Evaluating the Safety of Oral Propranolol Therapy in Patients With PHACE Syndrome

Key Points

Question

Is oral propranolol safe to use for the treatment of infantile hemangioma in patients with PHACE (posterior fossa malformations, hemangioma, arterial anomalies, cardiac defects, eye anomalies) syndrome?

Findings

This multicenter cohort study describes the use of oral propranolol in 76 infants with PHACE syndrome with no reports of serious adverse events. There was no significant difference in the rate of serious adverse events between patients with PHACE syndrome and patients without PHACE syndrome who received oral propranolol for infantile hemangioma.

Meaning

These data support the safety of oral propranolol in patients with PHACE syndrome.

Abstract

Importance

Oral propranolol is widely considered to be first-line therapy for complicated infantile hemangioma, but its use in patients with PHACE (posterior fossa malformations, hemangioma, arterial anomalies, cardiac defects, eye anomalies) syndrome has been debated owing to concerns that the cardiovascular effects of the drug may increase the risk for arterial ischemic stroke.

Objective

To assess the incidence of adverse events among patients with PHACE syndrome receiving oral propranolol for infantile hemangioma.

Design, Setting, and Participants

This multicenter retrospective cohort study assessed the incidence of adverse events among 76 patients with PHACE syndrome receiving oral propranolol for infantile hemangioma at 11 tertiary care, academic pediatric dermatology practices. Medical records from January 1, 2010, through April 25, 2017, were reviewed.

Exposures

Patients received oral propranolol, 0.3 mg/kg/dose or more.

Main Outcomes and Measures

The main outcome was the rate and severity of adverse events occurring throughout the course of treatment with oral propranolol, as documented in the medical records. Adverse events were graded from 1 to 5 using a scale derived from the Common Terminology Criteria for Adverse Events and were considered to be serious if they were grade 3 or higher.

Results

A total of 76 patients (59 girls and 17 boys; median age at propranolol initiation, 56 days [range, 0-396 days]) met the inclusion criteria. There were no reports of serious adverse events (ie, stroke, transient ischemic attack, or cardiovascular events) during treatment with oral propranolol. A total of 46 nonserious adverse events were reported among 29 patients (38.2%); the most commonly reported nonserious adverse events were sleep disturbances and minor gastrointestinal tract and respiratory tract symptoms. In a comparison with 726 infants who received oral propranolol for hemangioma but did not meet criteria for PHACE syndrome, there was no significant difference in the rate of serious adverse events experienced during treatment (0 of 76 patients with PHACE syndrome and 3 of 726 patients without PHACE syndrome [0.4%]).

Conclusions and Relevance

This study found that oral propranolol was used to treat infantile hemangioma in 76 patients with PHACE syndrome and that no serious adverse events were experienced. These data provide support for the safety of oral propranolol in this patient population.

This cohort study assesses the incidence of adverse events among patients with PHACE (posterior fossa malformations, hemangioma, arterial anomalies, cardiac defects, eye anomalies) syndrome receiving oral propranolol for infantile hemangioma.

Introduction

PHACE is the acronym used to desribe the association of an infantile hemangioma with posterior fossa malformations, arterial anomalies, cardiac defects or aortic coarctation, and eye anomalies. Anomalies of the cervical and/or cerebral vasculature are common (91%) and may rarely lead to arterial ischemic stroke.¹ Oral propranolol is the widely accepted first-line agent for the treatment of complicated infantile hemangioma,^2,3 but its use in PHACE syndrome was initially debated owing to concerns that systemic β-blockade could further increase the risk of stroke. However, patients with PHACE syndrome often present with large, rapidly proliferating infantile hemangiomas that necessitate aggressive treatment. In response to the increasing clinical use of oral propranolol in PHACE syndrome, we initiated this investigation to better characterize the drug’s safety for this rare population.

Methods

This multicenter retrospective cohort study assessed the incidence of adverse events (AEs) among 76 patients with PHACE syndrome receiving oral propranolol for infantile hemangioma at 11 tertiary care, academic pediatric dermatology practices. Medical records from January 1, 2010, through April 25, 2017, were reviewed. Patients with a diagnosis of definite PHACE syndrome⁴ were included in the study if they initiated oral propranolol before 2 years of age and received 0.3 mg/kg/dose or more for a minimum of 4 weeks. Patients were excluded if their treatment with propranolol had previously been reported, or if information on AEs was unavailable. Institutional review board approval was obtained to review medical records from 11 academic pediatric dermatology practices: Children’s Hospital of Wisconsin, Lurie Children’s Hospital of Chicago, Centre Hospitalier Universitaire Sainte-Justine, University of California San Francisco Benioff Children’s Hospital, Columbia University, Children’s Mercy Hospital, Boston Children’s Hospital, Mayo Clinic, John Hopkins All Children’s Hospital, Seattle Children’s Hospital, and Hospital de la Santa Creu i Sant Pau. Parental consent was waived as the data in the study were deidentified.

Data on demographic characteristics, PHACE syndrome phenotype, stroke risk,⁴ concurrent medications, dose and duration of propranolol, and AEs occurring during therapy were recorded in a REDCap (Research Electronic Data Capture) database. Data on AEs were collected from medical records (typically documented by the treating physician in ambulatory encounters), urgent care visits, and inpatient progress notes. The severity of each AE was determined using a 1 to 5 scale (where 1 indicates a mild or asymptomatic event that does not require intervention and 5 indicates an event that results in death) adapted from Common Terminology Criteria for Adverse Events, version 5 (eTable in the Supplement).⁵ Adverse events were considered to be serious if they were grade 3 or higher.

The primary outcome measure was the rate of AEs. Secondary outcome measures included the associations between stroke risk, propranolol dose and duration, and concomitant medications. Statistical analysis was performed using χ² tests, with P < .05 considered to be statistically significant.

To better contextualize the safety of propranolol use in patients with PHACE syndrome, the rate of AEs among patients with PHACE syndrome was compared with the rate of AEs among patients who received propranolol for infantile hemangioma but did not meet the diagnostic criteria for PHACE syndrome.⁶ Contemporaneous data were collected with identical inclusion criteria from the same institutions, allowing for a relative risk comparison between patients with PHACE syndrome and those without PHACE syndrome.

Results

Patients with PHACE syndrome were enrolled at 11 sites, with a mean of 7 (range, 2-22) patients per site (Table 1). Of the 76 patients who met the inclusion criteria, 12 (16%) were categorized as high risk for stroke and 33 (43%) were categorized as intermediate risk for stroke. Anomalies of major cervical and cerebral vessels were observed in 62 patients (82%). Aortic arch abnormalities (including aortic coarctation) were observed in 16 patients (21%). Most patients initiated treatment in an inpatient setting (50 [66%]) with the 20 mg/5 mL solution (61 [80%]) divided initially into 3 times daily dosing (65 [86%]).

Table 1. Characteristics of Study Patients.

Characteristic	Patients With PHACE Syndrome (n = 76)	Patients Without PHACE Syndrome (n = 726)
Demographics, No. (%)
Female	59 (77.6)	516 (71.1)
Gestational age at delivery, median (range), wk	39 (27-42)	39 (24-42)
Indication for treatment with propranolol, No. (%)
Risk of disfigurement	57 (75.0)	551 (75.9)
Vision threatening	48 (63.2)	182 (25.1)
Ulceration	23 (30.3)	152 (20.9)
Airway infantile hemangioma	13 (17.1)	26 (3.6)
Feeding difficulty	2 (2.6)	39 (5.4)
Unknown or other	5 (6.6)	67 (9.2)
Concurrent hemangioma treatment, No. (%)
Corticosteroids, oral	24 (31.6)	10 (1.4)
Timolol, topical	12 (15.8)	37 (5.1)
Corticosteroids, topical	10 (13.2)	4 (0.6)
Corticosteroids, intralesional	2 (2.6)	0
Vincristine	2 (2.6)	0
Age at propranolol initiation, median (range), d	56 (0-396)	113 (0-694)
Weight at propranolol initiation, median (range), kg	5.0 (2.1-9.5)	6.0 (2.0-15.0)
Maximum propranolol dose, median (range), mg/kg/d	2.0 (1.0-3.0)	Unavailable
Length of treatment, median (range), wk	71 (18-186)	Unavailable

Abbreviation: PHACE, posterior fossa malformations, hemangioma, arterial anomalies, cardiac defects, and eye anomalies.

There were no reports of serious AEs during propranolol treatment, including stroke, transient ischemic attack, or cardiovascular events. Twenty-nine patients (38%) reported a total of 46 nonserious AEs (Table 2),⁶ none of which resulted in discontinuation of propranolol. Rare episodes of asymptomatic hypoglycemia (1 patient), bradycardia (1 patient), and hypotension (3 patients) were discovered incidentally after drug initiation, but all events were less than grade 3 and did not require intervention. The parents of 2 patients reported that their children experienced seizure-like activity without loss of consciousness, but evidence of seizure was not corroborated by an electroencephalogram. The most common nonserious AEs were sleep disturbance, gastrointestinal tract symptoms, and respiratory tract symptoms.

Table 2. Comparing the Rates of Adverse Events Between Patients With PHACE Syndrome and Patients Without PHACE.

Adverse Event	Patients, No. (%)
	With PHACE Syndrome (n = 76)	Without PHACE Syndrome (n = 726)
Grade 1
Sleep disturbance	13 (17.1)	55 (7.6)
Gastrointestinal tract	7 (9.2)	8 (1.1)
Respiratory tract	4 (5.3)	9 (1.2)
Cold extremities	4 (5.3)	47 (6.5)
Hypotension	3 (3.9)	4 (0.6)
Seizure	2 (2.6)	0
Bradycardia	1 (1.3)	1 (0.1)
Hypoglycemia	1 (1.3)	2 (0.3)
Other	1 (1.3)	11 (1.5)
Grade 2
Respiratory	4 (5.3)	15 (2.1)
Gastrointestinal	3 (3.9)	11 (1.5)
Sleep disturbance	2 (2.6)	23 (3.2)
Other	1 (1.3)	11 (1.5)
Grade 3 (serious adverse events)	0	3 (0.4)a

Abbreviation: PHACE, posterior fossa malformations, hemangioma, arterial anomalies, cardiac defects, and eye anomalies.

^aSerious adverse events among patients without PHACE syndrome included 1 grade 3 respiratory event and 2 grade 3 hypoglycemic events.

Of the 29 patients who reported a nonserious AE, 6 (21%) were categorized as high risk for stroke, 10 (34%) were categorized as intermediate risk for stroke, and 13 (45%) were categorized as low risk for stroke. There was no significant association between the rate of AEs and stroke risk stratification (6 of 12 [50%] for patients at high risk vs 10 of 33 [30%] for patients at intermediate risk vs 13 of 31 [42%] for patients at low risk; P = .41). Experiencing an AE did not appear to be associated with a higher maximum dose of propranolol (median, 2.0 mg/kg/d for both groups; P = .81), length of treatment (median, 70 weeks for those who experienced an AE vs 71 weeks for those who had no AEs; P = .55), or concomitant use of oral corticosteroids (9 of 29 [31%] vs 15 of 47 [32%]; P > .99). The concomitant use of topical timolol did appear to increase the risk of an AE (odds ratio, 2.7 [95% CI, 0.76-9.41]); however, this difference did not reach statistical significance (7 of 29 [24%] vs 5 of 47 [11%]; P = .21).

Comparison With Patients Without PHACE Syndrome

Data were obtained for 726 patients who did not meet the criteria for PHACE syndrome but received propranolol for infantile hemangioma through a separate study (Table 1). Patients with PHACE syndrome experienced more nonserious, grade 1 AEs compared with the patients without PHACE syndrome (Table 2). However, there was no difference in the rate of serious, grade 3 AEs between patients with PHACE syndrome and those without PHACE syndrome (0% vs 3 [0.4%]).

Discussion

To our knowedge, this multicenter study of 76 patients comprises the largest cohort to date of patients with PHACE syndrome treated with propranolol. A comparison of this cohort with patients without PHACE syndrome revealed that those with PHACE syndrome experienced a higher rate of grade 1 AEs. Given that data on AEs were collected from medical records at follow-up visits, the higher rate of AEs among the PHACE syndrome cohort may be associated with the increased frequency of appointments and the closer monitoring that occurs in an inherently higher-risk population.

Although we report no incidence of stroke in this cohort, the severity of such an event warrants careful examination and a continued high index of suspicion. Stroke remains a rare and poorly understood complication of PHACE syndrome.⁷ Early apprehension regarding the use of propranolol in PHACE syndrome was rooted in theoretical concerns. Nonselective β-blockers could decrease cardiac output, reducing cerebral perfusion and resulting in watershed infarction distal to absent, stenosed, or occluded arteries lacking adequate collaterals. In reality, the determinants of infantile blood pressure and its association with perfusion are more complex. Several studies have demonstrated that propranolol decreases both heart rate and blood pressure, but the hemodynamic changes occurring at these doses are clinically insignificant and asymptomatic.^{6,8,9,10,11,12} Although it is difficult to provide evidence against an AE, to our knowledge, there has not yet been a published case of stroke in a patient with PHACE syndrome that is associated with propranolol use.¹³ Nevertheless, certain precautions can be undertaken to limit the AEs associated with propranolol.⁴ We believe that infants at risk for PHACE syndrome should undergo a physical examination and echocardiography prior to initiation of propranolol to rule out aortic arch coarctation. The lowest possible dose should be used, as should initial 3 times daily dosing to prevent large fluctuations in blood pressure. Concomitant use of topical timolol should be avoided because systemic absorption can occur, although the clinical significance of this finding is not yet well understood.¹⁴

Limitations

There are some limitations to our study. Retrospective studies tend to yield lower rates of AEs when compared with prospective studies, but it is unlikely that serious AEs (particularly stroke) are underreported in this study. As with many retrospective studies, there were variable lengths of follow-up, but our data appear to reflect all reported AEs at the time of publication.

Given the study design, patients requiring early discontinuation (<4 weeks) of propranolol therapy were not included in analysis. However, data from prospective studies did not suggest a high rate of early discontinuation.

Last, stroke and cardiovascular events are very rare among children, and our cohort may have been too small to detect these AEs. However, PHACE syndrome itself is a relatively rare disease, with less than 300 individuals currently enrolled in the PHACE Syndrome International Clinical Registry and Genetic Repository.

Conclusions

For 76 infants with PHACE syndrome, including 12 at high risk of stroke and 33 at intermediate risk of stroke, we report no serious AEs during treatment with oral propranolol. Larger prospective studies will be helpful in further characterizing the risks of oral propranolol in patients with PHACE syndrome.

Supplement.

eTable. Criteria for Grading Adverse Events, Adapted From the Common Terminology Criteria for Adverse Events (CTCAE)