Research

JAMA Dermatology | Original Investigation

Comparison of Efficacy and Safety Between Propranolol

and Steroid for Infantile Hemangioma
A Randomized Clinical Trial
Kyu Han Kim, MD, PhD; Tae Hyun Choi, MD, PhD; Yunhee Choi, PhD; Young Woon Park, MD;
Ki Yong Hong, MD, PhD; Dong Young Kim, MD; Yun Seon Choe, MD; Hyunjung Lee, RN;
Jung-Eun Cheon, MD, PhD; Jung-Bin Park, BS; Kyung Duk Park, MD, PhD; Hyoung Jin Kang, MD, PhD;
Hee Young Shin, MD, PhD; Jae Hoon Jeong, MD, PhD

Supplemental content
IMPORTANCE There are limited data from randomized clinical trials comparing propranolol
and steroid medication for treatment of infantile hemangioma (IH).

OBJECTIVE To determine the efficacy and safety of propranolol compared with steroid as a
first-line treatment for IH.

DESIGN, SETTING, AND PARTICIPANTS This randomized clinical noninferiority trial tested the
efficacy and safety of propranolol vs steroid treatment for IH at a single academic hospital. All
participants were diagnosed with IH between June 2013 and October 2014, had normal heart
function, and had not been previously treated for IH.

INTERVENTIONS The participants were randomly assigned to either the propranolol group or
the steroid group. In the propranolol group, the patients were admitted, observed for adverse
effects for 3 days after treatment initiation, and then released and treated as outpatients for
16 weeks (2 mg/kg/d). In the steroid group, the patients were seen as outpatients from the
beginning and were also treated for 16 weeks (2 mg/kg/d).

MAIN OUTCOMES AND MEASURES The primary efficacy variable was the response to
treatment at 16 weeks, which was evaluated by the hemangioma volume using magnetic
resonance imaging before and at 16 weeks after treatment initiation. While comparing the
effect of medication between the groups, we monitored the adverse effects of both drugs.

RESULTS A total of 34 patients (15 boys, 19 girls; mean age, 3.3 months; range, 0.3-8.2
months) were randomized to receive either propranolol or steroid treatment (17 in each
treatment group). Guardians for 2 patients in the steroid group withdrew their consent,
and 1 patient in the propranolol group did not complete the efficacy test. The
intention-to-treat analysis, applying multiple imputations, found the treatment response rate
in the propranolol group to be 95.65%, and that of the steroid group was 91.94%. Because
the difference in response rate between the groups was 3.71%, propranolol was considered
noninferior. We found that there was no difference between the groups in safety outcomes.

CONCLUSIONS AND RELEVANCE Our trial demonstrated that propranolol was not inferior to
steroid with respect to therapeutic effects in IH.

TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01908972

Author Affiliations: Author
affiliations are listed at the end of this
article.
Corresponding Author: Jae Hoon
Jeong, MD, PhD, Department of
Plastic and Reconstructive Surgery,
Seoul National University
Bundang Hospital, 82,
Gumi-ro 173 Beon-gil, Bundang-gu,
Seongnam-si Gyeonggi-do 13620,
JAMA Dermatol. 2017;153(6):529-536. doi:10.1001/jamadermatol.2017.0250 Republic of Korea (psdrj2h@gmail
Published online April 19, 2017. .com).

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 Research Original Investigation
I
nfantile hemangioma (IH) is the most common tumor of
infants and young children.1,2 Although small IH lesions
typically do not cause problems, they often require treat-
ment because of the site of occurrence and associated com-
plications such as abnormal eye development or vision prob-
lems, airway obstruction, and bowel obstruction. 3 , 4
Historically, steroids have been used as the primary treat-
ment for IH.5,6 Steroids have been shown to be antiangio-
genic in a number of in vitro settings and also have shown good
therapeutic effects clinically. However, the use of steroids may
lead to various complications including gastroesophageal re-
flux and growth disorders, although these complications are
associated with long-term use and high dose.7 A type of anti-
cancer drug or immunomodulator, interferon alfa, may be used
for severe IH in cases where patients did not respond to
steroids.8,9 However, interferon alfa also has several possible
adverse effects, including fever, muscle pain, systemic myal-
gia, and in severe cases, liver damage, blood toxic effects, thy-
roid hormonal abnormality, and neurological and neurode-
velopmental toxic effects.8 Because of concerns about these
adverse effects, many guardians of pediatric patients prefer to
wait rather than accept treatment.
A study published in 2008 reported that an infant with IH
showed signs of improvement after receiving the β-blocker
propranolol.10 After the study, many centers conducted stud-
ies and published reports about the use of propranolol for
IH.10-25 Although propranolol has been used worldwide as an
effective treatment for IH, the majority of the studies con-
ducted on this off-label use of the drug have been insuffi-
cient to determine the efficacy and safety of propranolol com-
pared with steroid. In 2015, a randomized clinical trial verified
the effect of propranolol.25 However, the study results did not
provide evidence that propranolol could be used as a first-
line treatment. Therefore, the purpose of this study was to de-
termine the efficacy and safety of propranolol compared with
steroid as a first-line treatment for IH by randomized clinical
trial.
Methods
The trial protocol is provided as Supplement 1.
Study Population
Among patients aged 0 to 9 months diagnosed with IH at the
Seoul National University Hospital, those with normal heart
function and who had never been treated for IH were the tar-
get population. At least 1 of 3 IH characteristics was required
for patient inclusion in the study: 10% to 20% volume in-
crease in 2-4 weeks, IH-related organ dysfunction, and IH-
related aesthetic problem.
Study Oversight
This study was a single-institution, randomized, clinical, non-
inferiority trial to test the efficacy and safety of propranolol
vs steroid for IH treatment. In this study, the steroid group was
set as the control group to evaluate the noninferiority of the
experimental group (propranolol). The treatment response af-
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Efficacy and Safety of Propranolol vs Steroid for Infantile Hemangioma
Key Points
Question Can propranolol be used as a first-line treatment for
infantile hemangioma (IH)?
Findings In this noninferiority randomized clinical trial of 34
infants, the treatment response rate in the propranolol group was
95.65%, and that of the steroid group was 91.94%. Because the
difference in response rate between the groups was 3.71%,
propranolol was considered noninferior to steroid in therapeutic
effects in IH, and there was no difference between the groups in
safety outcomes.
Meaning Propranolol can be used as a first-line treatment for IH.
ter 16 weeks of treatment was used to determine the thera-
peutic index. Volume of the IH lesions was measured using
magnetic resonance imaging (MRI).
We received institutional review board approval from Seoul
National University Hospital (H-1212-016-446) and approval for
an investigational new drug from the Korea Food & Drug Ad-
ministration (20130047039). Guardians of all participants pro-
vided their written informed consent.
Study Design
Eligible patients were randomly assigned at a 1:1 ratio to the
propranolol group or steroid group. The Medical Research Col-
laborating Center at Seoul National University Hospital gen-
erated a randomization list and implemented randomization
using an interactive web-based system.
We measured the IH lesion volume using MRI while the
patient was under sedation with oral chloral hydrate
(50 mg/kg) prior to treatment initiation. The anteroposterior
diameter, width, and height were measured from T2 axial
and coronal images. We took medical photographs of all
lesions and recorded the surface area, color, ulceration, and
reepithelialization.
Propranolol Group
In the experimental group, we used a powdered form of pro-
pranolol, total daily dose 2 mg/kg/d (prepared from Indenol,
10-mg tablets) divided into 3 daily oral administrations. Chil-
dren who met the baseline criteria were admitted to the hospi-
tal. The treatment dose was gradually reached through the in-
duction treatment schedule. One hour after treatment initiation,
we measured vital signs and glucose levels and monitored
whether the patient showed any of the following complica-
tions: decreased heart rate, low blood pressure, hypoglyce-
mia, or difficulty breathing. After 3 days, the patient was re-
leased from the hospital and followed up as an outpatient 1, 4,
8, 12, 16, and 20 weeks after initial treatment.
After 16 weeks, the drug dose was adjusted by the taper-
ing schedule. In cases where the child’s guardian requested
treatment or treatment was required because of remaining
IH, the study protocol was not followed, and the researcher
used discretion to adjust the drug dose, depending on the
therapeutic response. In cases where a complication was
observed, treatment advice from a pediatrician was sought
immediately.
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 Efficacy and Safety of Propranolol vs Steroid for Infantile Hemangioma
Steroid Group
The control group was observed throughout the study as out-
patients. We used a single daily dose of an orally adminis-
tered prednisolone syrup (PRD Suspension, 1 mg/mL syrup),
2 mg/kg/d. One hour after the treatment initiation, vital signs
and glucose levels were measured, and signs of complica-
tions were monitored. The patient observation protocol, drug-
tapering regimen, and posttreatment management were the
same as for the experimental group.
Outcome Measures
The primary efficacy variable was the clinical response at 16
weeks, classified as follows: when the volume did not in-
crease or decreased by less than 25% after treatment began,
we defined it as stop of progression; when the volume de-
creased by 25% or more compared with the original size, we
defined it as regression. Both stop of progression and regres-
sion were defined as reaction. If the volume at the primary ef-
ficacy evaluation point was greater than the size measured
when treatment started, we called it an increase. Increase was
defined as a nonreaction.
The secondary efficacy variables included volume change,
surface area, and color of the IH lesion; the presence of ulcer-
ation; presence of reepithelialization; progression stop point;
regression point; and treatment compliance. The indepen-
dent, centralized, blinded evaluations of standardized photo-
graphs were performed at every visit. Once a week, the pa-
tient’s guardian measured and recorded the surface area of the
IH lesions and ulceration size even if they did not come to the
hospital.
For safety evaluation, we checked heart rate, blood pres-
sure, glucose level, and the presence of any complication such
as gastroesophageal reflux, hypertension, growth disability,
and adverse event.26-30
Statistical Analysis
The primary efficacy variable was the proportion of reaction
at 16 weeks. The planned sample size allowing for a 10% drop-
out rate was 34 patients to show the noninferiority of pro-
pranolol treatment with 80% power. We assumed the reac-
tion rates of the propranolol group and steroid group to be 85%
and 65%, respectively.16,31-33 The noninferiority margin was set
at −20%. To show that the reaction rate in the propranolol
group was noninferior to that in the steroid group, a noninfe-
riority analysis with a 1-sided test was applied at the 0.025 level;
that is, the hypothesis of inferiority would be rejected in the
lower boundary of the 95% confidence interval (CI) for pT-pC
(experimental group’s treatment reaction rate − control group’s
treatment reaction rate) if it was larger than −20%. The pri-
mary analysis was based on the intention-to-treat (ITT) popu-
lation, and missing outcomes were imputed using a multiple
imputation (MI) method.34 The variables included in the im-
putation model were the surface area of the IH lesion, the pro-
gression stop point, regression time point, color, ulceration size,
and presence of reepithelialization. Sensitivity analyses were
performed to assess the effect of missing values on the pri-
mary outcome in 2 ways: imputing all missing values as reac-
tion and as nonreaction. The analysis based on the per proto-
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Original Investigation Research
col (PP) population was performed as a sensitivity analysis to
determine whether the PP analysis provided results consis-
tent with those of the ITT analysis. The exact CI for differ-
ences between groups was estimated using R software (R for
Windows, version 3.1.2/R package–ExactCIdiff) when the pro-
portion of reaction was 100%.
The secondary efficacy variables were the percent changes
in volume of the IH lesions at 16 weeks from baseline, surface
area and color of the IH, presence of ulceration and ulcer-
ation size, presence of reepithelialization, the point of pro-
gression stop, regression, and treatment compliance. The vari-
ables measured repeatedly at 0, 1, 4, 8, 12, 16, and 20 weeks
were analyzed using a generalized estimating equation model
in which the effects of treatment, time, and the interaction be-
tween treatment and time were assessed after adjusting val-
ues at screening. The time to progression stop or regression
was compared between the 2 study groups using the Kaplan-
Meier method and log-rank test.
During the trial, the number and percentage of partici-
pants who experienced at least 1 adverse event were re-
corded for each event according to treatment, and were tested
using χ2 test or Fisher exact test. Information regarding the ex-
tent of adverse events, result, causality, and related mea-
sures also was arranged by treatment group.
Results
Participants
The participants were enrolled from June 2013 to October 2014.
The enrollment flowchart is presented in the Figure. Thirty-
four patients were enrolled and randomly assigned to either
the propranolol group (17 patients) or steroid group (17 pa-
tients). The guardians for 2 patients withdrew their consent
in the steroid group, and 1 patient in the propranolol did not
complete the efficacy test. For 1 patient in the steroid group,
the radiologist reported that it was impossible to measure the
volume of the IH lesion because of the unclear boundaries be-
tween the IH and normal tissue. The efficacy evaluation was
conducted in the PP analysis group, which included 30 target
participants (16 in the propranolol group, 14 in the steroid
group). The safety evaluation was conducted in the safety
population, which included 33 patients (17 in the propranolol
group, 16 in the steroid group).
As detailed in Table 1, none of the demographic differ-
ences between groups was statistically significant at below the
5% level (P < .05). For both groups, the face was the most com-
mon location of the IH (10 cases for the propranolol group and
13 for the steroid group). The MRI scans were conducted for
all patients at baseline, and the mean IH volume was 14 125 mm3
for the propranolol group and 9349 mm3 for the steroid group.
Although the mean volume for the steroid group was smaller,
there was no significant difference (P = .33). An image of the
lesion was taken for all participants in each group, and the mean
area for the propranolol group was 1318 mm2, while the mean
area for the steroid group was 1093 mm2. As with the volume,
there was no statistically significant difference between the
groups (P > .99).
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 Research Original Investigation
Figure. Study Flowchart Illustrating Randomization, Treatment,
Follow-up, and Data Analysis of the Study Participants
Patients at Seoul National University
Hospital assessed for eligibilitya
34 Randomized
17 Allocated to propranolol group 17 Allocated to steroid group
17 Received allocated intervention 15 Received allocated intervention
2 Withdrawal of consent
17 Participants completed treatment 15 Participants completed treatment
1 No primary efficacy evaluation 2 No primary efficacy evaluation
1 Failure to measure volume
17 Patients were included in ITT 17 Patients were included in ITT
analysis analysis
16 Patients were included in PP 14 Patients were included in PP
analysis analysis
PP indicates per protocol; ITT, intention to treat. Note that the efficacy
evaluation was conducted in the PP analysis group, which included 30
participants (16 in the propranolol group and 14 in the steroid group). The safety
evaluation was conducted in the safety population, which included 33
participants (17 in the propranolol group and 16 in the steroid group).
a
Number of patients not available.
Efficacy Outcomes
In the ITT analysis after applying MI, propranolol was not in-
ferior to steroid with respect to the proportion of reaction
(95.65% vs 91.94%, a difference of 3.71%; 95% CI, −15.43% to
22.84%). In addition, sensitivity analyses showed results con-
sistent with ITT analysis (Table 2).
The volume reduction in the propranolol group (55.87%)
was greater than in the steroid group (46.52%), but the differ-
ence was not statistically different (P = .27). The surface area
of the IH after treatment initiation significantly decreased over
time in both groups (model-estimated average over time,
1013.6, 960.3, 917.6, 832.7, 781.9 and 736.8 mm2 at 1, 4, 8, 12,
16, and 20 weeks after initial treatment; P = .02), although there
was no significant difference between groups (13.2 mm2; 95%
CI, −269.1 to 242.6 mm2; P = .92). As detailed in eFigure 1 in
Supplement 2, there were no significant differences between
the treatment groups and over time in other secondary effi-
cacy evaluations such as IH color, presence of reepithelializa-
tion, presence of ulceration, size of ulceration, and medica-
tion administration.
The numbers of patients showing progression stop or re-
gression were 17 and 15 in the propranolol group and the ste-
roid group, respectively. The median time to progression stop
or regression was 12 days in the propranolol group (95% CI, 11-15
days) and 11 days in the steroid group (95% CI, 10-14 days) af-
ter treatment initiation. The occurrence of progression stop or
regression over time was not significantly different between
the groups (P = .34). When considering regression to be a de-
crease of at least 25%, 13 and 9 patients experienced regres-
sion in the propranolol and steroid groups, respectively, with
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Efficacy and Safety of Propranolol vs Steroid for Infantile Hemangioma
median respective times of 62 and 120 days after treatment ini-
tiation. The occurrence of regression over time was not sig-
nificantly different between the groups (P = .53).
Safety Outcomes
Safety analysis was conducted for the remaining 33 patients
(safety population). The heart rate (131.88 vs 147.63 bpm;
P = .003), body temperature (36.66°C vs 36.96°C; P = .04), and
blood glucose level (103 vs 121 mg/dL; P = .002) after initial
medication administration in the propranolol group were sig-
nificantly lower than those in the steroid group. Two patients
in steroid group showed growth disability. As detailed in
Table 3, there was no significant difference between the groups
in safety outcomes.
One or more adverse events were observed in 31 patients
(16 in the propranolol group and 15 from the steroid group;
P > .90 for the difference between the groups). In the pro-
pranolol group, there were 70 adverse events across 16 pa-
tients, and in the steroid group, there were 60 adverse events
across 15 patients. No serious adverse events occurred. The ad-
verse events that occurred were minor and not related to the
treatment.
Discussion
After propranolol was introduced for IH treatment in 2008, it
has been used worldwide because it is considered more effec-
tive and safer than steroid treatment.10 However, there has been
limited evidence for propranolol’s efficacy and safety be-
cause of the lack of randomized clinical trials. Very recently,
2 randomized clinical trials for propranolol and steroid were
reported.23,24 However, they were not designed as confirma-
tive studies: the sample size was not predetermined for enough
statistical power, and inflation of type I error in the studies was
not considered. In addition, the studies had a high dropout rate:
only 11 of 30 patients in the one trial and 11 of 19 in the other
completed treatment.23,24 Moreover, the steroid group had a
higher dropout rate in both trials (6 patients of 10 patients in
one study, 6 patients of 8 patients in the other).23,24 Another
well-planned, randomized clinical trial was reported very
recently.25 However, the authors could not prove that pro-
pranolol can be used as a first-line treatment for IH because
propranolol was compared with placebo. Moreover, only 19 of
55 patients completed treatment in the placebo group.
We enrolled 34 patients to show noninferiority of pro-
pranolol and made the minimum dropout rate. We had set the
reaction rate based on response rates in published studies that
used the same primary efficacy variables.16,31-33 However, the
reaction rate in the steroid group was higher than expected.
We thought that the reaction rate, which was evaluated by IH
volume, could not exactly match the results of previous stud-
ies that evaluated the surface area of IH. The sensitivity for the
reaction seemed to be higher when we used volumetrics to
measure response.
To our knowledge, this is the first well-designed random-
ized clinical trial evaluating the efficacy and safety of pro-
pranolol compared with steroid in the treatment of IH. The first
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 Efficacy and Safety of Propranolol vs Steroid for Infantile Hemangioma Original Investigation Research

Table 1. Demographic and Baseline Clinical Characteristics of the Study Patientsa

Propranolol Group Steroid Group
Characteristics (n = 17) (n = 17) P Value
Patients
Age, mo 3.6 (0.3-8.2) 3.0 (0.8-8.0) .37b
Boys, No. (%) 7 (41) 8 (47) .73c
Weight, kg 6.45 (1.73) 6.02 (1.68) .48b
Height, cm 61.75 (6.05) 60.51 (5.96) .55b
Blood pressure, mm Hg
Systolic 88 (80-112) 91 (76-108) .40d
Diastolic 49.82 (10.76) 50.59(10.69) .84b
Heart rate, beats/min 128 (109-167) 140 (118-160) .11d
Respiration rate, breaths/min 36 (30-40) 36 (32-44) .86d
Body temperature, °C 36.89 (0.41) 36.93 (0.38) .80b
Hemangiomas
Location, No. (%) of patients
Scalp 1 (6) 2 (12)e >.99f
Face 10 (59)g 13 (76) .46f
Chest 2 (12)g 0 .48f
Abdomen 1 (6) 0 >.99f
Back 1 (6) 0 >.99f
Upper extremity 3 (18) 2 (12) >.99f
Lower extremity 0 1 (6)e >.99f
Size
Volume, mm3 by MRI 14 125.35 (18 246.77) 9349.54 (16 015.69) .33d
Surface area, mm2 1318.06 (1833.07) 1093.51 (1316.68) >.99d
Height, mm 4.26 (2.22) 3.71 (2.49) .50b
Color, No. (%) of patients
Red 11 (65) 14 (82) .48f
Purple 2 (12) 1 (6) NR
Abbreviations: MRI, magnetic
Blue 1 (6) 0 NR resonance imaging, NR, not reported.
Gray 0 1 (6) NR a
Unless otherwise indicated, data are
Apricot 0 0 NR reported as mean (range) or mean
(SD).
Other 3 (18) 1 (6) NR
b
Independent t test.
Purple/blue 1 (6) 0 NR
c
χ2 Test.
Red/blue 0 1 (6) NR d
Wilcoxon rank-sum test.
Red to purple 1 (6) 0 NR e
Two lesions in 1 patient in the
Reddish purple 1 (6) 0 NR propranolol group (both the scalp
Ulcer, No. (%) of patients and lower extremity).
f
Yes 1 (6) 1 (6) >.99f Fisher exact test.
g
Reepithelization, No. (%) of patients Two lesions in 1 patient in the
steroid group (both the face and
Yes 2 (12) 0 .48f
chest).

strength is that this study was performed in a single center;
therefore, all participants received their treatments in the same
environment. The second strength is that we used MRI to mea-
sure IH lesion volume. Most clinical trials use photography and
measure surface area of the IH because MRI has cost and
convenience issues even though it is most useful for IH
evaluation.18,22-25,35-37 Moreover, the radiologist evaluated the
volume independently and blindly. Third, this study had a very
low dropout rate compared with other studies.23-25 It is very
difficult to get permission from parents because the partici-
pants are very young infants. Moreover, young parents have
knowledge about IH and treatment. As a result, they already
prefer propranolol treatment over the use of steroid.24 We over-
came these circumstances by cordial, thoughtful explanation
of the experiment before permission was obtained and dur-
ing follow-up. In addition, there were no serious complica-
tions or adverse events observed during the trial. Other stud-
ies have reported that adverse effects greatly influenced the
dropout rate.23,24
This trial showed that the therapeutic effects of proprano-
lol were not inferior to that of steroid. In addition, we found
that there was no significant difference between the 2 groups
in terms of safety outcomes. The 2 previously published ran-
domized clinical trials conducted on the use of propranolol and
steroid showed conflicting results regarding the efficacy and
speed of treatment response.23,24 In one study, propranolol was

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 Research Original Investigation Efficacy and Safety of Propranolol vs Steroid for Infantile Hemangioma

Table 2. Efficacy Outcomes

Propranolol Steroid
Characteristic Group Group pT-pC (95% CI) P Value
Primary Efficacy Evaluation
ITT analysis group applying MI, %
Reaction 95.65 91.94
3.71 (−15.43 to 22.84) NR
Nonreaction 4.35 8.06
Missing values replaced with
“nonreaction,” No. (%) of patients
Reaction 16 (94) 14 (82)
11.76 (−9.53 to 33.06) NR
Nonreaction 1 (6) 3 (18)
Missing values replaced with
“reaction,” No. (%) of patients
Reaction 17 (100) 17 (100)
0 (−18.65 to 18.65)a NR
Nonreaction 0 0
PP population, No. (%) of patients
Reaction 16 (100) 14 (100)
0 (−20.59 to 23.16)a NR
Nonreaction 0 0
Secondary Efficacy Evaluationb
Change in hemangioma volume, −55.87 (18.92) −46.52 (26.24)
NR .27c
mean (SD), %
Progression stop and regression Abbreviations: ITT, intention to treat;
point MI, multiple imputation; NR, not
Cases, No. 17 15 reported; PP, per protocol;
NR .34d pT-pC, experimental group’s
Median time, d 12 11
treatment reaction rate − control
Regression point group’s treatment reaction rate.
Cases, No. 13 9 a
Exact confidence interval.
NR .53d
Median time, d 62 120 b
A complete report of secondary
Compliance efficacy evaluation data is provided
in Supplement 2.
Duration of medication, mean 120.29 (24.99) 128.53 (25.86)
NR .44e c
Independent t test.
(SD), d
d
Outpatient visits, mean (SD), 7.00 (0.00) 6.29 (1.99) e Log-rank test.
NR .16
No. e
Wilcoxon rank-sum test.

Table 3. Adverse Events in the Safety Population

Study Participants, No. (%)

Propranolol Group Steroid Group
Variable (n = 17) (n = 16) P Value
Adverse events
Serious adverse event 0 0
Any adverse event 16 (94) 15 (94) >.99a
b
Known risks associated with drugs
Bradycardia 0 0
Hypotension 5 (29) 1 (7) .18a
Hypoglycemia 0 0
Trouble breathing 0 0
a
Gastroesophageal reflux 0 0 Fisher exact test.
b
c A complete list of adverse events is
Hypertension 7 (41) 7 (47) .75
provided in Supplement 2.
Growth disability 0 2 (13) .21a c
χ2 Test.

shown to have better efficacy: the adverse effects profile and
speed of treatment response were both superior.23 However,
in another study, both medications showed similar efficacy,
and propranolol had significantly fewer severe adverse events,
although the treatment response to steroid was faster.24 We
believe that our results provide stronger evidence of the non-
inferiority of propranolol for treatment of IH.
Limitations
Although the sample size in the present study was predeter-
mined to show noninferiority, it is difficult to provide strong
evidence of safety outcomes. According to a recent meta-
analysis, the most commonly reported adverse effects of
steroids were altered growth and moon facies, and the inci-
dence of overall adverse effects was approximately 17.6%.21

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 Efficacy and Safety of Propranolol vs Steroid for Infantile Hemangioma Original Investigation Research

The most common adverse effects of propranolol were
hypotension, bradycardia, and hypoglycemia, and it was
reported that about 13.7% of patients experienced adverse
effects with propranolol therapy.21 The incidence of compli-
cations varied among studies and depended on the defini-
tion of complication. As safety cannot be assessed based on
the complication rate alone, physicians must make appro-
priate clinical decisions.
There are other factors that should be considered when
using propranolol. Physicians should consider complica-
tions, hospital admission, vital sign monitoring, and cost
before administering propranolol, even though many cen-
ters are now eliminating inpatient initiation and reducing
monitoring, making the costs comparable to those for ste-
roid use. The concerns about neurocognitive issues caused
by propranolol have led to atenolol being considered as an
alternative for the treatment of IH.38 While there was little
published research about the use of atenolol for IH at the
time the present trial was ongoing, several studies have
since been reported.35,38,39 The risk of pulmonary adverse
effects and hypoglycemia are decreased because of the
characteristics of atenolol as a selective β1-blocker. More-
over, atenolol is less likely to produce central nervous
system–related adverse effects. 35,38 However, studies in
patients with IH are lacking. We believe that further studies
on the use of atenolol as a treatment for IH are needed.
The present study was not a double-blind trial. Since only
the patients in the propranolol group were hospitalized for the
study, each was aware of the group in which they were placed.
We chose to give up a double-blind trial to be faithful to each
drug protocol. And it was difficult to evaluate safety out-
comes based solely on this study. Another limitation was that
we did not evaluate which dose would be most effective in this
study, and instead used 2 mg/kg/d for both drugs because this
dose was used in the current literature. Some studies have re-
ported that 3 mg/kg/d is the best dose of steroid for treating
IH, but no randomized clinical trials have been conducted to
confirm the dose-response relationship for steroids.33,40 How-
ever, a randomized clinical trial found propranolol to be more
effective at 3 mg/kg/d than at 1 mg/kg/d.25 Although increas-
ing the dose typically yields a better response rate, it also could
increase the likelihood of complications.41
Conclusions
Our trial demonstrated that propranolol was not inferior to ste-
roid with respect to therapeutic effects in IH.

ARTICLE INFORMATION
Accepted for Publication: January 24, 2017.
Published Online: April 19, 2017.
doi:10.1001/jamadermatol.2017.0250
Author Affiliations: Department of Dermatology,
Seoul National University College of Medicine,
Seoul, Republic of Korea (K. H. Kim, Y. W. Park,
D. Y. Kim, Choe); Institute of Human-Environment
Interface Biology, Seoul National University Medical
Research Center, Seoul, Republic of Korea
(K. H. Kim, D. Y. Kim); Laboratory of Cutaneous
Aging and Hair Research, Biomedical Research
Institute, Seoul National University Hospital, Seoul,
Republic of Korea (K. H. Kim, D. Y. Kim);
Department of Plastic and Reconstructive Surgery,
Institute of Human-Environment Interface Biology,
Seoul National University College of Medicine,
Seoul, Republic of Korea (T. H. Choi, Lee); Division
of Medical Statistics, Medical Research
Collaborating Center, Seoul National University
College of Medicine, Seoul National University
Hospital, Seoul, Republic of Korea (Y. Choi);
Department of Plastic and Reconstructive Surgery,
Seoul National University Hospital, Seoul, Republic
of Korea (Hong); Department of Radiology, Seoul
National University College of Medicine, Seoul,
Republic of Korea (Cheon); Department of
Medicine, Seoul National University School of
Medicine (Master Course), Seoul, Republic of Korea
(J.-B. Park); Department of Pediatrics, Cancer
Research Institute, Seoul National University
College of Medicine, Seoul National University
Children’s Hospital, Seoul, Republic of Korea
(K. D. Park, Kang, Shin); Department of Plastic and
Reconstructive Surgery, Seoul National University
Bundang Hospital, Gyeonggi, Republic of Korea
(Jeong).
Author Contributions: Drs T. Choi and Jeong had
full access to all of the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis. Drs K. Kim and T. Choi
contributed equally to this article as co–first authors.
Concept and design: K. Kim, T. Choi, Y. Park, Cheon,
Jeong.
Acquisition, analysis, or interpretation of data:
K. Kim, T. Choi, Y. Choi, Hong, D. Kim, Choe, Lee,
Cheon, J. Park, K. Park, Kang, Shin, Jeong.
Drafting of the manuscript: T. Choi, Y. Choi, Cheon,
K. Park, Jeong.
Critical revision of the manuscript for important
intellectual content: K. Kim, T. Choi, Y. Choi, Y. Park,
Hong, D. Kim, Choe, Lee, Cheon, J. Park, Kang, Shin,
Jeong.
Statistical analysis: K. Kim, T. Choi, Y. Choi, Y. Park.
Obtained funding: K. Kim, T. Choi, Kang, Shin.
Administrative, technical, or material support:
K. Kim, T. Choi, Y. Park, Hong, Cheon, J. Park.
Study supervision: K. Kim, T. Choi, Cheon, K. Park,
Kang, Shin.
Conflict of Interest Disclosures: None reported.
Funding/Support: This research was supported by
grant 12172MFDS231 from the Ministry of Food and
Drug Safety, Republic of Korea.
Role of the Funder/Sponsor: The funder had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Additional Contributions: The authors would like
to thank Christina S. Kim, BA, for English
proofreading. She received no compensation for
her contributions.
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