,16,19 Surviving infants often also require exogenous oxygen for an extended period of time. Such complications may ultimately have long-term neurodevelopmental consequences for these infants.20,21 Trials of sildenafil are challenging because there are a variety of mechanisms to diagnose pulmonary hypertension. Providers often diagnose pulmonary
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hypertension on the basis of clinical symptoms and ventilatory requirements alone or in conjunction with echocardiography findings demonstrating an elevation in pulmonary pressures. Although cardiac catheterization is considered the gold standard for the diagnosis of pulmonary hypertension, it is often not used because of the invasive nature of the test and the critical condition of the infants with pulmonary hypertension. Adding to the challenge of standardizing studies of sildenafil is the wide clinical spectrum of severity of pulmonary hypertension in infants. As a result of such complexities, systematic studies assessing risks and benefits of sildenafil use in infants are difficult, and the safety and effectiveness of sildenafil as a therapy for pulmonary hypertension in infants remain ill-defined, with limited studies and case reports available to support routine use of this drug in infants.6,17,22–31 In the present systematic review, the existing evidence for sildenafil use in term infants with pulmonary hypertension and in premature infants at risk for BPD or with BPD-associated pulmonary hypertension was assessed. We investigated outcomes, including death before discharge, length of hospitalization, duration of mechanical ventilation and the reduction in pulmonary hypertension as evidenced by improvement in oxygenation.
MATERIALS AND METHODS Research Questions The primary questions of the present review were the following: (1) Does sildenafil use improve inhospital mortality in term infants with pulmonary hypertension or premature infants with BPDassociated pulmonary hypertension compared with placebo or inhaled nitric oxide (iNO); and (2) Does sildenafil use in premature infants prevent or treat BPD as defined by oxygen requirement at 36 weeks’ corrected gestational age (GA)? We also hypothesized that sildenafil use would reduce the intermediate outcomes of hospital stay and the duration of mechanical ventilation for surviving infants; these end points might confer long-term neurodevelopmental benefits.
Criteria for Selection of Studies Original trials were included, including randomized and nonrandomized controlled trials regardless of year of publication (with sufficient data published in
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K.M. Perez and M. Laughon English or Spanish) for inclusion eligibility. Studies of sildenafil were analyzed that included term or nearterm infants (Z35 weeks’ GA and r28 days old) with pulmonary hypertension who were exposed to sildenafil during their initial hospitalization. We also included studies of sildenafil use in premature infants (Z22 weeks’ GA and o32 weeks’ GA) at risk for developing BPD or with BPD-associated pulmonary hypertension during their initial neonatal intensive care unit course. Studies of sildenafil in term or premature infant populations with congenital cardiac defects or congenital diaphragmatic hernia were excluded. Studies with placebo or iNO therapy comparators were included. We excluded studies with other comparators, such as prostanoids (eg, iloprost) or other combination pulmonary vasodilator therapies. Although prostanoids are another alternative used for the treatment of pulmonary hypertension in infants, similarly limited data exist assessing the efficacy and safety of these medications in infants, thus making any comparisons between sildenafil and prostanoids difficult. Conversely, iNO is FDA approved for use in term or near-term infants with hypoxic respiratory failure and pulmonary hypertension with better safety and efficacy data available.32 Outcome measures of interest included death before discharge, duration of mechanical ventilation, and duration of hospitalization, as well as changes in oxygenation as evidenced by changes in calculated oxygenation index (OI).
Search Methods for Identification of Studies A systematic search of the literature was performed by using MEDLINE, PubMed, EMBASE, Cochrane Library, and International Pharmaceutical Abstracts databases from their establishment through January 26, 2015. Filters were used to maximize original research, with limitations set to exclude reviews, editorials, or errata as possible. A medical librarian helped to develop a search strategy using appropriate search terms. The search terms used included combinations of the following key words: “sildenafil,” “acetildenafil,” “UK-92480-10,” “UK-92,480-10,” “NCX-911,” “newborn,” “neonate,” “infant,” “premie,” “preterm,” “premature birth,” “premature baby,” and “premature infant.” No language restrictions or date limits were applied to the search. “UK92480-10,” “UK-92,480-10,” and “NCX-911” are ] 2015
MeSH entry terms for sildenafil. Previous reviews and bibliographic citations of relevant publications were examined to elicit any other studies that should have been included for review. We also searched for ongoing studies on ClinicalTrials.gov.
Study Selection and Analysis Two independent reviewers (K.P. and M.L.) determined inclusion for full-text review of abstracts and titles obtained by the search. When disagreement occurred about inclusion for full-text review, the reviewers discussed their findings, and consensus was obtained. If consensus could not be obtained, the abstract was submitted for full-text review. Eligible studies as determined by full-text review were included in the systematic review. The quality of the study, research design, analysis, and results were abstracted from included studies.
Assessment of Risk of Bias of Included Studies Internal validity of included studies was determined by using the Cochrane risk of bias tool.33 Risk of bias was rated as low, high, or unclear based on sequence generation, allocation concealment, blinding of participants/personnel, blinding of outcome assessors, and selective reporting of outcomes and/or incomplete outcome data.
RESULTS Study Characteristics From the 802 articles screened, 726 citations were determined to be irrelevant for various reasons, including study subjects being animals, wrong patient population with a focus on erectile dysfunction or pregnancy, and wrong study design and/or wrong intervention(s) reported within the abstract. In total, 76 full-text articles were reviewed for eligibility. Of these, 71 articles did not meet eligibility criteria for inclusion in the systematic review. In total, we identified 4 full-text articles and 1 abstract meeting the criteria for inclusion (Figure).17,22,23,34,35 Included studies comprised 3 full-text articles and 1 abstract describing the use of sildenafil for term or near-term infants with PPHN and 1 full-text article of sildenafil use in premature infants o28 weeks’ GA. All 4 full-text articles were approved by the respective institutional review boards; the abstract did not mention whether the protocol was approved by the institutional review boards.
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Identification
273 duplicates removed
802 studies screened
726 studies excluded
Included
Eligibility
1075 records identified through the database search
Screening
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76 articles assessed for eligibility for inclusion
71 full-text articles excluded: 35 wrong study design/outcomes 1 wrong language 10 case studies/case series 8 wrong patient population 10 not original research 3 wrong comparator 4 duplicates (abstract presentation before publication)
5 studies included in qualitative review
Figure. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram.
Study characteristics are described in the Table. All 5 included studies were randomized controlled trials comparing sildenafil with placebo. The 4 included trials of sildenafil versus placebo in the treatment of PPHN were performed in low-resource settings in which iNO was not available. We found no trials comparing sildenafil with iNO therapy for term infants with PPHN in settings in which iNO was routinely available or trials evaluating the use of sildenafil in premature infants with BPD-associated pulmonary hypertension. There were no additional trials identified through bibliographic citations or other references. There was 1 ongoing clinical trial of sildenafil use in infants with PPHN on ClinicalTrials.gov; the study methods and outcomes data were not yet available, and the study was not included in this systematic review (ClinicalTrials.gov identifier, NCT01720524).
Intervention Characteristics Sildenafil dosing ranged from 1 mg/kg every 8 hours to 3 mg/kg every 6 hours in the included trials. All doses were given enterally. None of the studies
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evaluated intravenous sildenafil. No pharmacokinetic data were collected.
Participant Characteristics The 4 trials of sildenafil for PPHN included 137 term or near-term infants; 1 trial was available in abstract form only. In general, the trials included term (mean, 37.6 weeks) infants and those receiving mechanical ventilation with PPHN. PPHN was diagnosed and infants included if there was an elevation in OI. In 3 trials, the diagnosis also required specific echocardiographic criteria demonstrating elevated pulmonary pressures with or without the need for mechanical ventilation.17,22,34,35 The OI cutoff for inclusion varied between studies. Three of the 4 studies enrolled infants with OI 420 to 25. One trial limited inclusion to only those infants with severe pulmonary hypertension as demonstrated by an OI Z40.17 None of the infants required cardiac catheterization for the diagnosis of pulmonary hypertension. Infants with congenital diaphragmatic hernia or congenital heart disease were specified as excluded in 3 trials. Although all of the participants
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Table. Characteristics of included controlled trials. Source
Patient Population
Intervention
Comparator
Outcomes (Primary or Secondary)
Trial Design
Changes in Outcomes With Intervention
Term or near-term infants with pulmonary hypertension Improved OI by 6 hours, decreased duration of mechanical ventilation, higher frequency of survival (13/13 on sildenafil vs 8/11 on placebo)
Improved OI within 6 to 30 hours, improved oxygen saturations, improved survival (6/7 on sildenafil vs 1/6 on placebo)
Improved OI, no difference in duration of mechanical ventilation, improved survival (29/31 on sildenafil vs 12/20 on placebo). Improved
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(continued)
K.M. Perez and M. Laughon
Herrera Torres 24 infants (mean GA, Oral sildenafil 2 mg/kg/ Placebo (iNO OI, blood gas RCT et al,23 36.6 weeks) with dose Q6 hours unavailable) values, duration 2006 PPHN, diagnosed by without stated criteria of mechanical (Mexico) requirement of for discontinuing ventilation, mechanical therapy death ventilation, OI 425, and pulmonary hypertension (unclear how obtained) 13 sildenafil/11 placebo 13 infants o35.5 weeks Oral sildenafil 1 mg/kg/ Placebo (iNO Baquero OI, oxygen RCT (mean GA, 37.8 dose to 2 mg/kg/dose et al,17 unavailable) saturations, 2006 weeks) with PPHN Q6 hours until OI death (Colombia) diagnosed by o20 or an 8-dose requirement for maximum (whichever mechanical came first) ventilation, OI Z40 and echocardiogram with right to left shunting and estimated pulmonary pressures Z40 mm Hg 7 sildenafil / 6 placebo Change in RCT Vargas-Origel 51 term infants (mean Oral sildenafil 3 mg/kg/ Placebo (iNO initially oxygenation, et al,22 2010 GA, 38.2 weeks) aged dose Q6 hours until (Mexico) o48 hours with OI o10 unavailable, duration of PPHN diagnosed by though became mechanical OI 420 and available during ventilation, echocardiography the trial) death
Source
Patient Population
Intervention
Comparator
with evidence of tricuspid regurgitation 31 sildenafil/20 placebo Soliz et al,35 49 term (unknown mean Oral sildenafil 2 mg/kg/ Placebo (iNO GA*) infants aged 2009* dose Q6 hours unavailable) multicenter o72 hours with without stated criteria PPHN and OI 425 for discontinuing 29 sildenafil/20 therapy placebo Premature infants at risk for bronchopulmonary dysplasia König et al,34 20 infants o28 weeks Oral sildenafil 1 mg/kg/ Placebo 2014 (mean GA, 24.7 dose Q8 hours for 4 (Australia) weeks) receiving weeks mechanical ventilation on postnatal day 7 10 sildenafil/10 placebo
Outcomes (Primary or Secondary)
Trial Design
OI, blood gas RCT values, duration of mechanical ventilation, death
Right ventricular RCT systolic pressures, duration of mechanical ventilation, need for postnatal steroids, death
Changes in Outcomes With Intervention survival was not appreciated when considering infants who had baseline OI o40 Improved OI, decreased duration of mechanical ventilation, decreased mortality
No significant differences in right ventricular systolic pressures, no difference in duration of noninvasive respiratory support, increased number of days mechanically ventilated (median of 688 hours on sildenafil vs 227 hours on placebo), increased need for postnatal steroids, increased frequency of death (3/10 on sildenafil vs 1/10 on placebo)
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PPHN ¼ persistent pulmonary hypertension of the newborn; OI ¼ oxygenation index; iNO ¼ inhaled nitric oxide; RCT ¼ randomized controlled trial; GA ¼ gestational age; CLD ¼ chronic lung disease. * Exists in abstract form only. Limited data were available for extraction of study characteristics.
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Table. (continued).
K.M. Perez and M. Laughon were born in hospitals in which iNO was unavailable, iNO became available in 1 trial after 40 infants were recruited; the subsequent 11 infants were automatically assigned to sildenafil plus iNO in this particular trial.22 All infants could receive inotropic support and mechanical ventilation according to standard of care practice. The single trial evaluating the use of sildenafil in infants at risk for BPD enrolled 20 premature infants with a mean GA of 24.7 weeks and a mean birth weight of 680 g.34 Eligible infants were intubated at birth and mechanically ventilated on postnatal day 7. Infants were excluded if they were receiving iNO therapy or had congenital heart or lung defects.
Right ventricular pressures were measured by using echocardiography, with no difference in pressures noted between infants exposed to sildenafil or placebo. Infants receiving placebo required fewer days of mechanical ventilation compared with those receiving sildenafil (9.5 vs 28.7 days). In addition, more infants in the sildenafil group received postnatal steroids, and 3 of 10 infants died in the sildenafil group compared with 1 of 10 in the placebo group. None of these differences reached statistical significance. One infant stopped sildenafil after experiencing recurrent hypotension. No other adverse events were reported.
Risk of Bias Reported Outcome Measures All 4 studies evaluating sildenafil use in term infants with PPHN reported the outcome of change in OI and death.17,22,23,35 OI was calculated before administration of the study drug and recalculated at specified times after scheduled doses in each study. OI improved in nearly all studies by 6 to 8 hours after the initial sildenafil dose, with minimal to no improvement in OI after placebo administration. The improvement in OI reached statistical significance in all 4 trials. Death before discharge was also assessed in all 4 studies, with a significant difference between groups in mortality. A total of 19 deaths were documented among the 88 infants enrolled in the 3 trials for which full text was available. Three (5.9%) of 51 infants randomized to receive sildenafil died before hospital discharge compared with 16 (44%) of 37 infants who received placebo. In 1 of the trials, the difference in mortality between infants exposed to sildenafil versus placebo was minimal when analyzing deaths in infants with an OI o40.22 The number of deaths was not provided for the 1 trial for which only an abstract was available. The cause of death was not uniformly disclosed among studies. Three of the 4 studies also reported the duration of mechanical ventilation as an outcome.17,22,23,34 Duration of mechanical ventilation was shorter for infants in the sildenafil group in 2 trials,23,35 although no difference was noted in days mechanically ventilated in another.22 None of the trials assessed whether sildenafil shortened hospital stay. No adverse events were reported in the 3 full-text articles available for review. One trial evaluated outcomes for premature infants at risk for developing BPD after sildenafil exposure.34
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We were unable to determine the risk of selection bias because methods of sequence generation and allocation concealment were unclear or not mentioned for all of the randomized trials. The mechanism for blinding of participants and personnel was only detailed for 2 of the trials, whereas the bias introduced from inadequate blinding strategies was unclear for the remaining 3 trials. High risk for bias was noted in at least 1 of the trials as it pertained to incomplete outcome data and selective reporting. In addition, there was a high risk of bias introduced from early termination of 1 trial17 as well as the loss of randomization after iNO became available during active enrollment of participants in another trial.22 The risk of bias assessment summary is shown in the Appendix.
DISCUSSION We evaluated existing trials of sildenafil versus placebo or iNO in infants. Term infants exposed to sildenafil versus placebo had a lower incidence of mortality, although some temperance is justified given that none of the trials was conducted in areas with access to iNO. We also identified a single trial in premature infants at risk of BPD that was equivocal. Finally, although infants are commonly exposed, we did not find any trials of sildenafil versus placebo in premature infants with BPD-associated pulmonary hypertension. Unfortunately, there are few data to guide safe and effective dosing of sildenafil in these populations. The benefit of sildenafil is uncertain in term infants with PPHN in settings in which therapies such as high-frequency ventilation and iNO are available.31,36
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Clinical Therapeutics INO is FDA-labeled for use in term or near-term infants with hypoxic respiratory failure and pulmonary hypertension to improve oxygenation and prevent the need for extracorporeal life support.32 In settings in which iNO is unavailable or prohibitively expensive, sildenafil may offer a cheaper, more accessible alternative to iNO. However, sildenafil has been associated with adverse events, including systemic hypotension (particularly after intravenous administration at higher doses), and clinicians should monitor for such adverse effects when initiating this drug.31,36 One trial investigating the use of intravenous sildenafil for PPHN in the setting of iNO availability is currently enrolling participants (Clinical Trials.gov identifier, NCT01720524). In premature infants, investigators have reported the use of oral sildenafil for pulmonary hypertension and BPD in cohort studies and case series.24,26,29,37,38 In general, echocardiography is used to diagnose and monitor BPD-associated pulmonary hypertension.29,37,38 The majority of infants exposed to sildenafil in these cohorts had improved echocardiographic evidence of pulmonary hypertension. However, because of the nature of cohort studies, it is unclear if sildenafil improved these morbidities or if the improvement is because of the natural history of pulmonary hypertension and BPD in premature infants. Despite sildenafil exposure, 20% of exposed infants still died, usually of BPD-associated pulmonary hypertension.29,38 Furthermore, investigators have reported potentially serious adverse effects associated with sildenafil use in premature infants, including hypotension, pulmonary hemorrhage, and cerebral hemorrhage in various case reports and observational studies.12,36,38,39 Further studies of sildenafil are needed in this population. Investigators have studied multiple drugs, including sildenafil, that might be used to reduce the incidence of BPD.40 We found only 1 randomized controlled pilot trial that assessed the use of sildenafil in premature infants.34 The trial utilized sildenafil early (after day of life 7) in infants at risk of developing BPD. Infants randomized to receive sildenafil required mechanical ventilation for longer periods, required postnatal steroids more frequently, and had a higher incidence of death compared with placebo. Although the differences between the sildenafil and placebo groups did not reach statistical significance, these
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outcomes will need to be evaluated carefully in future trials. Because of these concerns, sildenafil use for the prevention of BPD should be studied in early phase trials before its wide adoption for the prevention of BPD in premature infants. Sildenafil is a medicine without sufficient evidence to determine safety, efficacy, or appropriate dosing in infants, and thus dosing and indications have been derived from adult and older-child data. To address these gaps, several teams of investigators are conducting trials of sildenafil. For example, the Pediatric Trials Network is supporting a pharmacokinetic study of sildenafil through the Best Pharmaceuticals for Children Act (ClinicalTrials.gov identifier, NCT01670136). The primary goal of the study is to determine the pharmacokinetics of sildenafil in premature infants with BPD-associated pulmonary hypertension and in younger premature infants at risk for BPD (ClinicalTrials.gov identifier, NCT01670136); a secondary aim is to evaluate the safety profile of sildenafil in premature infants. Data obtained from this study and similar ongoing studies (ClinicalTrials. gov identifier, NCT02244528) will help guide appropriate dosing for future investigations of sildenafil in the infant population.
CONCLUSIONS In resource-limited settings, sildenafil may offer a less expensive and life-saving alternative for infants with PPHN. Currently, there is no evidence to support sildenafil use for term infants with PPHN in areas in which iNO and/or high-frequency ventilation are available. In addition, there is little evidence to support sildenafil for the prevention of BPD. Although sildenafil is commonly used in premature infants with BPD-associated pulmonary hypertension, it remains unclear if use of this drug leads to improved outcomes. Sildenafil dosing, safety, and efficacy trials are needed to determine if it is beneficial for the treatment of BPD-associated pulmonary hypertension or in the prevention of BPD. Future areas of research could include pharmacokinetic studies to determine the appropriate sildenafil dosage, safety studies to determine optimal dosing and adverse events, and randomized trials to determine the safety and feasibility of sildenafil use for PPHN or BPD-associated pulmonary hypertension in premature infants.
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K.M. Perez and M. Laughon
ACKNOWLEDGMENTS We thank Rachael Posey, pharmacy medical librarian, for helping develop a search strategy for this systematic review. Both authors contributed equally to this manuscript. Krystle M. Perez is a 3rd year neonatology fellow at the University of North Carolina in Chapel Hill, NC. Matthew M. Laughon is a professor at the University of North Carolina in Chapel Hill, NC. Dr. Laughon receives support from the NICHD and from the U.S. government for his work in pediatric and neonatal clinical pharmacology under the Best Pharmaceuticals for Children Act.
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CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest regarding the content of this article.
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SUPPLEMENTAL MATERIALS Supplemental tables accompanying this article can be found in the online version at http://dx.doi.org/ 10.1016/j.clinthera.2015.07.019.
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LA: INO Therapuetics. 2013. Available for download from: http:// dailymednlmnihgov/dailymed/dru gInfocfm?setid=762b51be-1893-4c d1-9511-e645fc420d3a. Accessed 2015. Higgins JPT, Green S. Cochrane Collaboration. Chichester, England; Hoboken, NJ: Wiley-Blackwell; 2008. König K, Barfield CP, Guy KJ, et al. The effect of sildenafil on evolving bronchopulmonary dysplasia in extremely preterm infants: a randomised controlled pilot study. J Matern Fetal Neonatal Med. 2014; 27:439–444. Soliz A, Concha E, Romero F. Oral Sildenafil Treatment as Therapy for Persistent Pulmonary Hypertension of the Newborn: A Multicenter Randomized Trial. Pediatric Academic Societies Annual Meeting; 2009; Baltimore MD, 2009. Khorana M, Yookaseam T, Layangool T, et al. Outcome of oral sildenafil therapy on
37.
38.
39.
40.
persistent pulmonary hypertension of the newborn at Queen Sirikit National Institute of Child Health. J Med Assoc Thai. 2011;94(Suppl 3):S64–S73. Nyp M, Sandritter T, Poppinga N, et al. Sildenafil citrate, bronchopulmonary dysplasia and disordered pulmonary gas exchange: any benefits? J Perinatol. 2012;32:64–69. Trottier-Boucher M, Lapointe A, Malo J, et al. Treatment of pulmonary arterial hypertension using sildenafil in neonates with bronchopulmonary dysplasia. Paediatrics and Child Health (Canada). 2014;19:e64. Samada K, Shiraishi H, Aoyagi J, Momoi MY. Cerebral hemorrhage associated with sildenafil (Revatio) in an infant. Pediatr Cardiol. 2009;30: 998–999. Beam KS, Aliaga S, Ahlfeld SK, et al. A systematic review of randomized controlled trials for the prevention of bronchopulmonary dysplasia in infants. J Perinatol. 2014;34:705–710.
Address correspondence to: Matthew Laughon, Division of NeonatalPerinatal Medicine, UNC Hospital, CB#7596, Chapel Hill, NC 275997596. E-mail: [email protected]
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K.M. Perez and M. Laughon
Table B1. Risk of Bias Summary (review authors’ judgments about each risk of bias item for each included study)
?
Other bias
] 2015
Low risk of bias
Selective reporting (reporting bias)
+
Incomplete outcome data (attrition bias)
König 2014
Blinding of outcome assessors (detection bias)
Soliz 2009 (abstract only)
Blinding of participants/personnel (performance bias)
Vargas -Origel 2010
Allocation concealment (selection bias)
Baquero 2006
Random sequence generation (selection bias)
Herrera Torres 2006
?
?
?
?
+
−
?
?
?
+
?
+
+
−
?
?
?
?
+
−
−
?
?
?
?
?
?
?
?
?
+
?
−
+
+
Unclear risk of bias
−
High risk of bias
10.e1
Sildenafil in Term and Premature Infants: A Systematic Review Krystle M. Perez, MD; and Matthew Laughon, MD, MPH Division of Neonatal-Perinatal Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina ABSTRACT Purpose: Numerous medications are used off-label in term and premature infants, with limited safety or efficacy data. Although sildenafil is approved by the US Food and Drug Administration for the treatment of pulmonary hypertension in adults, it is not approved for use in children. However, sildenafil use in term and premature infants with pulmonary hypertension is increasing. The goal of this study was to review controlled trials evaluating the efficacy of sildenafil use in: (1) term infants with pulmonary hypertension; (2) premature infants at risk for developing bronchopulmonary dysplasia (BPD); and (3) premature infants with BPD-associated pulmonary hypertension. Methods: MEDLINE, PubMed, EMBASE, Cochrane Database of Systematic Reviews, and International Pharmaceutical Abstracts databases were searched for citations related to sildenafil use in term or near-term infants with pulmonary hypertension or premature infants at risk for BPD or with BPDassociated pulmonary hypertension. Randomized and nonrandomized controlled trials were searched for that evaluated sildenafil use in term and premature infants compared with placebo or inhaled nitric oxide alone. Included studies were limited to English or Spanish language. Risk of bias was determined by using the Cochrane risk of bias tool. Findings: Five trials (4 full-text articles and 1 abstract) of the 802 screened citations met the criteria for inclusion. All 5 trials were randomized controlled trials; the largest had 51 participants. Four of the trials (with a total of 137 subjects) evaluated the use of sildenafil versus placebo for term or near-term infants with persistent pulmonary hypertension of the newborn in low-resource settings in which inhaled nitric oxide was unavailable; there were no trials of sildenafil in areas in which inhaled nitric oxide is routinely available. The trials showed improvements in oxygenation index and a reduction in mortality in the
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sildenafil groups (5.9% vs 44%). One trial evaluated early sildenafil use (after day 7 of life) in premature infants for the prevention of BPD (n ¼ 20). More premature infants in the sildenafil group died, were exposed to postnatal steroids, and had higher rightsided ventricular pressures later during hospitalization; these differences were not statistically significant. No trials evaluated sildenafil versus placebo in premature infants with BPD-associated pulmonary hypertension. Implications: There is currently little evidence to support the use of sildenafil in term or near-term infants with persistent pulmonary hypertension of the newborn in areas in which inhaled nitric oxide is available. More data are needed to determine the effectiveness and dosing of sildenafil in improving outcomes for term and premature infants. Sildenafil dosing and safety studies are needed, especially among premature infants, before efficacy trials are performed. (Clin Ther. 2015;]:]]]–]]]) & 2015 Elsevier HS Journals, Inc. All rights reserved. Key words: premature infant, sildenafil, pulmonary hypertension, bronchopulmonary dysplasia.
INTRODUCTION The majority of medications are used off-label in infants, with no available studies to adequately determine the safety profile or effectiveness of these agents.1 Understanding the efficacy and safety of these medications in the pediatric population is a priority.2 Systematic reviews of existing literature and ongoing large trials to assess the safety and efficacy of these medications are needed. Sildenafil is a medication increasingly being used off-label in term and premature infants with pulmonary hypertension Accepted for publication July 23, 2015. http://dx.doi.org/10.1016/j.clinthera.2015.07.019 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.
1
Clinical Therapeutics and/or bronchopulmonary dysplasia (BPD) with a lack of systematic studies to support its use.3 Sildenafil is approved by the US Food and Drug Administration (FDA) for the treatment of pulmonary arterial hypertension (World Health Organization Group I) to improve exercise ability and delay clinical worsening in adults.4 Sildenafil is a potent inhibitor of type 5 phosphodiesterase, the predominant isoform in the lung that metabolizes cyclic guanosine monophosphate, and produces pulmonary vasodilation by potentiating the effects of endogenous nitric oxide. Since its approval for the treatment of pulmonary arterial hypertension in adults, the off-label use of sildenafil in infants has increased.3 After noting an increased risk of death at high doses of sildenafil compared with low doses in 1 long-term pediatric clinical trial, the FDA released a black box warning in 2012 recommending against the use of long-term sildenafil use in children aged 1 to 17 years.5,6 In addition to the concerns regarding mortality, numerous other potential adverse effects of sildenafil have been suggested, including severe systemic hypotension, pulmonary hemorrhage, or increased incidence of retinopathy of prematurity, but none has been consistently reported.7–12 Pulmonary hypertension in premature and term infants represents a heterogeneous group of diagnoses that collectively are associated with poor outcomes. Causes of pulmonary hypertension include congenital heart disease, congenital diaphragmatic hernia, and persistent pulmonary hypertension of the newborn (PPHN) secondary to meconium aspiration syndrome or other hypoxic respiratory failure in term infants and premature infants.13–15 Pulmonary hypertension can also occur in premature infants with BPD later during their hospitalization.13,15,16 Despite new technologies and therapies, the estimated mortality of infants diagnosed with pulmonary hypertension remains at 10% to 20%.13,15–18 Infants with pulmonary hypertension may require prolonged mechanical ventilation, need extracorporeal life support, or progress into right-sided heart failure.13,15,16,19 Surviving infants often also require exogenous oxygen for an extended period of time. Such complications may ultimately have long-term neurodevelopmental consequences for these infants.20,21 Trials of sildenafil are challenging because there are a variety of mechanisms to diagnose pulmonary hypertension. Providers often diagnose pulmonary
2
hypertension on the basis of clinical symptoms and ventilatory requirements alone or in conjunction with echocardiography findings demonstrating an elevation in pulmonary pressures. Although cardiac catheterization is considered the gold standard for the diagnosis of pulmonary hypertension, it is often not used because of the invasive nature of the test and the critical condition of the infants with pulmonary hypertension. Adding to the challenge of standardizing studies of sildenafil is the wide clinical spectrum of severity of pulmonary hypertension in infants. As a result of such complexities, systematic studies assessing risks and benefits of sildenafil use in infants are difficult, and the safety and effectiveness of sildenafil as a therapy for pulmonary hypertension in infants remain ill-defined, with limited studies and case reports available to support routine use of this drug in infants.6,17,22–31 In the present systematic review, the existing evidence for sildenafil use in term infants with pulmonary hypertension and in premature infants at risk for BPD or with BPD-associated pulmonary hypertension was assessed. We investigated outcomes, including death before discharge, length of hospitalization, duration of mechanical ventilation and the reduction in pulmonary hypertension as evidenced by improvement in oxygenation.
MATERIALS AND METHODS Research Questions The primary questions of the present review were the following: (1) Does sildenafil use improve inhospital mortality in term infants with pulmonary hypertension or premature infants with BPDassociated pulmonary hypertension compared with placebo or inhaled nitric oxide (iNO); and (2) Does sildenafil use in premature infants prevent or treat BPD as defined by oxygen requirement at 36 weeks’ corrected gestational age (GA)? We also hypothesized that sildenafil use would reduce the intermediate outcomes of hospital stay and the duration of mechanical ventilation for surviving infants; these end points might confer long-term neurodevelopmental benefits.
Criteria for Selection of Studies Original trials were included, including randomized and nonrandomized controlled trials regardless of year of publication (with sufficient data published in
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K.M. Perez and M. Laughon English or Spanish) for inclusion eligibility. Studies of sildenafil were analyzed that included term or nearterm infants (Z35 weeks’ GA and r28 days old) with pulmonary hypertension who were exposed to sildenafil during their initial hospitalization. We also included studies of sildenafil use in premature infants (Z22 weeks’ GA and o32 weeks’ GA) at risk for developing BPD or with BPD-associated pulmonary hypertension during their initial neonatal intensive care unit course. Studies of sildenafil in term or premature infant populations with congenital cardiac defects or congenital diaphragmatic hernia were excluded. Studies with placebo or iNO therapy comparators were included. We excluded studies with other comparators, such as prostanoids (eg, iloprost) or other combination pulmonary vasodilator therapies. Although prostanoids are another alternative used for the treatment of pulmonary hypertension in infants, similarly limited data exist assessing the efficacy and safety of these medications in infants, thus making any comparisons between sildenafil and prostanoids difficult. Conversely, iNO is FDA approved for use in term or near-term infants with hypoxic respiratory failure and pulmonary hypertension with better safety and efficacy data available.32 Outcome measures of interest included death before discharge, duration of mechanical ventilation, and duration of hospitalization, as well as changes in oxygenation as evidenced by changes in calculated oxygenation index (OI).
Search Methods for Identification of Studies A systematic search of the literature was performed by using MEDLINE, PubMed, EMBASE, Cochrane Library, and International Pharmaceutical Abstracts databases from their establishment through January 26, 2015. Filters were used to maximize original research, with limitations set to exclude reviews, editorials, or errata as possible. A medical librarian helped to develop a search strategy using appropriate search terms. The search terms used included combinations of the following key words: “sildenafil,” “acetildenafil,” “UK-92480-10,” “UK-92,480-10,” “NCX-911,” “newborn,” “neonate,” “infant,” “premie,” “preterm,” “premature birth,” “premature baby,” and “premature infant.” No language restrictions or date limits were applied to the search. “UK92480-10,” “UK-92,480-10,” and “NCX-911” are ] 2015
MeSH entry terms for sildenafil. Previous reviews and bibliographic citations of relevant publications were examined to elicit any other studies that should have been included for review. We also searched for ongoing studies on ClinicalTrials.gov.
Study Selection and Analysis Two independent reviewers (K.P. and M.L.) determined inclusion for full-text review of abstracts and titles obtained by the search. When disagreement occurred about inclusion for full-text review, the reviewers discussed their findings, and consensus was obtained. If consensus could not be obtained, the abstract was submitted for full-text review. Eligible studies as determined by full-text review were included in the systematic review. The quality of the study, research design, analysis, and results were abstracted from included studies.
Assessment of Risk of Bias of Included Studies Internal validity of included studies was determined by using the Cochrane risk of bias tool.33 Risk of bias was rated as low, high, or unclear based on sequence generation, allocation concealment, blinding of participants/personnel, blinding of outcome assessors, and selective reporting of outcomes and/or incomplete outcome data.
RESULTS Study Characteristics From the 802 articles screened, 726 citations were determined to be irrelevant for various reasons, including study subjects being animals, wrong patient population with a focus on erectile dysfunction or pregnancy, and wrong study design and/or wrong intervention(s) reported within the abstract. In total, 76 full-text articles were reviewed for eligibility. Of these, 71 articles did not meet eligibility criteria for inclusion in the systematic review. In total, we identified 4 full-text articles and 1 abstract meeting the criteria for inclusion (Figure).17,22,23,34,35 Included studies comprised 3 full-text articles and 1 abstract describing the use of sildenafil for term or near-term infants with PPHN and 1 full-text article of sildenafil use in premature infants o28 weeks’ GA. All 4 full-text articles were approved by the respective institutional review boards; the abstract did not mention whether the protocol was approved by the institutional review boards.
3
Identification
273 duplicates removed
802 studies screened
726 studies excluded
Included
Eligibility
1075 records identified through the database search
Screening
Clinical Therapeutics
76 articles assessed for eligibility for inclusion
71 full-text articles excluded: 35 wrong study design/outcomes 1 wrong language 10 case studies/case series 8 wrong patient population 10 not original research 3 wrong comparator 4 duplicates (abstract presentation before publication)
5 studies included in qualitative review
Figure. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram.
Study characteristics are described in the Table. All 5 included studies were randomized controlled trials comparing sildenafil with placebo. The 4 included trials of sildenafil versus placebo in the treatment of PPHN were performed in low-resource settings in which iNO was not available. We found no trials comparing sildenafil with iNO therapy for term infants with PPHN in settings in which iNO was routinely available or trials evaluating the use of sildenafil in premature infants with BPD-associated pulmonary hypertension. There were no additional trials identified through bibliographic citations or other references. There was 1 ongoing clinical trial of sildenafil use in infants with PPHN on ClinicalTrials.gov; the study methods and outcomes data were not yet available, and the study was not included in this systematic review (ClinicalTrials.gov identifier, NCT01720524).
Intervention Characteristics Sildenafil dosing ranged from 1 mg/kg every 8 hours to 3 mg/kg every 6 hours in the included trials. All doses were given enterally. None of the studies
4
evaluated intravenous sildenafil. No pharmacokinetic data were collected.
Participant Characteristics The 4 trials of sildenafil for PPHN included 137 term or near-term infants; 1 trial was available in abstract form only. In general, the trials included term (mean, 37.6 weeks) infants and those receiving mechanical ventilation with PPHN. PPHN was diagnosed and infants included if there was an elevation in OI. In 3 trials, the diagnosis also required specific echocardiographic criteria demonstrating elevated pulmonary pressures with or without the need for mechanical ventilation.17,22,34,35 The OI cutoff for inclusion varied between studies. Three of the 4 studies enrolled infants with OI 420 to 25. One trial limited inclusion to only those infants with severe pulmonary hypertension as demonstrated by an OI Z40.17 None of the infants required cardiac catheterization for the diagnosis of pulmonary hypertension. Infants with congenital diaphragmatic hernia or congenital heart disease were specified as excluded in 3 trials. Although all of the participants
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Table. Characteristics of included controlled trials. Source
Patient Population
Intervention
Comparator
Outcomes (Primary or Secondary)
Trial Design
Changes in Outcomes With Intervention
Term or near-term infants with pulmonary hypertension Improved OI by 6 hours, decreased duration of mechanical ventilation, higher frequency of survival (13/13 on sildenafil vs 8/11 on placebo)
Improved OI within 6 to 30 hours, improved oxygen saturations, improved survival (6/7 on sildenafil vs 1/6 on placebo)
Improved OI, no difference in duration of mechanical ventilation, improved survival (29/31 on sildenafil vs 12/20 on placebo). Improved
5
(continued)
K.M. Perez and M. Laughon
Herrera Torres 24 infants (mean GA, Oral sildenafil 2 mg/kg/ Placebo (iNO OI, blood gas RCT et al,23 36.6 weeks) with dose Q6 hours unavailable) values, duration 2006 PPHN, diagnosed by without stated criteria of mechanical (Mexico) requirement of for discontinuing ventilation, mechanical therapy death ventilation, OI 425, and pulmonary hypertension (unclear how obtained) 13 sildenafil/11 placebo 13 infants o35.5 weeks Oral sildenafil 1 mg/kg/ Placebo (iNO Baquero OI, oxygen RCT (mean GA, 37.8 dose to 2 mg/kg/dose et al,17 unavailable) saturations, 2006 weeks) with PPHN Q6 hours until OI death (Colombia) diagnosed by o20 or an 8-dose requirement for maximum (whichever mechanical came first) ventilation, OI Z40 and echocardiogram with right to left shunting and estimated pulmonary pressures Z40 mm Hg 7 sildenafil / 6 placebo Change in RCT Vargas-Origel 51 term infants (mean Oral sildenafil 3 mg/kg/ Placebo (iNO initially oxygenation, et al,22 2010 GA, 38.2 weeks) aged dose Q6 hours until (Mexico) o48 hours with OI o10 unavailable, duration of PPHN diagnosed by though became mechanical OI 420 and available during ventilation, echocardiography the trial) death
Source
Patient Population
Intervention
Comparator
with evidence of tricuspid regurgitation 31 sildenafil/20 placebo Soliz et al,35 49 term (unknown mean Oral sildenafil 2 mg/kg/ Placebo (iNO GA*) infants aged 2009* dose Q6 hours unavailable) multicenter o72 hours with without stated criteria PPHN and OI 425 for discontinuing 29 sildenafil/20 therapy placebo Premature infants at risk for bronchopulmonary dysplasia König et al,34 20 infants o28 weeks Oral sildenafil 1 mg/kg/ Placebo 2014 (mean GA, 24.7 dose Q8 hours for 4 (Australia) weeks) receiving weeks mechanical ventilation on postnatal day 7 10 sildenafil/10 placebo
Outcomes (Primary or Secondary)
Trial Design
OI, blood gas RCT values, duration of mechanical ventilation, death
Right ventricular RCT systolic pressures, duration of mechanical ventilation, need for postnatal steroids, death
Changes in Outcomes With Intervention survival was not appreciated when considering infants who had baseline OI o40 Improved OI, decreased duration of mechanical ventilation, decreased mortality
No significant differences in right ventricular systolic pressures, no difference in duration of noninvasive respiratory support, increased number of days mechanically ventilated (median of 688 hours on sildenafil vs 227 hours on placebo), increased need for postnatal steroids, increased frequency of death (3/10 on sildenafil vs 1/10 on placebo)
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PPHN ¼ persistent pulmonary hypertension of the newborn; OI ¼ oxygenation index; iNO ¼ inhaled nitric oxide; RCT ¼ randomized controlled trial; GA ¼ gestational age; CLD ¼ chronic lung disease. * Exists in abstract form only. Limited data were available for extraction of study characteristics.
Clinical Therapeutics
6
Table. (continued).
K.M. Perez and M. Laughon were born in hospitals in which iNO was unavailable, iNO became available in 1 trial after 40 infants were recruited; the subsequent 11 infants were automatically assigned to sildenafil plus iNO in this particular trial.22 All infants could receive inotropic support and mechanical ventilation according to standard of care practice. The single trial evaluating the use of sildenafil in infants at risk for BPD enrolled 20 premature infants with a mean GA of 24.7 weeks and a mean birth weight of 680 g.34 Eligible infants were intubated at birth and mechanically ventilated on postnatal day 7. Infants were excluded if they were receiving iNO therapy or had congenital heart or lung defects.
Right ventricular pressures were measured by using echocardiography, with no difference in pressures noted between infants exposed to sildenafil or placebo. Infants receiving placebo required fewer days of mechanical ventilation compared with those receiving sildenafil (9.5 vs 28.7 days). In addition, more infants in the sildenafil group received postnatal steroids, and 3 of 10 infants died in the sildenafil group compared with 1 of 10 in the placebo group. None of these differences reached statistical significance. One infant stopped sildenafil after experiencing recurrent hypotension. No other adverse events were reported.
Risk of Bias Reported Outcome Measures All 4 studies evaluating sildenafil use in term infants with PPHN reported the outcome of change in OI and death.17,22,23,35 OI was calculated before administration of the study drug and recalculated at specified times after scheduled doses in each study. OI improved in nearly all studies by 6 to 8 hours after the initial sildenafil dose, with minimal to no improvement in OI after placebo administration. The improvement in OI reached statistical significance in all 4 trials. Death before discharge was also assessed in all 4 studies, with a significant difference between groups in mortality. A total of 19 deaths were documented among the 88 infants enrolled in the 3 trials for which full text was available. Three (5.9%) of 51 infants randomized to receive sildenafil died before hospital discharge compared with 16 (44%) of 37 infants who received placebo. In 1 of the trials, the difference in mortality between infants exposed to sildenafil versus placebo was minimal when analyzing deaths in infants with an OI o40.22 The number of deaths was not provided for the 1 trial for which only an abstract was available. The cause of death was not uniformly disclosed among studies. Three of the 4 studies also reported the duration of mechanical ventilation as an outcome.17,22,23,34 Duration of mechanical ventilation was shorter for infants in the sildenafil group in 2 trials,23,35 although no difference was noted in days mechanically ventilated in another.22 None of the trials assessed whether sildenafil shortened hospital stay. No adverse events were reported in the 3 full-text articles available for review. One trial evaluated outcomes for premature infants at risk for developing BPD after sildenafil exposure.34
] 2015
We were unable to determine the risk of selection bias because methods of sequence generation and allocation concealment were unclear or not mentioned for all of the randomized trials. The mechanism for blinding of participants and personnel was only detailed for 2 of the trials, whereas the bias introduced from inadequate blinding strategies was unclear for the remaining 3 trials. High risk for bias was noted in at least 1 of the trials as it pertained to incomplete outcome data and selective reporting. In addition, there was a high risk of bias introduced from early termination of 1 trial17 as well as the loss of randomization after iNO became available during active enrollment of participants in another trial.22 The risk of bias assessment summary is shown in the Appendix.
DISCUSSION We evaluated existing trials of sildenafil versus placebo or iNO in infants. Term infants exposed to sildenafil versus placebo had a lower incidence of mortality, although some temperance is justified given that none of the trials was conducted in areas with access to iNO. We also identified a single trial in premature infants at risk of BPD that was equivocal. Finally, although infants are commonly exposed, we did not find any trials of sildenafil versus placebo in premature infants with BPD-associated pulmonary hypertension. Unfortunately, there are few data to guide safe and effective dosing of sildenafil in these populations. The benefit of sildenafil is uncertain in term infants with PPHN in settings in which therapies such as high-frequency ventilation and iNO are available.31,36
7
Clinical Therapeutics INO is FDA-labeled for use in term or near-term infants with hypoxic respiratory failure and pulmonary hypertension to improve oxygenation and prevent the need for extracorporeal life support.32 In settings in which iNO is unavailable or prohibitively expensive, sildenafil may offer a cheaper, more accessible alternative to iNO. However, sildenafil has been associated with adverse events, including systemic hypotension (particularly after intravenous administration at higher doses), and clinicians should monitor for such adverse effects when initiating this drug.31,36 One trial investigating the use of intravenous sildenafil for PPHN in the setting of iNO availability is currently enrolling participants (Clinical Trials.gov identifier, NCT01720524). In premature infants, investigators have reported the use of oral sildenafil for pulmonary hypertension and BPD in cohort studies and case series.24,26,29,37,38 In general, echocardiography is used to diagnose and monitor BPD-associated pulmonary hypertension.29,37,38 The majority of infants exposed to sildenafil in these cohorts had improved echocardiographic evidence of pulmonary hypertension. However, because of the nature of cohort studies, it is unclear if sildenafil improved these morbidities or if the improvement is because of the natural history of pulmonary hypertension and BPD in premature infants. Despite sildenafil exposure, 20% of exposed infants still died, usually of BPD-associated pulmonary hypertension.29,38 Furthermore, investigators have reported potentially serious adverse effects associated with sildenafil use in premature infants, including hypotension, pulmonary hemorrhage, and cerebral hemorrhage in various case reports and observational studies.12,36,38,39 Further studies of sildenafil are needed in this population. Investigators have studied multiple drugs, including sildenafil, that might be used to reduce the incidence of BPD.40 We found only 1 randomized controlled pilot trial that assessed the use of sildenafil in premature infants.34 The trial utilized sildenafil early (after day of life 7) in infants at risk of developing BPD. Infants randomized to receive sildenafil required mechanical ventilation for longer periods, required postnatal steroids more frequently, and had a higher incidence of death compared with placebo. Although the differences between the sildenafil and placebo groups did not reach statistical significance, these
8
outcomes will need to be evaluated carefully in future trials. Because of these concerns, sildenafil use for the prevention of BPD should be studied in early phase trials before its wide adoption for the prevention of BPD in premature infants. Sildenafil is a medicine without sufficient evidence to determine safety, efficacy, or appropriate dosing in infants, and thus dosing and indications have been derived from adult and older-child data. To address these gaps, several teams of investigators are conducting trials of sildenafil. For example, the Pediatric Trials Network is supporting a pharmacokinetic study of sildenafil through the Best Pharmaceuticals for Children Act (ClinicalTrials.gov identifier, NCT01670136). The primary goal of the study is to determine the pharmacokinetics of sildenafil in premature infants with BPD-associated pulmonary hypertension and in younger premature infants at risk for BPD (ClinicalTrials.gov identifier, NCT01670136); a secondary aim is to evaluate the safety profile of sildenafil in premature infants. Data obtained from this study and similar ongoing studies (ClinicalTrials. gov identifier, NCT02244528) will help guide appropriate dosing for future investigations of sildenafil in the infant population.
CONCLUSIONS In resource-limited settings, sildenafil may offer a less expensive and life-saving alternative for infants with PPHN. Currently, there is no evidence to support sildenafil use for term infants with PPHN in areas in which iNO and/or high-frequency ventilation are available. In addition, there is little evidence to support sildenafil for the prevention of BPD. Although sildenafil is commonly used in premature infants with BPD-associated pulmonary hypertension, it remains unclear if use of this drug leads to improved outcomes. Sildenafil dosing, safety, and efficacy trials are needed to determine if it is beneficial for the treatment of BPD-associated pulmonary hypertension or in the prevention of BPD. Future areas of research could include pharmacokinetic studies to determine the appropriate sildenafil dosage, safety studies to determine optimal dosing and adverse events, and randomized trials to determine the safety and feasibility of sildenafil use for PPHN or BPD-associated pulmonary hypertension in premature infants.
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K.M. Perez and M. Laughon
ACKNOWLEDGMENTS We thank Rachael Posey, pharmacy medical librarian, for helping develop a search strategy for this systematic review. Both authors contributed equally to this manuscript. Krystle M. Perez is a 3rd year neonatology fellow at the University of North Carolina in Chapel Hill, NC. Matthew M. Laughon is a professor at the University of North Carolina in Chapel Hill, NC. Dr. Laughon receives support from the NICHD and from the U.S. government for his work in pediatric and neonatal clinical pharmacology under the Best Pharmaceuticals for Children Act.
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12.
13.
CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest regarding the content of this article.
14.
SUPPLEMENTAL MATERIALS Supplemental tables accompanying this article can be found in the online version at http://dx.doi.org/ 10.1016/j.clinthera.2015.07.019.
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Address correspondence to: Matthew Laughon, Division of NeonatalPerinatal Medicine, UNC Hospital, CB#7596, Chapel Hill, NC 275997596. E-mail: [email protected]
Volume ] Number ]
K.M. Perez and M. Laughon
Table B1. Risk of Bias Summary (review authors’ judgments about each risk of bias item for each included study)
?
Other bias
] 2015
Low risk of bias
Selective reporting (reporting bias)
+
Incomplete outcome data (attrition bias)
König 2014
Blinding of outcome assessors (detection bias)
Soliz 2009 (abstract only)
Blinding of participants/personnel (performance bias)
Vargas -Origel 2010
Allocation concealment (selection bias)
Baquero 2006
Random sequence generation (selection bias)
Herrera Torres 2006
?
?
?
?
+
−
?
?
?
+
?
+
+
−
?
?
?
?
+
−
−
?
?
?
?
?
?
?
?
?
+
?
−
+
+
Unclear risk of bias
−
High risk of bias
10.e1