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A retrospective assessment of the safety of sildenafil use in pediatric pulmonary hypertension

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A retrospective assessment of the safety of sildenafil use in pediatric pulmonary hypertension

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Content 1

A Retrospective Assessment of the Safety of Sildenafil Use in Pediatric Pulmonary Hypertension
by
Payal Shah
_______________________________________________________________________
A Thesis Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements of the Degree
MASTER OF SCIENCE
(CLINICAL, BIOMEDICAL AND TRANSLATIONAL INVESTIGATIONS)
December 2014

2

DEDICATION
To my parents, grandparents, husband and mentors

3

ACKNOWLEDGEMENTS
I would like to express my sincere gratitude to everyone without whom this thesis would
not have been accomplished. First and foremost, I acknowledge Dr. Roberta Kato, my mentor
and study chair, for providing me an opportunity to work on this project and sharing the vast
knowledge. Her continuous optimism concerning this work and unreserved help led me to
finish my thesis step by step. I owe you immensely for motivation, generosity and your
vivacious attitude throughout the work. Dr. Stanely Azen, co-director and advisor of my degree
program, study chair and an enthusiastic mentor for providing excellent guidance on statistical
analysis and wisdoms of encouragement. Dr.Shazia Bhombal, neonatologist and cardiologist
and committee-member, for your guidance on interpretation of echocardiograms and cardiac
catheterization parameters.
Dr. Aliva De, pulmonologist, a special thanks to you for finding an appropriate subject,
understanding, motivating and always helping me with research when I was trapped in
dilemmas. Dr. Jacqueline Szmuszkovicz, cardiologist, for stimulating interesting talks and
constructive discussions. I am grateful to my family, for their unconditional love and blessings.
My brothers, for always draining my stress and making me smile. Last but not the least; I am
indebted to my husband, for inspiring, encouraging and backing me up in tough times. His
continuous support in pursuing my study is invaluable to me.

4

TABLE OF CONTENTS
Dedication 2
Acknowledgements 3
List of Tables 5
List of Figures 6
Abbreviations 7
Abstract 9
Introduction 10
Pulmonary hypertension: Scope of the problem 10
Phosphodisestarase-5 type inhibitors: Mechanism of action 12
Materials and Methods 15
Data Collection 16
Statistical analysis 19
Results 20
Discussion 28
Future perspectives 32
References 33

5

LIST OF TABLES:
Table 1. Critical differences between pediatric and adult pulmonary hypertension 12
Table 2. Patient demographics 21
Table 3. Co-morbidities 22
Table 4. Treatment characteristics 23

6

LIST OF FIGURES:
Figure 1. Pathophysiology of pulmonary hypertension 10
Figure 2. Pathophysiology of pulmonary hypertension 11
Figure 3. Mechanism of action of PDE-5 13
Figure 4. Unadjusted OR and 95% CI of factors associated with mortality 24
Figure 5. Risk factors predicting mortality on multivariate analysis 25
Figure 6. Kaplan Meier survival estimation by sildenafil dose 26
Figure 7. Sildenafil use and mortality compared to ICU mortality over 5-years 27

7

ABBREVIATIONS:
ACD Alveolar capillary dysplasia
ASD Atrial septal defect
AUC Area under curve
BPD Bronchopulmonary dysplasia
CDH Congenital diaphragmatic hernia
cGMP Cyclic guanosine monophosphate
CHD Congenital heart disease
CHLA Children’s Hospital Los Angeles
CI Confidence interval
CLD Chronic lung disease
ECMO Extracorporeal membrane oxygenation
ET-1 Endothelin-1
FDA US Food and Drug administration
ICU Intensive care unit
IPAH Idiopathic pulmonary arterial hypertension
IVS Inter-ventricular septum
LCI Lower confidence interval
NEC Necrotizing enterocolitis
NICU Neonatal intensive care unit
NO Nitric oxide
8

OR Odd’s ratio
PAH Pulmonary arterial hypertension
PAP Pulmonary artery pressure
PDA Patent ductus arteriosus
PDE-5 Phosphodiesterase type inhibitor-5
PgI2 Prostacyclin
PH Pulmonary hypertension
PPHN Persistent pulmonary hypertension
ROC Receiver operating curve
RV Right ventricle
RVP Right ventricular pressure
TR Tricuspid regurgitation
UCI Upper confidence interval
USC University of Southern California
VSD Ventricular septal defect

9

ABSTRACT
The FDA recommends against prescribing sildenafil to children with pulmonary arterial
hypertension based on the STARTS-1 trial. STARTS-1 did not study children less than 1 year of
age and the mortality risk in infants is unknown. The objective was to assess the safety of
sildenafil use in an infant population. We conducted a retrospective review of hospitalized
infants in the intensive care units of Children’s Hospital Los Angeles (CHLA) who received
sildenafil between 2008 and 2012. Patients with complex congenital heart disease were
excluded. We analyzed patient characteristics, comorbidities and treatment characteristics.
Primary outcome was survival at discharge. Sildenafil dose ranges were based on the STARTS-1
trial and categorized as low <1.5mg/kg/day; medium 1.5-3.75 mg/kg/day; high 3.76-7.5
mg/kg/day; very high >7.5 mg/kg/day. 147 infants were studied. 82% of patients had severe
pulmonary hypertension. Our data revealed 29% mortality at discharge. Mortality increased
with increasing sildenafil dose, 14% (low), 19% (medium), 49% (high), and 90% (very high). On
multivariate analysis of sildenafil dose use, other PH therapies, presence of persistent cardiac
shunts and duration of sildenafil, odds of dying were significantly higher with combined high
and very high sildenafil dose groups compared to combined low and medium dose groups (OR
13.18, p<0.0001). We conclude that sildenafil was given to critically ill infants with multiple risk
factors for mortality. Though higher doses cannot be causally related to mortality, there
appears to be no added benefit to therapy by escalating the sildenafil dose.

10

INTRODUCTION:
Pulmonary hypertension: Scope of problem
Pulmonary hypertension is defined as a mean pulmonary arterial pressure of >25 mm of
Hg at rest or 30 mm of Hg at exercise.
1,2
It is a rare insidious disorder contributes significantly
to morbidity and mortality in pediatric populations.
3–5
Mean survival was less than 1 year for
pediatrics .
2,6,7
Exact incidence and prevalence of PH in pediatrics is unknown.
5
In children, up to
40% of cases of PH accounts for idiopathic pulmonary hypertension while congenital heart
disease accounts for up to 50% of cases.
3,4
Pathophysiology of PH includes increased vascular
tone and reactivity, abnormal structural remodeling of vessels wall, thrombosis and
intraluminal obstruction, and impaired vascular growth and surface area.
5
(Figure 1 & 2)

Figure 1. Pathophysiology of pulmonary hypertension
8

11

Figure 2. Pathophysiology of pulmonary hypertension
9

Pediatric PH is distinct from its adult counterpart in several ways and is an area of
emerging knowledge and research.
1–3,5,10,11
The difference exists in terms of etiologic
classification, disease course, genetics, structure, vascular function and therapeutic responses
(Table 1) .
2,5,12,13
The neonatal and infant populations represent a unique sub-group in
pediatrics where the physiologic transition of fetus to newborn interplay with perinatal risk
factors along with parameters of lung growth and development.
5,14,15
There have been recent
attempts for separate classification of PH in pediatrics.
10,16
In general, pulmonary vascular injury
and endothelial dysfunction results due to several adverse stimuli such as- hypoxia, hyperoxia,
12

hemodynamic stress, inflammation, oxidative stress and others.
5

Table 1. Critical differences between pediatric and adult PH
13

 Intrinsically linked to developmental biology of cardiopulmonary system;
 Timing of vascular injury during susceptible periods of adaptation and development
(inflammation, infection, hyperoxia, stress, others);
 Role of vascular disease beyond PH alone (e.g., distal lung growth as in BPD, CDH, lung
hypoplasia);
 Differences in genetics, vascular function and structure, and responsiveness to
therapeutic strategies;
 Developmental difference in drug metabolism, pharmacokinetics and
pharmacodynamics;
 Additional importance of “preventive strategies” as well as approaches targeting
“reverse remodeling”;
 Maturational changes in right and left ventricular function.

Phosphodiesterase type 5 inhibitor: Mechanism of action
The aim of medical treatment is to dilate and reverse the abnormal remodeling of the
pulmonary vascular bed and to restore endothelial function. Current therapeutic options for PH
in children include mainly prostacyclin (PgI2), nitric oxide (NO) and endothelin-1 (ET-1)
pathways.
17
These approaches are based on studies in adult population, but there is little
evidence on the pharmacodynamics, pharmacokinetics, disease mechanism and toxicities in
children with PH.
18
One of the therapeutic agents, phosphodiesterase type 5 inhibitors (PDE-5)
dilate pulmonary vascular bed by preventing the breakdown of cyclic guanosine
monophosphate (cGMP) through the NO pathway. PDE-5 inhibition preserves intracellular
cGMP concentrations and enhances cGMP–mediated vasodilation. It also augments
antiproliferative actions in smooth muscle cells (Figure 3).
19–21

13

Figure 3. Mechanism of action of PDE-5
22

Sildenafil, a highly selective PDE-5, has been widely used as an off-label medication for
the treatment of pediatric PH and is not FDA approved in the pediatric population. Small
randomized trials have assessed the use of sildenafil for PPHN
23–25
. Moreover, the recently
published data from the double-blind, placebo-controlled Sildenafil in Treatment-Naive
Children, Aged 1 to 17 Years, With Pulmonary Arterial Hypertension (STARTS-1) and STARTS-2
trials have raised controversy about the safety and efficacy of sildenafil in the pediatric
population. This study led to an FDA black box warning for the use of sildenafil in the 1 -17 year
age group
26–29
, raising concerns among physicians caring for patients with pulmonary arterial
hypertension (PAH).
30
The underlying etiology of pulmonary arterial hypertension in the STARTS
trial was idiopathic/hereditary PAH and PH associated with cardiac disease. Several of the
subjects had complex congenital heart disease. The STARTS trial did not address the use of
sildenafil in the neonatal or infant populations where potential etiology of the PH often
includes PPHN, cardiac disease, pulmonary hypoplasia due to developmental anomalies, or
14

chronic lung disease of infancy. The other interesting finding of the STARTS trial was the dose
ranges of sildenafil therapy and the observed mortality with their high dose groups. With the
FDA warning on the prescription of sildenafil for children and the absence of safety and dosing
guidelines for infants, generates the need for more research in this area.
Children’s Hospital Los Angeles (CHLA) is a large tertiary care center with a level III
neonatal intensive care unit (NICU), pediatric ICU and cardiac ICU serving a large referral basin
in the greater Los Angeles area. Our objective was to evaluate the use of sildenafil in our
hospital intensive care units (ICU) over the last 5 years and assess the safety of sildenafil use in
an infant population.

15

MATERIALS AND METHODS
We conducted a retrospective review of hospitalized infants less than one year of age at
CHLA who received sildenafil during the period of January 1, 2008 and December 31, 2012.
Patients were identified from inpatient pharmacy records. Patients with complex congenital
heart disease were excluded. A majority of these infants were in the NICU and only a few were
admitted to either the cardiac or pediatric intensive care units. The study was approved by the
CHLA Institutional Review Board (13-00071).

16

DATA COLLECTION:
Medical records were reviewed for patient demographic information including gender,
race and ethnicity, gestational age, birth weight, age at admission, age at start of sildenafil, age
at diagnosis of pulmonary hypertension and duration of hospitalization. Birth weight was
categorized as less than 2.5kg and equal to or greater than 2.5kg. Gestational age was defined
as preterm if less than 37 weeks and full term if equal to or greater than 37 weeks.
Medical records were reviewed for the co-morbid conditions pulmonary hypertension,
chronic lung disease (CLD), bronchopulmonary dysplasia (BPD), idiopathic pulmonary arterial
hypertension (IPAH), PPHN, meconium aspiration, congenital diaphragmatic hernia, pulmonary
hypoplasia, alveolar capillary dysplasia (ACD), simple congenital heart disease,
chromosomal/genetic abnormality and necrotizing enterocolitis (NEC). Severity of pulmonary
hypertension was graded as mild, moderate and severe as documented by the referring
hospital or at the time of admission after reviewing echocardiograms for tricuspid regurgitation
(TR) jet, right ventricular pressure (RVP), pulmonary artery pressure (PAP), cardiac shunts,
shape of inter-ventricular septum (IVS), dilation of right ventricle (RV) and cardiac
catheterization data. PH was graded as mild to moderate if IVS was rounded or mildly flattened
and/or mild to moderate dilation of RV and/or TR jet was less than 3m/sec, RVP less than
40mmHg; severe if there was systemic or supra systemic RVP and/or TR jet was greater than
3m/sec and/or IVS was flattened or deviated to left ventricle and/or presence of bi-directional
shunt. If PH severity was not documented in the echocardiogram or cardiac catheterization
reports, the echocardiogram information was reviewed by two pediatric cardiologists to
17

determine PH severity. Chronic lung disease was defined based on provider assigned diagnosis
of chronic lung disease in the patient’s medical records. BPD was graded as mild, moderate,
severe according to the National Institutes of Health consensus definition
31
. Mild BPD if no
oxygen requirement, moderate, if oxygen requirement greater than 21% F
iO2
, and severe, if
oxygen requirement greater than 21% F
iO2
via positive pressure ventilation at corrected 36
weeks or 56 days post-natal age. Simple congenital heart disease included atrial septal defect
(ASD), ventricular septal defect (VSD) and/or patent ductus arteriosus (PDA). If the simple
congenital heart disease did not resolve spontaneously, medically or surgically, patients were
defined as having persistent cardiac shunts. Complex heart disease patients were not included
in our study as they represent a different pathophysiology and complexity of disease.
Treatment characteristics included respiratory support during hospitalization and at the
time of discharge, extracorporeal membrane oxygenation (ECMO), use of vasopressors,
diuretics and use of the other PH medications, epoprostenol (prostacyclin) and bosentan
(endothelin 1 receptor antagonist). Data was collected for dose and duration of sildenafil. If
sildenafil was started at an initial dose and titrated during the hospitalization, the final dose of
sildenafil was used for analysis. Sildenafil doses were based on the STARTS-1 trial and
categorized as low<1.5mg/kg/day; medium=1.5-3.75mg/kg/day; and high=3.76-7.5mg/kg/day.
These dose groups are expected to achieve target concentrations of 47, 140 and 373 ng/ml with
approximately 53%, 77% and 90% inhibition of PDE-5 activity respectively in vitro.
26,32,33
In
addition, a fourth category of very high>7.5mg/kg/day was used for doses higher than the dose
ranges used in the STARTS-1 trial, but recommended in the Lexi-Comp online formulary,
18

Children’s Hospital Los Angeles. For patients who received intravenous sildenafil, the oral dose
equivalent (10 mg intravenous sildenafil equal to 20 mg oral dose) was used for analysis.
The primary end point of our study was vital status at discharge, categorized as alive or
deceased. General mortality statistics for the CHLA ICUs for the study period was determined.

19

STATISTICAL ANALYSIS:
Univariate analysis was conducted to compare the outcomes at discharge, dead versus
alive. Logistic regression was used for all continuous and categorical variables. All quantitative
data was expressed as median with interquartile range. Continuous variables were assessed for
linearity on logit scale and duration of sildenafil was transformed on natural log scale. Because
of the small sample size in the sildenafil dose groups, low and medium dose groups were
combined and high and very high dose groups were combined. The interaction and
confounding for each variable was assessed one at a time in the logistic regression model.
Further, multivariate logistic regression was performed to adjust for all potential confounders.
A p-value of ≤0.05 was considered to be statistically significant. All tests were two-sided. The
statistical software STATA/IC 13 was used for data analysis. Chi-square goodness-of-fit for
overall fit as well as regression diagnostics for each subject was performed. Sensitivity analysis
was assessed for the main effects model. Kaplan-Meier survival analysis was estimated for
sildenafil dose categories against duration of sildenafil use in days.

20

RESULTS
During the study period, 526 patients received sildenafil during hospitalization. Among
the 392 infants, 147 met inclusion criteria for the study. Our data revealed 29% mortality at
discharge. Table 2 describes the demographic characteristics of the two outcome groups, alive
and dead. Additional co-morbidities for the two groups are listed in Table 3. The groups were
similar in sex, ethnicity, gestational age and birth weight. Treatment characteristics and
respiratory support for the two groups are described in Table 4. Patients who died were almost
all on vasopressors (98%) and 37% were also on other medications like epoprostenol and
bosentan for pulmonary hypertension.

21

Table 2. Patient Demographics
Alive, n=104 Dead, n=43
Sex, n (%)
Male 58 (56) 25 (58)
Female 46 (44) 18 (42)
Ethnicity, n (%)
Hispanic 56 (54) 18 (42)
Non-Hispanic white 14 (13) 8 (19)
Asian/pacific 8 (8) 4 (9)
Black 12 (12) 7 (16)
Other 14 (13) 6 (14)
Gestational age, n (%)
Preterm 48 (46) 18 (41)
Full term 56 (54) 25 (59)
Birth weight, n (%)
a

<2.5 kg 31 (38) 17 (49)
>2.5 kg 51 (62) 18 (51)
Age at admission in days,
median (IQR) 2 (1-97) 4 (1-101)
Duration of hospitalization in days,
median (IQR) 42 (18-109) 21 (5-37)
Age at discharge in days,
median (IQR) 94 (30-187) 36 (16-159)
Age at start of sildenafil in days,
median (IQR) 11 (2-116) 17 (3-125)
Duration of sildenafil in days,
median (IQR) 20 (11-61) 11 (4-31)
a
Percentage calculated using available data: alive=82, dead=35

22

Table 3. Co-morbidities
Alive, n=104 Dead, n=43 Unadjusted Odds Ratio
n (%) n (%) (95% CI)
Severity of pulmonary
hypertension
a

Mild to moderate 20 (20) 5 (12) 1.0 (Ref)
Severe 76 (78) 36 (88) 1.89 (0.66-5.45)
IPAH 6 (6) 2 (5) 0.79 (0.15-4.11)
Chronic lung disease 67 (64) 17 (40) 0.36 (0.17-0.75)*
Severe bronchopulmonary
dysplasia
b

31 (30) 9 (21) 1.59 (0.29-8.56)
Meconium aspiration 25 (24) 4 (9) 0.32 (0.10-0.99)*
Congenital diaphragmatic
hernia
20 (19) 12 (28) 1.63 (0.71-3.71)
Unrepaired CDH
¶
0 (0) 6 (50) -
Pulmonary hypoplasia 39 (38) 16 (37) 0.99 (0.47-2.06)
Alveolar capillary dysplasia 1 (1) 4 (9) 10.56 (1.14-97.47)*
Simple congenital heart
disease
94 (90) 35 (81) 0.47 (0.16-1.27)
Persistent cardiac shunt
c¶
40 (43) 24 (71) 3.18 (1.37-7.4)*
Chromosomal/genetic
abnormality
18 (17) 10 (23) 1.5 (0.62-3.61)
Necrotizing enterocolitis 2 (2) 1 (2) 1.21 (0.11-13.75)
IPAH, idiopathic pulmonary arterial hypertension
a
Percentage calculated using available data: alive=96, dead=41
b
Percentage calculated using available data: alive=103, dead=43
c
Percentage calculated using available data: alive=93, dead=34
¶
Percentage calculated using the number of patients with comorbid condition
* p value < 0.05

23

Table 4. Treatment characteristics
Alive, n=104 Dead, n=43
n (%) n (%)
Sildenafil dose groups
(mg/kg/day)

Low (<1.5) 38 (37) 6 (14)
Medium (1.5-3.75) 47 (45) 11 (26)
High (3.76-7.5) 18 (17) 17 (40)
Very high(>7.5) 1 (1) 9 (21)
Mechanical ventilation 101 (97) 43 (100)
ECMO 35 (34) 16 (37)
Respiratory support at discharge
Nasal cannula 44 (42) 1 (2)
Mechanical ventilation 27 (26) 41 (95)
Non-invasive ventilation 4 (4) 0(0)
Use of vasopressors 89(86) 41(98)
Use of other PH medications

11 (11) 16 (37)
ECMO, extracorporeal membrane oxygenation
PH, pulmonary hypertension

Epoprostenol and bosentan

24

On univariate analysis of risk factors for mortality (Figure 4), use of other PH therapies
(OR 4.08, CI 1.67-9.97 p=0.002) had significantly higher odds of dying. Odds of dying were
significantly higher in combined high and very high dose groups compared to low and medium
dose groups (OR 6.84, CI 3.11-15.05, p<0.0001). Patients with persistent cardiac shunts had
higher risk of mortality compared to patients whose shunts closed during the hospitalization
(OR 3.18, CI 1.37-7.4, p=0.007). Presence of chronic lung disease (OR 0.36, CI 0.17-0.75,
p=0.006) and meconium aspiration at birth (OR 0.32, CI 0.1-0.99, p=0.049) were associated with
a lower risk of mortality. For every 10% increase in duration of sildenafil, there was 43%
decrease in mortality (OR 0.68, CI 0.51-0.89, p=0.005).

Figure 4. Unadjusted OR and 95% CI of factors associated with mortality
25

On multivariate analysis (Figure 5), odds of dying were statistically significantly higher
with sildenafil combined high and very high dose group after adjusting for other variables (OR
13.18, CI 4.4-39.49, p<0.0001). Use of other PH therapies were associated with a higher risk of
mortality (OR 5.13, CI 1.43-18.37, p=0.012). Patients with persistent cardiac shunts had higher
odds of dying compared to patients with closed cardiac shunts (OR 2.64, CI 0.89-7.83, p=0.08).
Every 10% increase in duration of sildenafil, resulted in 69% decrease in mortality (OR 0.53, CI
0.36-0.80, p=0.002). One outlier was noted on regression diagnostics and was excluded in the
multivariate model. There was no evidence of lack of fit in the model from chi-square
goodness-of-fit test (p=0.92). Based on receiver operating characteristics (ROC) curve analysis,
our model provided an excellent discrimination between the two outcome groups (AUC=0.88).

Figure 5. Risk factors predicting mortality on multivariate analysis
26

Kaplan Meier survival (Figure 6) for sildenafil doses showed that there was a statistically
significant difference in survival among different doses of sildenafil (p=0.0002). The mortality
associated with sildenafil dose groups were 14% (low), 19% (medium), 49% (high), and 90%
(very high).

Figure 6. Kaplan Meier survival estimation by sildenafil dose
Sildenafil dose categories; Low <1.5mg/kg/day; medium 1.5-3.75mg/kg/day;
high 3.76-7.5mg/kg/day; very high >7.5 mg/kg/day

27

When compared to mortality statistics of CHLA’s ICUs for the same period, the mortality
in our population was 4.6 compared to 1.3 per 1000 patient-days for the ICUs. Over the 5 year
study period, the number of patients started on sildenafil increased from 16 patients in 2008 to
43 patients in 2012. The overall ICU mortality for this period remained stable with a range 1.76-
2.04 per 1000 patient days (Figure 7).

Figure 7. Sildenafil use and mortality compared to ICU mortality over 5-years

Number
Year
No. of deaths on
sildenafil/year
Total no. of patients
started on
sildenafil/year
ICU mortality/1000
patient days
Expon. (No. of deaths on
sildenafil/year)
Expon. (Total no. of
patients started on
sildenafil/year)
28

DISCUSSION
Our retrospective study assessed the use of sildenafil in patients less than one year of
age in a major tertiary children’s hospital. Our study revealed a 29% mortality rate in the infant
population that received sildenafil. The mortality per 1000 patient days for our population was
higher than the overall ICU mortality for the same period. Overall this was a very medically
complex patient population with a significant number of patients with severe pulmonary
hypertension, prematurity, BPD and on ventilatory support. Some of the patients who died had
underlying conditions such as alveolar capillary dysplasia, unrepaired severe congenital
diaphragmatic hernia or chromosomal and genetic abnormalities that inherently have poor
prognosis. Patients who died were also more likely to receive additional PH therapies such as
prostacyclin or endothelin-1 receptor antagonist. On univariate analysis, dose of sildenafil, use
of other PH medications for sildenafil, alveolar capillary dysplasia and persistent cardiac shunts
were significantly associated with higher odds of mortality. Eighty-eight percent of patients
who died had severe pulmonary hypertension, though this was not a risk factor for predicting
mortality on analysis. A quarter of patients with severe pulmonary hypertension were also on
additional vasodilator therapy for pulmonary hypertension, and use of other vasodilator
medications was significantly associated with mortality.
Increasing sildenafil dose resulted in a 13.18 fold increased risk of mortality for the
combined high and very high dose groups on multivariate analysis. Our data is consistent with
the increased mortality that was observed in STARTS-1 and 2 trials. However, a major limitation
of our study is that it is retrospective, and we do not have a matched control population.
Higher doses of sildenafil may have been administered based on severity of disease in these
29

patients. Further, patients who died had a shorter duration of sildenafil use, which may have
reflected a more critically ill population of infants who were unlikely to benefit from this
medication even at higher doses.
The duration of hospitalization and sildenafil use for patients who died was shorter than
those who were alive at discharge. Humpl et al
34
recruited 25 patients with pulmonary
hypertension for an open label study of sildenafil and 16 of the patients were infants. On long-
term follow-up, they experienced the death of 9 patients, 8 of whom were treated with
sildenafil. They did not attribute any of the deaths to the use of the medication, but their
numbers were small and statistical analysis was not performed. Our mortality of 29% is higher
than the 20% mortality reported by Mourani et al
20
in their retrospective review of pulmonary
hypertension in infants with chronic lung disease. Their median duration of sildenafil use in
patients who died was longer than patients who were alive. The larger population size in our
study and the fact that some of our patients were referred and hospitalized (34%) with a prior
diagnosis of PH, who may or may not have been on therapy prior to transfer, may have
attributed for this difference.
About half of our population was preterm, over 80% of whom had BPD. The
pathophysiology and landscape of BPD has changed over the years. The classically described
fibro-proliferative pattern of “old BPD” has evolved into a pattern of restricted alveolar and
pulmonary vascular growth manifesting as a “new BPD” phenotype.
35–37
Knowledge and
understanding of the vascular remodeling and development of PH in association with BPD is
growing. The estimated incidence of this association is 18-37% and predisposes to higher
morbidity and mortality.
38,39
Sildenafil has been used as an off-label medication in these
30

patients with chronic PH. Small studies have suggested a potential benefit with the use of
sildenafil in BPD.
40
Advances in perinatal and post-natal care and availability of long-term home
ventilation strategies have overall improved survival in severe BPD patients.
41
BPD severity,
gestational age and birth weight did not appear to confound our findings or significantly affect
the odds of mortality in our population. Chronic lung disease and meconium aspiration patients
had lower risk of mortality in our study, likely partly from improvement in neonatal
management strategies. We were not able to reliably include PPHN in our analysis as by
discharge other etiologies of PH were identified that were not consistent with the diagnosis of
PPHN.
The presence of a persistent cardiac shunt was associated with significantly increased
odds of mortality (3.18) on univariate analysis. Seventy one percent of patients who died had
unrepaired congenital heart disease or patent defect. These lesions included ASD, VSD and PDA.
Small left to right shunts are often left unrepaired in early life. In the final multivariate model,
the odds of mortality with patent shunt were still high but not statistically significant. As
duration of sildenafil was also part of the multivariate model and longer hospitalization was
associated with lower odds of mortality, it is possible that cardiac shunts had closed over time
and were no longer significant. There is no data in the literature reviewing outcomes in patients
with such small unrepaired cardiac lesions. Further research is warranted for a better
understanding of this issue.
We also observed increased use of sildenafil over the 5 year period of our retrospective
study. Since our numbers were small, we could not determine any temporal association of
sildenafil use and number of deaths. However, the overall hospital mortality remained stable
31

over this study period. A recent study on temporal trends of sildenafil use in pediatric patients
less than 17 years of age demonstrated a seven-fold increase in the use of sildenafil among
hospitalized patients from 2004 to 2011 while the overall all-cause crude mortality rate for
hospitalized children declined over the same period.
42
Though this does not signify any casual
associations between sildenafil use and mortality, it highlights the need for further research in
this area.
The results of the STARTS-1 and 2 trials have stirred debate in the pulmonary
hypertension community about the safety of sildenafil use in the pediatric population. The
STARTS trials did not study infants less than 1 year of age. In our study addressing Sildenafil use
in infants, mortality increased with increasing sildenafil dose, 14% (low), 19% (medium), 49%
(high), and 90% (very high). On multivariate analysis, odds of dying were significantly higher
with combined high and very high sildenafil dose groups compared to combined low and
medium dose groups (OR 13.18, p<0.0001). Based on the results of our retrospective study,
though higher doses cannot be causally related to mortality, increasing the dose of sildenafil did
not appear to provide a therapeutic benefit to these patients.

32

FUTURE PERSPECTIVES:
 As a part of future research, we would like to study the safety of sildenafil use in
infants with PH and complex congenital heart diseases.
 We have observed that patent cardiac shunts are significant contributors of
mortality. We would like to study safety of use of sildenafil along with persistent
cardiac shunts in preterm neonates. Because premature neonates, already at risk
for development of chronic lung disease, with moderate increases in pulmonary
blood flow due to cardiac shunts may be at increased risk for respiratory
compromise.
 We would also like to design a randomized, placebo controlled trial of sildenafil
in infants with pulmonary hypertension at CHLA.

33

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Asset Metadata

Creator Shah, Payal Malay (author)

Core Title A retrospective assessment of the safety of sildenafil use in pediatric pulmonary hypertension

School Keck School of Medicine

Degree Master of Science

Degree Program Clinical, Biomedical and Translational Investigations

Publication Date 11/07/2014

Defense Date 11/05/2014

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag Infants,mortality,OAI-PMH Harvest,pulmonary hypertension,Safety,sildenafil

Format application/pdf (imt)

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Azen, Stanley (committee chair), Kato, Roberta (committee chair), Bhombal, Shazia (committee member)

Creator Email dr.payal_shah@yahoo.com,payalsha@usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c3-515353

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