Selectivity and the choice of beta-blockers for infantile hemangiomas

By Warren R. Heymann, MD
Sept. 11, 2017

Has there ever been a more radical change in therapy following a serendipitous discovery than the use of propranolol for infantile hemangiomas (IHs)? Since the landmark report of Léauté-Labrèze in 2008 (1), propranolol has rapidly become the first-line treatment for IHs;  nearly 800 papers detailing its use have been published since.

According to Léauté-Labrèze, the exact mechanisms of action of propranolol are incompletely understood; regulation of hemangioma cell proliferation may be effected via catecholamines or the VEGF pathway. (2)
 
The vast majority of IHs do not require treatment; however, up to 15% demonstrate complications such as obstruction, ulceration, or disfigurement, necessitating intervention. Even though propranolol is now the treatment of choice for IHs, adverse reactions may occur. The most common are sleep disorders, somnolence, and irritability. Others include bronchospasm, bronchiolitis, and asymptomatic hypotension. Rare, but potentially serious side effects include bradycardia, exposure of a previously undiagnosed atrioventricular block, and hypoglycemia.

A study of propranolol administered to 28 children with IHs (21 girls and 7 boys, mean age at onset of treatment: 8.8 months) focused on adverse reactions of the drug. All 28 patients had a good response. In two patients, systemic corticosteroid therapy was tapered successfully after propranolol was initiated. Propranolol was also an effective treatment for hemangiomas in 4 patients older than 1 year of age. Side effects that needed intervention and/or close monitoring were not dose dependent and included symptomatic hypoglycemia (n = 2; 1 patient also taking prednisone), hypotension (n = 16, of which 1 was symptomatic), and bronchial hyperreactivity (n = 3). Restless sleep (n = 8), constipation (n = 3) and cold extremities (n = 3) were observed. The authors concluded that propranolol appears to be an effective treatment option for IHs even in the nonproliferative phase and after the first year of life. Potentially harmful adverse effects include hypoglycemia, bronchospasm, and hypotension. (3)

In a letter in the same issue of JAAD, commenting on their study (detailed above), 2 patients who experienced severe adverse reactions to propranolol (bronchial hyperreactivity and sleep disturbances, respectively), were treated with atenolol instead. Compared to the lipophilic, nonselective beta-blocker propranolol, atenolol is a selective, hydrophilic, beta-1 antagonist. Atenolol is less likely to produce pulmonary side effects and does not cross the blood-brain barrier, thereby diminishing the risk of nightmares and hallucinations. The authors used an atenolol dose of 0.5 mg/kg per day for the first 7 days, followed by 1 mg/kg per day. Both patients had an excellent response to treatment. (4)

In subsequent study of atenolol for IHs, de Graaf et al assessed 30 consecutive patients with IHs treated with atenolol. The therapeutic effect was judged by clinical assessment and quantified by using a visual analogue scale (VAS) and the Haemangioma Activity Score (HAS). Side effects were also evaluated. The atenolol cohort was compared with a previously described cohort of 28 patients treated with propranolol (presumably those patients detailed in reference 3). Clinical involution was present in 90% (27/30) of the IH patients treated with atenolol. Mild side effects occurred in 40% (12/30) of these patients and severe side effects (hypotension) occurred in 3% (1/30). Quantitative improvement of the IHs in the atenolol group (n=27) showed no significant difference in either the VAS score or the HAS compared to the propranolol group (n=24). The authors concluded that atenolol is effective in the treatment of IH, similar to propranolol, but less frequently associated with severe side effects. They recommended randomized clinical trials to evaluate the efficacy and safety of atenolol treatment in IHs. (5)

In a randomized trial of 23 patients with IHs, 13 patients were treated with atenolol and 10 with propranolol. Patients treated with atenolol had a complete response of 53.8% compared to 60% with propranolol. These results were nonsignificant (P = .68). Relevant adverse events were not reported. The authors concluded that atenolol appears to be as effective as propranolol. (6)

Ji et al treated 70 patients IH who completed 24 weeks of treatment with atenolol. IH growth abruptly stopped for 93.4% of patients within the fourth week of treatment. In ulcerated IHs, complete healing of the ulcerations occurred in an average treatment time of 5.5 weeks. An “excellent” treatment response (compete or nearly complete resolution of the IH) was observed in 56.5% of patients at week 24. No significant hypoglycemia, bronchospasm, bradycardia, or hypotension occurred. The most common adverse event was diarrhea, followed by agitation and sleep disturbance.This study demonstrated that atenolol was effective and safe at a dose of 1 mg/kg per day for 24 weeks in the treatment of proliferating IHs. (7)

The most recent study involved 27 children with IHs treated with atenolol compared to a matched group of 53 children with IHs treated with propranolol. There was no statistically significant difference in pre- and posttreatment modified HAS scores between the two groups (p = 0.60). There was no significant difference in the overall rate of adverse effects (p = 0.10), although 11% of patients treated with propranolol experienced reactive airway symptoms, whereas this was not seen in any of the patients treated with atenolol. This study supported previous findings that atenolol is at least as effective as propranolol for treatment of IHs and poses less risk of bronchospasm. (8)

Should atenolol supplant propranolol for IHs? In my estimation, there is not enough data to warrant that — yet. I agree with the conclusion of Bayart et al who state that for patients with contraindications to propranolol therapy, or those who develop adverse effects, atenolol is the preferable agent. This is similar to the advice I give my daughters on choosing a mate — be selective and avoid those with adverse reactions.

1. Léauté-Labrèze C, et al. Propranolol for severe hemangiomas of infancy. N Engl J Med 2008; 358: 2649-51.
2. Léauté-Labrèze C, et al. Infantile hemangioma. Lancet 2017; 390: 85-94.
de Graaf M, et al. Adverse effects of propranolol when used in the treatment of hemangiomas: A case series of 28 infants. J Am Acad Dermatol 2011; 65: 320-7.
3. Raphaël MF, et al. Atenolol: A promising alternative to propranolol for the treatment of hemangiomas. J Am Acad Dermatol 2011; 65: 420-1.
4. de Graaf M, et al. Treatment of infantile haemangiomas with atenolol: Comparison with a historical propranolol group. J Plast Reconstr Aesthet Surg 2013; 66:1732-40.
5. Abarzūa-Araya A, et al. Atenolol versus propranolol for the treatment of infantile hemangiomas: A randomized controlled study. J Am Acad Dermatol 2014; 70: 1045-9.
6. Ji Y, et al. Oral atenolol therapy for proliferating infantile hemangioma: A prospective study. Medicine (Baltimore) 2016; 95(24) e3908.
7. Bayart CB, et al. Atenolol versus propranolol for treatment of infantile hemangiomas during the proliferative phase: A retrospective noninferiority study. Pediatr Dermatol 2017; 34: 413-21.

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