Source: Pope E, Lara-Corrales I, Sibbald C, et al. Noninferiority and safety of nadolol vs propranolol in infants with infantile hemangioma: a randomized clinical trial. JAMA Pediatr. 2022;176(1):34-41; doi:10.1001/jamapediatrics.2021.4565Investigators from multiple institutions conducted a blinded randomized trial to compare the effectiveness and safety of nadolol and propranolol for treatment of children with infantile hemangioma (IH). Study participants were enrolled at 2 academic pediatric dermatology clinics in Canada and included infants with a corrected gestational age of 1-6 months who had a facial IH >1.5 cm or IH ≥3 cm on other parts of the body with the potential to cause functional impairment or cosmetic disfigurement. At enrollment, study patients were randomized to receive oral nadolol or propranolol. Infants in both groups were begun on 0.5 mg/kg/day, with the dose increased to a maximum of 2.0 mg/kg/d. Participants were enrolled for up to 52 weeks. At study visits, investigators, blinded to treatment group, assessed change from baseline in IH bulk and color using 100 mm visual analogue scales (VAS) that had previously been validated, with VAS scores ranging from -100, indicating increase in bulk or persistent dis-coloration, to +100, indicating complete resolution or normal skin color. The primary outcome was change in VAS scores for bulk and color at 24 weeks. A priori, it was determined that nadolol was non-inferior to propranolol if the difference in bulk and color VAS scores between groups was >-10 units. T-tests were used to compare scores between groups. Cox regression was used to compare rates of achieving 75% and 100% shrinkage of IH among children in the 2 treatment groups. Parents reported adverse events in their children, and decreases in blood pressure and blood glucose levels were assessed at study visits.Data were analyzed on 71 patients, including 35 receiving nadolol and 36 randomized to propranolol. The mean age at enrollment was 3.2 months for those in the nadolol group and 3.1 months for infants receiving propranolol; 74% and 86%, respectively, of participants in the nadolol and propranolol groups were female. At 24 weeks, differences in VAS scores for bulk and color between children in the 2 treatment groups were 8.8 units (95% CI, 2.7, 14.9) and 17.1 units (95% CI, 7.2, 30), both in favor of nadolol and meeting the non-inferiority criteria. Time to 100% involution was significantly shorter in infants receiving nadolol than in those receiving propranolol (hazard ratio [HR], 2.1; 95% CI, 1.2, 3.7); there was not a statistically significance between groups in time to 75% involution (HR, 1.6; 95% CI, 0.9, 2.6). Adverse events were similar in the 2 groups, with no serious adverse events related to study participation reported.The authors conclude that nadolol was non-inferior to propranolol for treatment of children with IH.Dr Dubik has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.IH is the most common vascular tumor of infancy, affecting 4.5% of neonates.1 Typically absent or barely evident at birth, IH arise during the first few weeks of life.2 Risk factors include: females, Caucasians, prematurity with low birth weight, and twins.2 80% of IH develop on the head and neck region.3 Although most regress spontaneously by age 4 years without complication, approximately 10% to 15% can cause significant functional or cosmetic sequelae and warrant treatment.4Historically, treatment of IH relied on corticosteroids or surgery.5 However, regression of IH with propranolol was serendipitously discovered in 2008, quickly became first-line therapy, and is the only FDA-approved treatment for complicated IH.5,6Propranolol, a lipophilic nonselective beta-adrenergic receptor antagonist, has a well-established safety profile. However, propranolol crosses the blood-brain barrier and can cause CNS effects, such as disturbances of sleep.6 Like propranolol, nadolol is a non-selective beta-blocker, but nadolol is less lipophilic and less likely to cause CNS side effects.Use of nadolol was first reported in a small retrospective study in 2013.7 Similar to the results of a recent study of atenolol for IH, the results of the current investigation indicate that the effectiveness of nadolol is at least non-inferior to propranolol. (See AAP Grand Rounds. 2021;46[1]:6.)8The COVID-19 pandemic slowed down recruitment, and this study was concluded early, just shy of the 78 patients needed to adequately power it. However, the authors argue that further recruitment likely would not have affected the results.For the treatment of IH, nadolol appears to be at least as effective as propranolol.Although the theoretical pharmacokinetic superiority of nadolol (vs propranolol) was not borne out in the current study in terms of a reduction in adverse events, we await the results of a larger (post COVID-19?) trial. Regardless of drug choice, therapy is best restricted to the minority of infants with IH-associated impaired vision, respiration, and hearing, and those with ulcerated or disfiguring lesions and platelet consumption.4
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May 25, 2023
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