Propranolol 3 mg/kg/day for 6 Months May Increase Hemangioma Resolution in Infants with Proliferating Infantile Hemangioma
EBM Focus - Volume 10, Issue 8
Infantile hemangiomas are benign vascular tumors that occur in 1-10% of infants and usually appear between 1-8 weeks after birth (Paediatr Perinat Epidemiol 2008 Nov;22(6):520, Paediatr Perinat Epidemiol 2012 Mar;26(2):156, Br J Dermatol 2014 Apr;170(4):907). Though the majority of infantile hemangiomas ultimately involute and do not require treatment, some proliferating hemangiomas require systemic therapy (Semin Pediatr Surg. 2014 Aug;23(4):162-7). Several case series and small randomized trials have suggested that the beta-blocker propranolol may inhibit hemangioma growth (Pediatrics 2011 Aug;128(2):e259, Br J Dermatol 2013 Jul;169(1):181, J Pediatr Surg 2012 Apr;47(4):707) and cohort studies have found propranolol to be more effective than systematic corticosteroids (Ann Plast Surg 2015 Feb;74(2):237, Pediatr Dermatol 2011 Nov-Dec;28(6):649). Although propanolol has been used more frequently based on these studies, strong evidence supporting its use from a large randomized trial is lacking. A recent randomized trial compared oral propranolol vs. placebo for 6 months in 460 infants aged 1-5 months with proliferating hemangiomas. To determine the most effective propranolol treatment regimen, infants were randomized to 1 of 4 propranolol regimens or placebo, with propranolol regimens including 1 mg/kg/day for 3 months then placebo for 3 months, 3 mg/kg/day for 3 months then placebo for 3 months, 1 mg/kg/day for 6 months, and 3 mg/kg/day for 6 months.
Overall, 29% of infants withdrew from the study, mostly due to a lack of efficacy. The randomized treatment group significantly influenced the discontinuation rate, with 65% of infants in the placebo group, 36% of infants in the 3-month propranolol groups, and 14% of infants in the 6-month propranolol groups withdrawing before 24 weeks. A prespecified interim analysis was performed when 188 patients (including dropouts) reached the 24 week time point to determine which regimen had the highest success rate and would be included in the final efficacy analysis of a single propranolol regimen vs. placebo. Dose and duration of propranolol was significantly associated with treatment success (defined as complete or nearly complete resolution of the target hemangioma) at interim analysis. Treatment success occurred in 38% with propranolol 1 mg/kg/day for 6 months (p = 0.004 vs. placebo) and 63% with propranolol 3 mg/kg/day for 6 months (p < 0.001 vs. placebo) compared to 8% with placebo at interim analysis. There were no significant differences comparing 3-month propranolol treatments vs. placebo. In the 24 week efficacy analysis comparing 3 mg/kg/day propranolol for 6 months vs. placebo, treatment success occurred in 60% vs. 4% (p < 0.001, NNT 2). This propranolol regimen was also associated with an increased rate of improvement at 5 weeks (88% vs. 5%, p < 0.001, NNT 2). There were no significant differences in serious adverse events or adverse events during treatment among all groups.
This trial suggests that propranolol 3 mg/kg/day for 6 months may be effective for resolving hemangiomas in infants with proliferating hemangiomas requiring treatment. Although propranolol treatment was associated with a slightly higher rate of adverse events, such as diarrhea, sleep disorders, and bronchitis, this increase was not significant and adverse events due to important known propranolol associated risks (hypoglycemia, hypotension, bradycardia, and bronchospasm) were rare in all groups. These results support the use of propranolol as first-line therapy for infantile hemangiomas.