Research
Original Investigation
Propranolol vs Prednisolone for Symptomatic Proliferating Infantile Hemangiomas A Randomized Clinical Trial Nancy M. Bauman, MD; Robert J. McCarter, ScD; Philip C. Guzzetta, MD; Jennifer J. Shin, MD, SM; Albert K. Oh, MD; Diego A. Preciado, MD, PhD; Jianping He, MS; Elizabeth Anne Greene, MD; Katherine B. Puttgen, MD
IMPORTANCE While propranolol is touted as superior to prednisolone for treating infantile
hemangiomas (IH), a randomized clinical trial (RCT) comparing the outcome and tolerability of these medications for symptomatic, proliferating IH has not been reported. OBJECTIVES To determine if oral propranolol is more efficacious and better tolerated than prednisolone in treating symptomatic, proliferating IH and to determine the feasibility of conducting a multi-institutional, RCT comparing efficacy and tolerability of both medications. DESIGN, SETTING, AND PARTICIPANTS Phase 2, investigator-blinded, multi-institutional RCT conducted in 3 academic vascular anomalies clinics on 19 of 44 eligible infants aged between 2 weeks and 6 months. All participating patients had symptomatic proliferating IH treated between September 1, 2010, and August 1, 2012. INTERVENTIONS Treatment with oral propranolol vs prednisolone (2.0 mg/kg/d) until halted
owing to toxic effects or clinical response. MAIN OUTCOMES AND MEASURES Primary outcome was change in IH size after 4 months of therapy. Secondary outcomes were response rate and frequency and severity of adverse events (AEs). RESULTS The primary outcome showed no difference in lesion size or affected skin area after 4 months of therapy: 41% and 1.32 mm2 for prednisolone vs 64% and 0.55 mm2 for propranolol (P = .12 for lesion size, and P = .56 for affected skin area). Longitudinal analyses showed a faster response in total lesion outer dimension with prednisolone (P = .03), but this advantage over time was not noted when central clearing and outer dimension were included in the analysis (P = .91). The overall frequency of AEs was similar (44 for prednisolone vs 32 for propranolol) (P = .84), but prednisolone-treated participants had more grade 3 severe AEs (11 vs 1) (P = .01), particularly growth retardation resulting in size and weight below the fifth percentile. Early study withdrawal owing to AEs occurred in 6 (75%) of 8 patients in the prednisolone group but 0 of 11 propranolol-treated participants. The mean duration of therapy was shorter for prednisolone (141 vs 265 days), reflecting the higher rate of early withdrawals. CONCLUSIONS AND RELEVANCE Both medications show similar efficacy for reducing the area of symptomatic, proliferating IH. Although prednisolone showed a faster response rate, propranolol was better tolerated with significantly fewer severe AEs. Propranolol should be the first line of therapy for symptomatic IH unless contraindicated or unless future studies demonstrate severe AEs from propranolol. Recruiting participants for a phase 3 RCT would be difficult owing to safety profiles measured here and emerging trends favoring propranolol. TRIAL REGISTRATION clinicaltrials.gov identifier: NCT00967226
JAMA Otolaryngol Head Neck Surg. doi:10.1001/jamaoto.2013.6723 Published online February 13, 2014.
Author Affiliations: Department of Otolaryngology, Children’s National Medical Center, Washington, DC (Bauman, Preciado); Department of Biostatistics, Children’s National Medical Center, Washington, DC (McCarter, He); Department of General Surgery, Children’s National Medical Center, Washington, DC (Guzzetta); Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts (Shin); Department of Plastic Surgery, Children’s National Medical Center, Washington, DC (Oh); Department of Cardiology, Children’s National Medical Center, Washington, DC (Greene); Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, Maryland (Puttgen). Corresponding Author: Nancy M. Bauman, MD, Department of Otolaryngology, Children’s National Medical Center, 111 Michigan Ave NW, Washington DC 20010 ([email protected]).
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Research Original Investigation
Propranolol vs Prednisolone for Infantile Hemangiomas
I
nfantile hemangiomas (IH) are the most common benign tumors of infancy, arising in 4% of live births.1,2 While IH exhibit a characteristic growth pattern of proliferation and subsequent involution during the first decade of life, 12% of lesions require consideration of therapy during infancy for indications including ulceration, bleeding, impairment of sensory organ function, airway compromise, and risk of permanent deformity in cosmetically sensitive regions.3,4 Subsequent to the recent serendipitous discovery of propranolol’s effects on symptomatic IH, 5 the nonselective β-blocker may be supplanting systemic corticosteroids as the initial therapy of choice. Since there are no drugs for IH approved by the US Food and Drug Administration, both medications are used as off-label treatments, and their perceived efficacy and tolerability stems from observational studies and expert opinion. To our knowledge, the present multiinstitutional, phase 2, randomized clinical trial (RCT) is the first to evaluate the performance of propranolol vs prednisolone in terms of (1) IH response, (2) medication tolerability, and (3) feasibility of conducting a phase 3 trial.
Methods Study Participants Written consent for study participation was obtained from all patients’ parents or guardians during the clinic evaluation. The study was reviewed by the Data Safety Monitoring Board (DSMB) quarterly, registered w ith clinic altrials.gov (NCT00967226), and approved by institutional review boards of the Children’s National Medical Center (CNMC) (No. 0000467), University of Iowa (UIHC) (No. 201004770), and Johns Hopkins Hospital (JHH) (No. NA_00049604). All consecutive eligible infants aged 2 weeks to 6 months with actively proliferating and symptomatic IH evaluated in the outpatient vascular anomalies clinics of the study institutions were invited to participate without sexual or racial restriction. Lesions were considered symptomatic if they impaired function (including breathing, eating, vision, and hearing), were ulcerated, caused pain, or were in cosmetically sensitive regions. Exclusion criteria included inadequate social support, nonproliferating IH, other treatment for IH, liver disease, abnormal blood glucose level (BG), hypertension, hypotension, reactive airway disease, cardiac anomalies, and PHACE (posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities)6,7 if significantly narrowed intracranial vasculature was present. Intake history included demographic data, IH characteristics, and medical history. Participants self- reported race and ethnicity. A complete physical examination was completed, including evaluation of vital signs and nonfasting BG. Hypoglycemia was defined as BG lower than 70 mg/dL. Imaging studies were completed only when necessary to confirm diagnosis, determine IH extent, or evaluate for PHACE.6,7 Participants with stridor or beard distribution of IH underwent airway endoscopy to exclude subglottic hemangiomas. Liver ultrasonography was performed for participants with 4 or more hemangiomas. E2
Study Design and Interventions This multi-institution, single-blind, placebo-controlled RCT targeted enrolling 55 participants per group to achieve 80% power to detect a 30% absolute reduction in lesion size between groups assuming the smallest reduction was at least 50%. Consenting participants were randomized to prednisolone or propranolol using a CNMC institutional tamper-proof, pregenerated encrypted schedule, which allocated equal assignments to both treatments within institutions and within lesions affecting and not affecting vision. Medications were dispensed free of charge. No stipend was provided. At enrollment, the blinded investigators assigned a number to each of the IH corresponding to 1 of 76 unique body segments 8 and recorded the following established parameters of the IH8: type (superficial, deep, or mixed), presence of ulceration, total area (product of transverse and longitudinal measurements in square millimeters), degree of normal intervening skin (deep lesions, none; superficial and mixed lesions, 75%-100%, 50%-74%, 25%-49%, 10%-24%, or .11) (Table 2). Longitudinal Analysis of TSA The longitudinal analysis of the impact of treatment group on TSA showed that the rate of decline was statistically significantly faster in the prednisolone group (P = .04) (Figure 2A). When baseline TSA was taken into account (by adjusting for the larger baseline TSA in the propranolol group at the outset), results were similarly significant (P = .03) (Figure 2B). When individual month intervals were examined with the model as a predictor, no significant differences were noted at the individual month timeframes in both the univariate and the adjusted analysis. Longitudinal Analysis of AdjTSA The AdjTSA response over time was similar in both groups in both the unadjusted baseline (P = .20) and adjusted baseline analysis (P = .91) (Figure 3) Sensitivity Analysis When excluding the data from the 2 noncompliant patients, there was still no difference between adjTSA (P = .12) or TSA (P = .57) in the primary analysis, and longitudinal unadjusted and adjusted analyses were consistent with the intention-totreat analysis. Duration of Therapy (Excluding Early Withdrawals) For participants concluding the study (2 [25%] of 8 in the prednisolone group and 9 [82%] of 11 in the propranolol group), the mean time in days from start to finish of therapy was 323 (95% CI, 223-423) for propranolol and 300 for prednisolone (95% CI, 0-643). Regrowth after medication weaning was noted in 2 propranolol-treated participants and 1 prednisolone-treated participant, all of whom responded to resuming treatment with their respective medications.
3. Adverse Events There were more early withdrawals due to medicationrelated concerns in the prednisolone group than in the propranolol group (6:1) (P = .01). Adverse events were the cause E4
Early withdrawal Prednisolone 5 AE 1 LP Deferred Propranolol 1 Adjuvant 1 Noncompliant
Study enrollment at Children’s National Medical Center (CNMC), University of Iowa (UIHC), and Johns Hopkins Hospital (JHH). AE indicates adverse event; tx, treatment; LP, local physician.
of study withdrawal in none of the propranolol participants but in 5 of 6 of the prednisolone participants, either at the request of the primary care physician (owing to growth concerns; n = 4) or the request of the parents (owing to marked flushing and sweating that stopped with prednisolone treatment cessation; n = 1) (Table 3). Despite the absence of AEs, another prednisolone participant withdrew at the recommendations of his pediatrician and ophthalmologist, who counseled the parents that their infant should be treated with propranolol. A single propranolol-treated participant withdrew from the study, even though her lesion was regressing markedly after 5 months of therapy, because the parents requested laser treatment of telangiectasias. This necessitated study withdrawal because alternative treatment was a study exclusion criterion. Another propranolol participant expressed regrets about being in the study and withdrew immediately after enrollment but requested propranolol treatment outside the study. The frequency of all AEs was similar in the prednisolone and propranolol groups (44 vs 32) (P > .84), but severe AEs (CTCAE grade 3) occurred more frequently in prednisolone participants (11 vs 1) (P = .01) (Table 3). Nine of the severe AEs in prednisolone participants were related to decline in linear growth and/or weight to less than 5% of the standardized growth curve measures and greater than 50% from participant’s pretherapy measures. The remaining severe AEs were due to adrenal crisis associated with viral gastroenteritis (n = 1) and severe dehydration warranting hospitalization (n = 1). The severe AE in the propranolol participant was dehydration warranting hospitalization. No propranolol-treated participant experienced significant decline in growth or weight. Propranolol participants had significantly more pulmonary symptoms than prednisolone participants (14 vs 5) (P < .001), predominantly upper respiratory tract infections (URTIs) (Table 3). The number of vascular AEs was comparable but reflected BP increases in prednisolone participants and BP decreases in propranolol participants. All vascular changes were asymptomatic and resolved spontaneously. One propranolol participant developed asymptomatic hypoglycemia after the first dose of propranolol (64 mg/dL). Per protocol, the next dose of propranolol was skipped, and BG remained above 70 mg/dL for subsequent doses.
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Propranolol vs Prednisolone for Infantile Hemangiomas
Original Investigation Research
Table 1. Baseline Demographic and Clinical Characteristics of Participants as Randomizeda Characteristic
Prednisolone
Total, No. (%)
8 (100)
Discussion Propranolol 11 (100)
Sex, No. (%) Female
6 (75.0)
8 (72.7)
Male
2 (25.0)
3 (27.3)
White
6 (75.0)
9 (81.8)
Black
2 (25.0)
1 (9.1)
Asian
0
1 (9.1)
5 (62.5)
5 (45.5)
Color, No. (%)
Ethnicity, No. (%) Hispanic Non-Hispanic Enrollment age, mean (95% CI), mo
3 (37.5)
6 (54.5)
4.0 (2.8-5.2)
2.5 (1.7-3.4)
Lesion site Periorbital
3 (37.5)
1 (9.1)
Cheek
2 (25.0)
0
Nasal tip
2 (25.0)
1 (9.1)
Ear
0
2 (18.2)
Lip
0
2 (18.2)
Beard
1 (12.5)
1 (9.1)
Frontotemporal
0
1 (9.1)
Breast
0
1 (9.1)
Forehead
0
1 (9.1)
None
7 (87.5)
9 (81.8)
Mild (50%)
1 (12.5)
1 (9.1)
Local
8 (100)
6 (54.5)
Segmental
0
3 (27.3)
Intermediate
0
2 (18.2)
Ulceration
Morphology
Depth Superficial
2 (25.0)
3 (27.3)
Deep
2 (25.0)
2 (18.2)
Mixed
4 (50.0)
6 (54.5)
Lesion size, median (95% CI), cm2 By outer margins (TSA)
3.1 (0.8-10.5)
5.0 (1.9-25.6)
Adjusted for normal skin (AdjTSA)
2.5 (0.2-9.4)
5.0 (1.5-24.3)
Abbreviations: AdjTSA, adjusted total surface area; TSA, total surface area. a
Unless otherwise noted, data are reported as number (percentage) of participants.
To our knowledge, the present study is the only phase 2 RCT to compare efficacy, in terms of reduction of IH size, as well as tolerability of propranolol vs prednisolone for treatment of symptomatic IH. Dramatic responses were seen with both medications (Figure 4). Study strengths include the rigorous adherence to enrolling only proliferating IH and the high rate of compliance, with fewer than 10% of missed monthly appointments. Since initiation of this study, propranolol has quickly become the first line of therapy for symptomatic IH,11 even in the absence of data comparing it with the historic standard of prednisolone. Completing a similar study on a larger scale may no longer be feasible or desirable, given the findings of the present series showing fewer severe AEs with propranolol. Propranolol’s rapid rise in popularity is remarkable.5 In September 2010, only 6 series described its use in 10 or more patients/series,12 but by December 2011, the number of treated patients reported had grown to 1200.13,14 Reports of propranolol’s efficacy quickly disseminated through the nonmedical community via the internet as well,12 and parents now present to our vascular anomalies clinic and request propranolol, should IH therapy be indicated. Enrollment of 19 participants instead of 55 was less than anticipated for several reasons. Patients often presented after the requisite period of active IH proliferation when prednisolone is considered most effective.15 Additionally, prior therapy was forbidden, so infants receiving any topical medications were ineligible. Most importantly, one of our collaborative institutions failed to recruit eligible participants during the entire first year of the study. It is now clear that the investigators from this institution had lost their point of equipoise and should not have agreed to participate in the study. The mounting evidence of propranolol’s efficacy made enrollment difficult for our second collaborative institution that joined the study 15 months after initiation. Although the low enrollment reduced the trial’s power to detect differences as originally designed, the randomization schedule prevented bias and still allowed the study to detect larger than anticipated differences. The high rate of dropout of prednisolonetreated participants owing to AEs occurred beyond the first third of the study and beyond the period when efficacy effect was established. Despite the limited enrollment and high dropout rate, the study provides evaluation of the relative effectiveness of the treatments superior to that of the uncontrolled observational case reports currently existing in the literature.
Table 2. Changes in IH Sizea From Baseline to 4 Months IH Parameter Change
Prednisolone
Propranolol
P Value
TSA, mean (95% CI)b
0.41 (0.10-0.72) (n = 4)
0.64 (0.44-0.83) (n = 8)
.12
TSA, mean (95% CI)c
0.63 (0.14-1.11) (n = 6)
0.57 (0.34-0.80) (n = 9)
.77
AdjTSA, median (25th-75th percentileb
1.32 (0.28-2.35) (n = 2)
0.55 (0.22-0.76) (n = 7)
.56
0.99 (0.28-1.93) (n = 4)
0.55 (0.22-0.76) (n = 7)
.45
AdjTSA, median (25th-75th percentile)c
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Abbreviations: AdjTSA, adjusted total surface area; IH, infantile hemangioma; TSA, total surface area. a
All size change is reported in square millimeters.
b
Data from 4 months only.
c
Data from 4 months with 5-month data allowed as a surrogate if the 4-month mark was missed.
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Research Original Investigation
Propranolol vs Prednisolone for Infantile Hemangiomas
Figure 2. Longitudinal Analyses of Treatment Effects on Infantile Hemangioma (IH)
Figure 3. Longitudinal Analyses of Treatment Effects on Adjusted Surface Area of Infantile Hemangioma (IH), Including Central Clearing (AdjTSA) A
Prednisolone Propranolol
8 P =.04 6
4
2
0
–2
P =.20 5 4 3 2 1 0
–1 1
2
3
4
5
6
7
8
9
10
11
12
1
2
3
4
5
Time, mo Propranolol 10 Prednisolone 6
10 6
8 7
8 4
9 6
8 4
3 2
6
7
8
9
10
11
12
2 2
3 2
1 1
2 1
0 1
Time, mo 3 3
3 3
2 1
3 2
1 1
Propranolol 8 Prednisolone 4
B
8 4
6 5
7 2
7 4
7 2
2 1
B
4
Surface Area Adjusted, mm2
P =.03
Estimated Affected Skin Area, mm2
8 Prednisolone Propranolol
6
4
2
0
–2
P =.91
Prednisolone Propranolol
3
2
1
0 1
2
3
4
5
6
7
8
9
10
11
12
1
2
3
4
5
Time, mo Propranolol 10 Prednisolone 6
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Prednisolone Propranolol
6
Estimated Affected Skin Area, mm2
Surface Area by Outer Dimension, mm2
A
10 6
8 7
8 4
9 6
8 4
3 2
6
7
8
9
10
11
12
2 2
3 2
1 1
2 1
0 1
Time, mo 3 3
3 3
2 1
3 2
1 1
Propranolol 8 Prednisolone 4
8 4
6 5
7 2
7 4
7 2
2 1
A, Univariate longitudinal analysis of change in IH outer margin total surface area (TSA) over time when treated with prednisolone vs propranolol. B, Longitudinal analysis of change in the TSA adjusted for baseline size differences. The numbers below the x-axis represent the number of lesions measured at each follow-up visit in each of the 2 treatment groups.
A, Univariate longitudinal analysis of the change in the AdjTSA of IH over time when treated with prednisolone vs propranolol. B, Longitudinal analysis of the change in AdjTSA adjusted for baseline size differences. The numbers below the x-axis represent the number of lesions measured at each follow-up visit in each of the 2 treatment groups.
Caretakers were not blinded because we could not justify unnecessarily admitting prednisolone participants to initiate therapy or unnecessarily withholding live vaccines from propranolol participants. Furthermore, caretakers needed to know the medication assignment to ensure participant safety. As an illustration, parents of a propranolol participant with poor oral intake owing to a gastrointestinal viral illness should withhold propranolol to prevent hypoglycemia, but parents of a prednisolone participant with the same symptom should not withhold prednisolone and should even possibly increase stress steroid coverage. Both medications were efficacious in reducing IH TSA and AdjTSA; prednisolone showed a faster response rate than propranolol for TSA but not for AdjTSA. However, the need to stop treatment with prednisolone in 75% of participants owing to AEs offsets its potential advantage. It remains unclear if either medication offers an advantage in change in TSA or AdjTSA beyond 12 months. The significantly higher rate of severe AEs in prednisolone participants prompting early withdrawal was remarkable. The overall number of AEs was similar, but those in pro-
pranolol subjects were predominantly grade 1 or 2, while the AEs in prednisolone subjects were grade 3 due to severe growth retardation. Although growth retardation is a predictable and temporary AE of prednisolone treatment in infants, the remarkable incidence necessitating study withdrawal was striking. After extensive deliberation, our DSMB concluded that the high rate of severe drug-related AEs warranting study withdrawal in prednisolone subjects was not offset by sufficient treatment advantages and that further enrollment should halt. It is likely that pediatricians caring for patients with IH share the concerns of our DSMB regarding the severe, albeit reversible, AEs associated with prolonged corticosteroid use. The decision to halt enrollment based on a wellrecognized AE of prednisolone was difficult, since it prevented the full comparison of the efficacy of these 2 medications. Knowledge of outcome efficacy may prove useful in the future should life-threatening cardiovascular events from propranolol occur or concerns of propranolol irreversibly affecting memory retention in children be demonstrated.16 Such findings might tilt the treatment scale away from propranolol, since
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Propranolol vs Prednisolone for Infantile Hemangiomas
Original Investigation Research
Table 3. Frequency of Adverse Events by Group Propranolol (n = 11 Patients)
Adverse Event (CTCAE Code)
Prednisolone (n = 8 Patients)
P Value
Most Severe AE per Participant, No. (%) of Participants Severity Total
9 (90.0)
7 (87.5)
Mild
1 (10.0)
0 (0)
.87 >.99
Moderate
7 (70.0)
2 (25)
.08
Severe
1 (10.0)
5 (62.5)
.04
Type Allergy/immunology (1)
1 (6.3)
0
>.99
Dermatologic (9)
1 (6.3)
0
>.99
Endocrine (10)
0
1 (10.0)
Gastrointestinal (11)
3 (18.8)
1 (10.0)
.55
Growth and development (12)
0
5 (50.0)
.004
Infection (15)
2 (12.5)
1 (10.0)
.85
Metabolic/laboratory (17)
0
1 (10.0)
.39
Pulmonary/respiratory (22)
8 (50.0)
1 (10.0)
.06
Vascular (28)
1 (6.3)
0
.39
>.99
All AEs (Including Multiple AEs Per Person), No. (%) of IH Lesionsa Severity Total
32 (100)
44 (100)
.84
Mild
10 (21.4)
22 (50.0)
.20
Moderate
21 (65.6)
11 (25.0)
.09
1 (3.1)
11 (25.0)
.01
Severe Type Allergy/immunology (1)
1 (0.02)
1 (0.02)
.82
Constitutional (7)
2 (0.05)
4 (0.09)
.54
Dermatologic (9)
2 (0.05)
1 (0.02)
.37
Endocrine (10)
0 (0.00)
8 (0.18)
.02
Gastrointestinal (11)
5 (0.11)
Growth and development (12)
0
Infection (15)
5 (0.11)
4 (0.09)
.44
Metabolic/laboratory (17)
0
1 (0.02)
>.99
Pulmonary/respiratory (22) Vascular (28)
B
C
D
5 (0.11)
.001
3 (0.07)
4 (0.09)
.98
A, Pretreatment postauricular infantile hemangioma (IH). B, Marked response of postauricular IH to 10 months of propranolol therapy. C, Pretreatment IH of the lip and chin. D, Response of lip and chin IH to 11 months of prednisolone therapy.
jamaotolaryngology.com
.74 .005
14 (0.32)
Figure 4. Hemangioma Response A
6 (0.14) 10 (0.23)
Abbreviations: AE, adverse events; CTCAE, Common Terminology Criteria for Adverse Events; IH, infantile hemangioma. a
P values are adjusted for the correlation between multiple events in the same participant.
severe growth restriction from prednisolone may be disturbing but is reversible.17 The favorable response profile of prednisolone is encouraging for patients with symptomatic IH and a contraindication to propranolol use. Notably, the rate of respiratory AEs, particularly URTIs, was higher in the propranolol-treated group. Larger studies will be required to determine if propranolol increases the risk or severity of URTIs. A major limitation of IH research has long been the lack of a validated objective method by which to measure growth and response to therapy. No such tool had been reported at the initiation of our study, but a recently described scale may prove useful for future IH studies.18 Clearly the most important remaining question of propranolol use is whether the medication merely hastens involution onset or actually improves the outcome of involution. This is particularly important because pharmacologic therapy with corticosteroids historically has been used only in symptomatic IH because of associated AEs, but the growing evidence of propranolol’s safety and efficacy is expanding its use JAMA Otolaryngology–Head & Neck Surgery Published online February 13, 2014
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Research Original Investigation
Propranolol vs Prednisolone for Infantile Hemangiomas
to even small, superficial facial lesions that may leave unsightly facial scars once involuted.13 Whether early initiation of propranolol treatment when an IH first presents as a macular, vascular blush prevents its growth into a raised, cosmetically deforming lesion also needs to be determined.
Conclusions The results of this RCT for treatment of symptomatic, proliferating IH show that prednisolone and propranolol showed no difference in the primary outcome of lesion area at 4 months
ARTICLE INFORMATION Submitted for Publication: September 20, 2013; final revision received November 8, 2013; accepted December 16, 2013. Published Online: February 13, 2014. doi:10.1001/jamaoto.2013.6723. Author Contributions: Drs Bauman and McCarter had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Bauman, McCarter, Guzzetta, Oh, Preciado, Puttgen. Acquisition of data: Bauman, Guzzetta, Oh, Greene, Puttgen. Analysis and interpretation of data: McCarter, Shin, Oh, Preciado, He, Greene, Puttgen Drafting of the manuscript: Bauman, McCarter, Guzzetta, Shin, Puttgen. Critical revision of the manuscript for important intellectual content: Bauman, McCarter, Guzzetta, Shin, Oh, Preciado, He, Greene, Puttgen. Statistical analysis: Bauman, McCarter, Shin, He, Puttgen. Obtained funding: Bauman. Administrative, technical, and material support: Bauman, McCarter, Guzzetta, Oh, Preciado, Greene, Puttgen. Study supervision: Bauman, Guzzetta, Greene, Puttgen. Manuscript review: Guzzetta, Oh, Preciado, Greene. Conflict of Interest Disclosures: Drs Bauman, McCarter, and Puttgen received modest salary support from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, and from the National Center for Research Resources of the National Institutes of Health to complete the study. Dr Shin receives book royalties from Springer Publishing and Plural Publishing for Evidence-Based Otolaryngology and Otolaryngology Prep and Practice, respectively. No other disclosures were reported. Funding/Support: Work for the research reported in this publication was supported by grant R21HD062959-02 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, and by grant UL1RR031988 from the National Center for Research Resources of the National Institutes of Health. Role of the Sponsor: The financial support was used for design and conduct of the study, study medications, and collection, interpretation and analysis of the data, but the sponsors themselves
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but that prednisolone may result in a faster rate of involution of a lesion’s outer margin over time. Propranolol, however, is better tolerated than prednisolone, with significantly fewer severe AEs leading to drug-related withdrawals. Based on similar efficacy between medications but the higher rate of severe AEs with prednisolone therapy, propranolol should be considered the first line of therapy for symptomatic IH if contraindications to its use do not exist. Further studies are necessary to determine whether there are additional, undemonstrated long-term AEs associated with propranolol use and if propranolol merely hastens the involution process or changes ultimate outcome.
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. Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional Contributions: The authors acknowledge the support of Ed Connor, MD, PriyaVaidyanathan, MD, and Marlene Lee, RN, who served on the DSMB; Jennifer Gode, RN, who served as clinical nurse coordinator for a portion of the study; Margie Brown, who assisted with manuscript preparation; and the study participants and their parents. Correction: This article was corrected on March 11, 2014, to fix a value in Figure 1. REFERENCES
hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities (PHACE) syndrome: a systematic review of the literature. Stroke. 2012;43(6):1672-1674. 8. Chiller KG, Passaro D, Frieden IJ. Hemangiomas of infancy: clinical characteristics, morphologic subtypes, and their relationship to race, ethnicity, and sex. Arch Dermatol. 2002;138(12):1567-1576. 9. Fleming S, Thompson M, Stevens R, et al. Normal ranges of heart rate and respiratory rate in children from birth to 18 years of age: a systematic review of observational studies. Lancet. 2011;377(9770):1011-1018. 10. Kent AL, Kecskes Z, Shadbolt B, Falk MC. Blood pressure in the first year of life in healthy infants born at term. Pediatr Nephrol. 2007;22(10): 1743-1749. 11. Blei F. Oral prednisolone for infantile hemangioma: efficacy and safety using a standardized treatment protocol. Plast Reconstr Surg. 2012;129(5):840e-841e, author reply 841e.
1. Kanada KN, Merin MR, Munden A, Friedlander SF. A prospective study of cutaneous findings in newborns in the United States: correlation with race, ethnicity, and gestational status using updated classification and nomenclature. J Pediatr. 2012;161(2):240-245.
12. Menezes MD, McCarter R, Greene EA, Bauman NM. Status of propranolol for treatment of infantile hemangioma and description of a randomized clinical trial. Ann Otol Rhinol Laryngol. 2011;120(10):686-695.
2. Kilcline C, Frieden IJ. Infantile hemangiomas: how common are they? a systematic review of the medical literature. Pediatr Dermatol. 2008;25(2):168-173.
13. Drolet BA, Frommelt PC, Chamlin SL, et al. Initiation and use of propranolol for infantile hemangioma: report of a consensus conference. Pediatrics. 2013;131(1):128-140.
3. Frieden IJ, Eichenfield LF, Esterly NB, Geronemus R, Mallory SB; American Academy of Dermatology Guidelines/Outcomes Committee. Guidelines of care for hemangiomas of infancy. J Am Acad Dermatol. 1997;37(4):631-637.
14. Marqueling AL, Oza V, Frieden IJ, Puttgen KB. Propranolol and infantile hemangiomas four years later: a systematic review. Pediatr Dermatol. 2013;30(2):182-191.
4. Haggstrom AN, Drolet BA, Baselga E, et al. Prospective study of infantile hemangiomas: clinical characteristics predicting complications and treatment. Pediatrics. 2006;118(3):882-887. 5. Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo J-B, Taïeb A. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008;358(24):2649-2651. 6. Frieden IJ, Reese V, Cohen D. PHACE syndrome: the association of posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities. Arch Dermatol. 1996;132(3):307-311. 7. Siegel DH, Tefft KA, Kelly T, et al. Stroke in children with posterior fossa brain malformations,
15. Bennett ML, Fleischer AB Jr, Chamlin SL, Frieden IJ. Oral corticosteroid use is effective for cutaneous hemangiomas: an evidence-based evaluation. Arch Dermatol. 2001;137(9):1208-1213. 16. Lonergan MH, Olivera-Figueroa LA, Pitman RK, Brunet A. Propranolol’s effects on the consolidation and reconsolidation of long-term emotional memory in healthy participants: a meta-analysis. J Psychiatry Neurosci. 2013;38(4):222-231. 17. Boon LM, MacDonald DM, Mulliken JB. Complications of systemic corticosteroid therapy for problematic hemangioma. Plast Reconstr Surg. 1999;104(6):1616-1623. 18. Haggstrom AN, Beaumont JL, Lai J-S, et al. Measuring the severity of infantile hemangiomas: instrument development and reliability. Arch Dermatol. 2012;148(2):197-202.
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Original Investigation
Propranolol vs Prednisolone for Symptomatic Proliferating Infantile Hemangiomas A Randomized Clinical Trial Nancy M. Bauman, MD; Robert J. McCarter, ScD; Philip C. Guzzetta, MD; Jennifer J. Shin, MD, SM; Albert K. Oh, MD; Diego A. Preciado, MD, PhD; Jianping He, MS; Elizabeth Anne Greene, MD; Katherine B. Puttgen, MD
IMPORTANCE While propranolol is touted as superior to prednisolone for treating infantile
hemangiomas (IH), a randomized clinical trial (RCT) comparing the outcome and tolerability of these medications for symptomatic, proliferating IH has not been reported. OBJECTIVES To determine if oral propranolol is more efficacious and better tolerated than prednisolone in treating symptomatic, proliferating IH and to determine the feasibility of conducting a multi-institutional, RCT comparing efficacy and tolerability of both medications. DESIGN, SETTING, AND PARTICIPANTS Phase 2, investigator-blinded, multi-institutional RCT conducted in 3 academic vascular anomalies clinics on 19 of 44 eligible infants aged between 2 weeks and 6 months. All participating patients had symptomatic proliferating IH treated between September 1, 2010, and August 1, 2012. INTERVENTIONS Treatment with oral propranolol vs prednisolone (2.0 mg/kg/d) until halted
owing to toxic effects or clinical response. MAIN OUTCOMES AND MEASURES Primary outcome was change in IH size after 4 months of therapy. Secondary outcomes were response rate and frequency and severity of adverse events (AEs). RESULTS The primary outcome showed no difference in lesion size or affected skin area after 4 months of therapy: 41% and 1.32 mm2 for prednisolone vs 64% and 0.55 mm2 for propranolol (P = .12 for lesion size, and P = .56 for affected skin area). Longitudinal analyses showed a faster response in total lesion outer dimension with prednisolone (P = .03), but this advantage over time was not noted when central clearing and outer dimension were included in the analysis (P = .91). The overall frequency of AEs was similar (44 for prednisolone vs 32 for propranolol) (P = .84), but prednisolone-treated participants had more grade 3 severe AEs (11 vs 1) (P = .01), particularly growth retardation resulting in size and weight below the fifth percentile. Early study withdrawal owing to AEs occurred in 6 (75%) of 8 patients in the prednisolone group but 0 of 11 propranolol-treated participants. The mean duration of therapy was shorter for prednisolone (141 vs 265 days), reflecting the higher rate of early withdrawals. CONCLUSIONS AND RELEVANCE Both medications show similar efficacy for reducing the area of symptomatic, proliferating IH. Although prednisolone showed a faster response rate, propranolol was better tolerated with significantly fewer severe AEs. Propranolol should be the first line of therapy for symptomatic IH unless contraindicated or unless future studies demonstrate severe AEs from propranolol. Recruiting participants for a phase 3 RCT would be difficult owing to safety profiles measured here and emerging trends favoring propranolol. TRIAL REGISTRATION clinicaltrials.gov identifier: NCT00967226
JAMA Otolaryngol Head Neck Surg. doi:10.1001/jamaoto.2013.6723 Published online February 13, 2014.
Author Affiliations: Department of Otolaryngology, Children’s National Medical Center, Washington, DC (Bauman, Preciado); Department of Biostatistics, Children’s National Medical Center, Washington, DC (McCarter, He); Department of General Surgery, Children’s National Medical Center, Washington, DC (Guzzetta); Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts (Shin); Department of Plastic Surgery, Children’s National Medical Center, Washington, DC (Oh); Department of Cardiology, Children’s National Medical Center, Washington, DC (Greene); Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, Maryland (Puttgen). Corresponding Author: Nancy M. Bauman, MD, Department of Otolaryngology, Children’s National Medical Center, 111 Michigan Ave NW, Washington DC 20010 ([email protected]).
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Research Original Investigation
Propranolol vs Prednisolone for Infantile Hemangiomas
I
nfantile hemangiomas (IH) are the most common benign tumors of infancy, arising in 4% of live births.1,2 While IH exhibit a characteristic growth pattern of proliferation and subsequent involution during the first decade of life, 12% of lesions require consideration of therapy during infancy for indications including ulceration, bleeding, impairment of sensory organ function, airway compromise, and risk of permanent deformity in cosmetically sensitive regions.3,4 Subsequent to the recent serendipitous discovery of propranolol’s effects on symptomatic IH, 5 the nonselective β-blocker may be supplanting systemic corticosteroids as the initial therapy of choice. Since there are no drugs for IH approved by the US Food and Drug Administration, both medications are used as off-label treatments, and their perceived efficacy and tolerability stems from observational studies and expert opinion. To our knowledge, the present multiinstitutional, phase 2, randomized clinical trial (RCT) is the first to evaluate the performance of propranolol vs prednisolone in terms of (1) IH response, (2) medication tolerability, and (3) feasibility of conducting a phase 3 trial.
Methods Study Participants Written consent for study participation was obtained from all patients’ parents or guardians during the clinic evaluation. The study was reviewed by the Data Safety Monitoring Board (DSMB) quarterly, registered w ith clinic altrials.gov (NCT00967226), and approved by institutional review boards of the Children’s National Medical Center (CNMC) (No. 0000467), University of Iowa (UIHC) (No. 201004770), and Johns Hopkins Hospital (JHH) (No. NA_00049604). All consecutive eligible infants aged 2 weeks to 6 months with actively proliferating and symptomatic IH evaluated in the outpatient vascular anomalies clinics of the study institutions were invited to participate without sexual or racial restriction. Lesions were considered symptomatic if they impaired function (including breathing, eating, vision, and hearing), were ulcerated, caused pain, or were in cosmetically sensitive regions. Exclusion criteria included inadequate social support, nonproliferating IH, other treatment for IH, liver disease, abnormal blood glucose level (BG), hypertension, hypotension, reactive airway disease, cardiac anomalies, and PHACE (posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities)6,7 if significantly narrowed intracranial vasculature was present. Intake history included demographic data, IH characteristics, and medical history. Participants self- reported race and ethnicity. A complete physical examination was completed, including evaluation of vital signs and nonfasting BG. Hypoglycemia was defined as BG lower than 70 mg/dL. Imaging studies were completed only when necessary to confirm diagnosis, determine IH extent, or evaluate for PHACE.6,7 Participants with stridor or beard distribution of IH underwent airway endoscopy to exclude subglottic hemangiomas. Liver ultrasonography was performed for participants with 4 or more hemangiomas. E2
Study Design and Interventions This multi-institution, single-blind, placebo-controlled RCT targeted enrolling 55 participants per group to achieve 80% power to detect a 30% absolute reduction in lesion size between groups assuming the smallest reduction was at least 50%. Consenting participants were randomized to prednisolone or propranolol using a CNMC institutional tamper-proof, pregenerated encrypted schedule, which allocated equal assignments to both treatments within institutions and within lesions affecting and not affecting vision. Medications were dispensed free of charge. No stipend was provided. At enrollment, the blinded investigators assigned a number to each of the IH corresponding to 1 of 76 unique body segments 8 and recorded the following established parameters of the IH8: type (superficial, deep, or mixed), presence of ulceration, total area (product of transverse and longitudinal measurements in square millimeters), degree of normal intervening skin (deep lesions, none; superficial and mixed lesions, 75%-100%, 50%-74%, 25%-49%, 10%-24%, or .11) (Table 2). Longitudinal Analysis of TSA The longitudinal analysis of the impact of treatment group on TSA showed that the rate of decline was statistically significantly faster in the prednisolone group (P = .04) (Figure 2A). When baseline TSA was taken into account (by adjusting for the larger baseline TSA in the propranolol group at the outset), results were similarly significant (P = .03) (Figure 2B). When individual month intervals were examined with the model as a predictor, no significant differences were noted at the individual month timeframes in both the univariate and the adjusted analysis. Longitudinal Analysis of AdjTSA The AdjTSA response over time was similar in both groups in both the unadjusted baseline (P = .20) and adjusted baseline analysis (P = .91) (Figure 3) Sensitivity Analysis When excluding the data from the 2 noncompliant patients, there was still no difference between adjTSA (P = .12) or TSA (P = .57) in the primary analysis, and longitudinal unadjusted and adjusted analyses were consistent with the intention-totreat analysis. Duration of Therapy (Excluding Early Withdrawals) For participants concluding the study (2 [25%] of 8 in the prednisolone group and 9 [82%] of 11 in the propranolol group), the mean time in days from start to finish of therapy was 323 (95% CI, 223-423) for propranolol and 300 for prednisolone (95% CI, 0-643). Regrowth after medication weaning was noted in 2 propranolol-treated participants and 1 prednisolone-treated participant, all of whom responded to resuming treatment with their respective medications.
3. Adverse Events There were more early withdrawals due to medicationrelated concerns in the prednisolone group than in the propranolol group (6:1) (P = .01). Adverse events were the cause E4
Early withdrawal Prednisolone 5 AE 1 LP Deferred Propranolol 1 Adjuvant 1 Noncompliant
Study enrollment at Children’s National Medical Center (CNMC), University of Iowa (UIHC), and Johns Hopkins Hospital (JHH). AE indicates adverse event; tx, treatment; LP, local physician.
of study withdrawal in none of the propranolol participants but in 5 of 6 of the prednisolone participants, either at the request of the primary care physician (owing to growth concerns; n = 4) or the request of the parents (owing to marked flushing and sweating that stopped with prednisolone treatment cessation; n = 1) (Table 3). Despite the absence of AEs, another prednisolone participant withdrew at the recommendations of his pediatrician and ophthalmologist, who counseled the parents that their infant should be treated with propranolol. A single propranolol-treated participant withdrew from the study, even though her lesion was regressing markedly after 5 months of therapy, because the parents requested laser treatment of telangiectasias. This necessitated study withdrawal because alternative treatment was a study exclusion criterion. Another propranolol participant expressed regrets about being in the study and withdrew immediately after enrollment but requested propranolol treatment outside the study. The frequency of all AEs was similar in the prednisolone and propranolol groups (44 vs 32) (P > .84), but severe AEs (CTCAE grade 3) occurred more frequently in prednisolone participants (11 vs 1) (P = .01) (Table 3). Nine of the severe AEs in prednisolone participants were related to decline in linear growth and/or weight to less than 5% of the standardized growth curve measures and greater than 50% from participant’s pretherapy measures. The remaining severe AEs were due to adrenal crisis associated with viral gastroenteritis (n = 1) and severe dehydration warranting hospitalization (n = 1). The severe AE in the propranolol participant was dehydration warranting hospitalization. No propranolol-treated participant experienced significant decline in growth or weight. Propranolol participants had significantly more pulmonary symptoms than prednisolone participants (14 vs 5) (P < .001), predominantly upper respiratory tract infections (URTIs) (Table 3). The number of vascular AEs was comparable but reflected BP increases in prednisolone participants and BP decreases in propranolol participants. All vascular changes were asymptomatic and resolved spontaneously. One propranolol participant developed asymptomatic hypoglycemia after the first dose of propranolol (64 mg/dL). Per protocol, the next dose of propranolol was skipped, and BG remained above 70 mg/dL for subsequent doses.
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Propranolol vs Prednisolone for Infantile Hemangiomas
Original Investigation Research
Table 1. Baseline Demographic and Clinical Characteristics of Participants as Randomizeda Characteristic
Prednisolone
Total, No. (%)
8 (100)
Discussion Propranolol 11 (100)
Sex, No. (%) Female
6 (75.0)
8 (72.7)
Male
2 (25.0)
3 (27.3)
White
6 (75.0)
9 (81.8)
Black
2 (25.0)
1 (9.1)
Asian
0
1 (9.1)
5 (62.5)
5 (45.5)
Color, No. (%)
Ethnicity, No. (%) Hispanic Non-Hispanic Enrollment age, mean (95% CI), mo
3 (37.5)
6 (54.5)
4.0 (2.8-5.2)
2.5 (1.7-3.4)
Lesion site Periorbital
3 (37.5)
1 (9.1)
Cheek
2 (25.0)
0
Nasal tip
2 (25.0)
1 (9.1)
Ear
0
2 (18.2)
Lip
0
2 (18.2)
Beard
1 (12.5)
1 (9.1)
Frontotemporal
0
1 (9.1)
Breast
0
1 (9.1)
Forehead
0
1 (9.1)
None
7 (87.5)
9 (81.8)
Mild (50%)
1 (12.5)
1 (9.1)
Local
8 (100)
6 (54.5)
Segmental
0
3 (27.3)
Intermediate
0
2 (18.2)
Ulceration
Morphology
Depth Superficial
2 (25.0)
3 (27.3)
Deep
2 (25.0)
2 (18.2)
Mixed
4 (50.0)
6 (54.5)
Lesion size, median (95% CI), cm2 By outer margins (TSA)
3.1 (0.8-10.5)
5.0 (1.9-25.6)
Adjusted for normal skin (AdjTSA)
2.5 (0.2-9.4)
5.0 (1.5-24.3)
Abbreviations: AdjTSA, adjusted total surface area; TSA, total surface area. a
Unless otherwise noted, data are reported as number (percentage) of participants.
To our knowledge, the present study is the only phase 2 RCT to compare efficacy, in terms of reduction of IH size, as well as tolerability of propranolol vs prednisolone for treatment of symptomatic IH. Dramatic responses were seen with both medications (Figure 4). Study strengths include the rigorous adherence to enrolling only proliferating IH and the high rate of compliance, with fewer than 10% of missed monthly appointments. Since initiation of this study, propranolol has quickly become the first line of therapy for symptomatic IH,11 even in the absence of data comparing it with the historic standard of prednisolone. Completing a similar study on a larger scale may no longer be feasible or desirable, given the findings of the present series showing fewer severe AEs with propranolol. Propranolol’s rapid rise in popularity is remarkable.5 In September 2010, only 6 series described its use in 10 or more patients/series,12 but by December 2011, the number of treated patients reported had grown to 1200.13,14 Reports of propranolol’s efficacy quickly disseminated through the nonmedical community via the internet as well,12 and parents now present to our vascular anomalies clinic and request propranolol, should IH therapy be indicated. Enrollment of 19 participants instead of 55 was less than anticipated for several reasons. Patients often presented after the requisite period of active IH proliferation when prednisolone is considered most effective.15 Additionally, prior therapy was forbidden, so infants receiving any topical medications were ineligible. Most importantly, one of our collaborative institutions failed to recruit eligible participants during the entire first year of the study. It is now clear that the investigators from this institution had lost their point of equipoise and should not have agreed to participate in the study. The mounting evidence of propranolol’s efficacy made enrollment difficult for our second collaborative institution that joined the study 15 months after initiation. Although the low enrollment reduced the trial’s power to detect differences as originally designed, the randomization schedule prevented bias and still allowed the study to detect larger than anticipated differences. The high rate of dropout of prednisolonetreated participants owing to AEs occurred beyond the first third of the study and beyond the period when efficacy effect was established. Despite the limited enrollment and high dropout rate, the study provides evaluation of the relative effectiveness of the treatments superior to that of the uncontrolled observational case reports currently existing in the literature.
Table 2. Changes in IH Sizea From Baseline to 4 Months IH Parameter Change
Prednisolone
Propranolol
P Value
TSA, mean (95% CI)b
0.41 (0.10-0.72) (n = 4)
0.64 (0.44-0.83) (n = 8)
.12
TSA, mean (95% CI)c
0.63 (0.14-1.11) (n = 6)
0.57 (0.34-0.80) (n = 9)
.77
AdjTSA, median (25th-75th percentileb
1.32 (0.28-2.35) (n = 2)
0.55 (0.22-0.76) (n = 7)
.56
0.99 (0.28-1.93) (n = 4)
0.55 (0.22-0.76) (n = 7)
.45
AdjTSA, median (25th-75th percentile)c
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Abbreviations: AdjTSA, adjusted total surface area; IH, infantile hemangioma; TSA, total surface area. a
All size change is reported in square millimeters.
b
Data from 4 months only.
c
Data from 4 months with 5-month data allowed as a surrogate if the 4-month mark was missed.
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E5
Research Original Investigation
Propranolol vs Prednisolone for Infantile Hemangiomas
Figure 2. Longitudinal Analyses of Treatment Effects on Infantile Hemangioma (IH)
Figure 3. Longitudinal Analyses of Treatment Effects on Adjusted Surface Area of Infantile Hemangioma (IH), Including Central Clearing (AdjTSA) A
Prednisolone Propranolol
8 P =.04 6
4
2
0
–2
P =.20 5 4 3 2 1 0
–1 1
2
3
4
5
6
7
8
9
10
11
12
1
2
3
4
5
Time, mo Propranolol 10 Prednisolone 6
10 6
8 7
8 4
9 6
8 4
3 2
6
7
8
9
10
11
12
2 2
3 2
1 1
2 1
0 1
Time, mo 3 3
3 3
2 1
3 2
1 1
Propranolol 8 Prednisolone 4
B
8 4
6 5
7 2
7 4
7 2
2 1
B
4
Surface Area Adjusted, mm2
P =.03
Estimated Affected Skin Area, mm2
8 Prednisolone Propranolol
6
4
2
0
–2
P =.91
Prednisolone Propranolol
3
2
1
0 1
2
3
4
5
6
7
8
9
10
11
12
1
2
3
4
5
Time, mo Propranolol 10 Prednisolone 6
E6
Prednisolone Propranolol
6
Estimated Affected Skin Area, mm2
Surface Area by Outer Dimension, mm2
A
10 6
8 7
8 4
9 6
8 4
3 2
6
7
8
9
10
11
12
2 2
3 2
1 1
2 1
0 1
Time, mo 3 3
3 3
2 1
3 2
1 1
Propranolol 8 Prednisolone 4
8 4
6 5
7 2
7 4
7 2
2 1
A, Univariate longitudinal analysis of change in IH outer margin total surface area (TSA) over time when treated with prednisolone vs propranolol. B, Longitudinal analysis of change in the TSA adjusted for baseline size differences. The numbers below the x-axis represent the number of lesions measured at each follow-up visit in each of the 2 treatment groups.
A, Univariate longitudinal analysis of the change in the AdjTSA of IH over time when treated with prednisolone vs propranolol. B, Longitudinal analysis of the change in AdjTSA adjusted for baseline size differences. The numbers below the x-axis represent the number of lesions measured at each follow-up visit in each of the 2 treatment groups.
Caretakers were not blinded because we could not justify unnecessarily admitting prednisolone participants to initiate therapy or unnecessarily withholding live vaccines from propranolol participants. Furthermore, caretakers needed to know the medication assignment to ensure participant safety. As an illustration, parents of a propranolol participant with poor oral intake owing to a gastrointestinal viral illness should withhold propranolol to prevent hypoglycemia, but parents of a prednisolone participant with the same symptom should not withhold prednisolone and should even possibly increase stress steroid coverage. Both medications were efficacious in reducing IH TSA and AdjTSA; prednisolone showed a faster response rate than propranolol for TSA but not for AdjTSA. However, the need to stop treatment with prednisolone in 75% of participants owing to AEs offsets its potential advantage. It remains unclear if either medication offers an advantage in change in TSA or AdjTSA beyond 12 months. The significantly higher rate of severe AEs in prednisolone participants prompting early withdrawal was remarkable. The overall number of AEs was similar, but those in pro-
pranolol subjects were predominantly grade 1 or 2, while the AEs in prednisolone subjects were grade 3 due to severe growth retardation. Although growth retardation is a predictable and temporary AE of prednisolone treatment in infants, the remarkable incidence necessitating study withdrawal was striking. After extensive deliberation, our DSMB concluded that the high rate of severe drug-related AEs warranting study withdrawal in prednisolone subjects was not offset by sufficient treatment advantages and that further enrollment should halt. It is likely that pediatricians caring for patients with IH share the concerns of our DSMB regarding the severe, albeit reversible, AEs associated with prolonged corticosteroid use. The decision to halt enrollment based on a wellrecognized AE of prednisolone was difficult, since it prevented the full comparison of the efficacy of these 2 medications. Knowledge of outcome efficacy may prove useful in the future should life-threatening cardiovascular events from propranolol occur or concerns of propranolol irreversibly affecting memory retention in children be demonstrated.16 Such findings might tilt the treatment scale away from propranolol, since
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Propranolol vs Prednisolone for Infantile Hemangiomas
Original Investigation Research
Table 3. Frequency of Adverse Events by Group Propranolol (n = 11 Patients)
Adverse Event (CTCAE Code)
Prednisolone (n = 8 Patients)
P Value
Most Severe AE per Participant, No. (%) of Participants Severity Total
9 (90.0)
7 (87.5)
Mild
1 (10.0)
0 (0)
.87 >.99
Moderate
7 (70.0)
2 (25)
.08
Severe
1 (10.0)
5 (62.5)
.04
Type Allergy/immunology (1)
1 (6.3)
0
>.99
Dermatologic (9)
1 (6.3)
0
>.99
Endocrine (10)
0
1 (10.0)
Gastrointestinal (11)
3 (18.8)
1 (10.0)
.55
Growth and development (12)
0
5 (50.0)
.004
Infection (15)
2 (12.5)
1 (10.0)
.85
Metabolic/laboratory (17)
0
1 (10.0)
.39
Pulmonary/respiratory (22)
8 (50.0)
1 (10.0)
.06
Vascular (28)
1 (6.3)
0
.39
>.99
All AEs (Including Multiple AEs Per Person), No. (%) of IH Lesionsa Severity Total
32 (100)
44 (100)
.84
Mild
10 (21.4)
22 (50.0)
.20
Moderate
21 (65.6)
11 (25.0)
.09
1 (3.1)
11 (25.0)
.01
Severe Type Allergy/immunology (1)
1 (0.02)
1 (0.02)
.82
Constitutional (7)
2 (0.05)
4 (0.09)
.54
Dermatologic (9)
2 (0.05)
1 (0.02)
.37
Endocrine (10)
0 (0.00)
8 (0.18)
.02
Gastrointestinal (11)
5 (0.11)
Growth and development (12)
0
Infection (15)
5 (0.11)
4 (0.09)
.44
Metabolic/laboratory (17)
0
1 (0.02)
>.99
Pulmonary/respiratory (22) Vascular (28)
B
C
D
5 (0.11)
.001
3 (0.07)
4 (0.09)
.98
A, Pretreatment postauricular infantile hemangioma (IH). B, Marked response of postauricular IH to 10 months of propranolol therapy. C, Pretreatment IH of the lip and chin. D, Response of lip and chin IH to 11 months of prednisolone therapy.
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.74 .005
14 (0.32)
Figure 4. Hemangioma Response A
6 (0.14) 10 (0.23)
Abbreviations: AE, adverse events; CTCAE, Common Terminology Criteria for Adverse Events; IH, infantile hemangioma. a
P values are adjusted for the correlation between multiple events in the same participant.
severe growth restriction from prednisolone may be disturbing but is reversible.17 The favorable response profile of prednisolone is encouraging for patients with symptomatic IH and a contraindication to propranolol use. Notably, the rate of respiratory AEs, particularly URTIs, was higher in the propranolol-treated group. Larger studies will be required to determine if propranolol increases the risk or severity of URTIs. A major limitation of IH research has long been the lack of a validated objective method by which to measure growth and response to therapy. No such tool had been reported at the initiation of our study, but a recently described scale may prove useful for future IH studies.18 Clearly the most important remaining question of propranolol use is whether the medication merely hastens involution onset or actually improves the outcome of involution. This is particularly important because pharmacologic therapy with corticosteroids historically has been used only in symptomatic IH because of associated AEs, but the growing evidence of propranolol’s safety and efficacy is expanding its use JAMA Otolaryngology–Head & Neck Surgery Published online February 13, 2014
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Research Original Investigation
Propranolol vs Prednisolone for Infantile Hemangiomas
to even small, superficial facial lesions that may leave unsightly facial scars once involuted.13 Whether early initiation of propranolol treatment when an IH first presents as a macular, vascular blush prevents its growth into a raised, cosmetically deforming lesion also needs to be determined.
Conclusions The results of this RCT for treatment of symptomatic, proliferating IH show that prednisolone and propranolol showed no difference in the primary outcome of lesion area at 4 months
ARTICLE INFORMATION Submitted for Publication: September 20, 2013; final revision received November 8, 2013; accepted December 16, 2013. Published Online: February 13, 2014. doi:10.1001/jamaoto.2013.6723. Author Contributions: Drs Bauman and McCarter had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Bauman, McCarter, Guzzetta, Oh, Preciado, Puttgen. Acquisition of data: Bauman, Guzzetta, Oh, Greene, Puttgen. Analysis and interpretation of data: McCarter, Shin, Oh, Preciado, He, Greene, Puttgen Drafting of the manuscript: Bauman, McCarter, Guzzetta, Shin, Puttgen. Critical revision of the manuscript for important intellectual content: Bauman, McCarter, Guzzetta, Shin, Oh, Preciado, He, Greene, Puttgen. Statistical analysis: Bauman, McCarter, Shin, He, Puttgen. Obtained funding: Bauman. Administrative, technical, and material support: Bauman, McCarter, Guzzetta, Oh, Preciado, Greene, Puttgen. Study supervision: Bauman, Guzzetta, Greene, Puttgen. Manuscript review: Guzzetta, Oh, Preciado, Greene. Conflict of Interest Disclosures: Drs Bauman, McCarter, and Puttgen received modest salary support from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, and from the National Center for Research Resources of the National Institutes of Health to complete the study. Dr Shin receives book royalties from Springer Publishing and Plural Publishing for Evidence-Based Otolaryngology and Otolaryngology Prep and Practice, respectively. No other disclosures were reported. Funding/Support: Work for the research reported in this publication was supported by grant R21HD062959-02 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, and by grant UL1RR031988 from the National Center for Research Resources of the National Institutes of Health. Role of the Sponsor: The financial support was used for design and conduct of the study, study medications, and collection, interpretation and analysis of the data, but the sponsors themselves
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but that prednisolone may result in a faster rate of involution of a lesion’s outer margin over time. Propranolol, however, is better tolerated than prednisolone, with significantly fewer severe AEs leading to drug-related withdrawals. Based on similar efficacy between medications but the higher rate of severe AEs with prednisolone therapy, propranolol should be considered the first line of therapy for symptomatic IH if contraindications to its use do not exist. Further studies are necessary to determine whether there are additional, undemonstrated long-term AEs associated with propranolol use and if propranolol merely hastens the involution process or changes ultimate outcome.
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. Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional Contributions: The authors acknowledge the support of Ed Connor, MD, PriyaVaidyanathan, MD, and Marlene Lee, RN, who served on the DSMB; Jennifer Gode, RN, who served as clinical nurse coordinator for a portion of the study; Margie Brown, who assisted with manuscript preparation; and the study participants and their parents. Correction: This article was corrected on March 11, 2014, to fix a value in Figure 1. REFERENCES
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