Propranolol equal to steroids in infantile hemangioma treatment

Propranolol was found comparable to steroids for efficacy and safety as a first-line treatment for infantile hemangioma, according to the results of a randomized clinical trial published in JAMA Dermatology.

The noninferiority study, which was conducted at a single academic hospital in the Republic of Korea, equally randomized 34 patients (15 boys, 19 girls, mean age 3.3 months) to one of the two treatment groups.

Patients in the propranolol group were admitted to the hospital, observed for adverse effects for three days after initiation of treatment of 2 mg/kg/d, and then released and treated as outpatients for the remainder of 16 weeks.

The steroid group received outpatient treatment from the beginning, also at 2 mg/kg/d for a total of 16 weeks. Hemangioma lesion volume was evaluated by magnetic resonance imaging (MRI). At 16 weeks, the treatment response rate was 95.65% for propranolol and 91.94% for steroid. There were also no safety differences between the two groups.

Hemangioma treatment

Prednisolone was first-line therapy for hemangiomas for many years before propranolol was recognized as a treatment for infantile hemangiomas, according to Kimberly Morel, M.D., an associate professor of dermatology and pediatrics at Columbia University Medical Center (CUMC), New York, who was not part of the study. 

“At the time the current study was initiated in 2013, clinicians were gaining experience with propranolol as a treatment option,” she says.

In fact, the first FDA-approved treatment for infantile hemangiomas, propranolol hydrochloride (Hemangeol, Pierre Fabre), was approved in March 2014, during the course of the study.

“What is surprising is that the methods in the study include an MRI to assess hemangioma volume before treatment and after therapy,” Dr. Morel says. “Although an objective measure, MRI is usually reserved for differentiating deep hemangiomas from other lesions under the skin surface, or for evaluating for central nervous system vascular abnormalities that may be seen in patients with segmental hemangiomas.”

In addition, hemangiomas are often treated for longer than 16 weeks, according to Dr. Morel. A randomized, controlled trial of oral propranolol for infantile hemangiomas in the New England Journal of Medicine in 2015 showed more effect on hemangiomas after six months of therapy compared to three months. Overall, 60% of just over 100 patients assigned to propranolol 3 mg/kg/d had complete or near complete resolution of their hemangioma at week 24. Therefore, “a longer treatment period in the current study may have detected a more significant difference between the groups.”

The authors of the current study note that 3 mg/kg/day of propranolol has been shown to be superior to 1 mg/kg/day. “However, in practice, hemangiomas often respond well to 2 mg/kg/day, so comparing to a higher dose may not have made a significant difference,” Dr. Morel says. 

NEXT:  Safety of propranolol

Safety of propranolol

To increase the safety of propranolol, Dr. Morel says that after the prescreening for cardiac disease and initial monitoring at the start of therapy, “parents need to understand to continue to feed frequently, as hypoglycemia may occur with prolonged fasting. In consultation with their provider, treatment is withheld when the patient is ill to minimize the risk of hypoglycemia, although patients with airway hemangiomas may need to remain on therapy with an alternate plan to avert hypoglycemia. Wheezing should also prompt an urgent evaluation, as bronchospasm is a contraindication to propranolol therapy.” 

Dr. Morel, a pediatric dermatologist at Morgan Stanley Children’s Hospital of New York-Presbyterian, says propranolol offers advantages to steroid in this patient population. “For instance, before propranolol was known to be effective for the treatment of hemangiomas, infants starting steroids would automatically need to be placed on three medications: prednisolone, trimethoprim-sulfamethoxazole to prevent PCP pneumonia, and ranitidine for gastrointestinal protection,” she says.

Moreover, any fevers would need to be promptly evaluated and treated, “given the risk of life-threatening infections while on steroids,” Dr. Morel says. 

Suppression of the hypothalamic-pituitary axis (HPA) was also a common side effect of prolonged prednisolone treatment. “Infants would require stress-dose steroids for illnesses and accidents for a period of time after therapy,” Dr. Morel says. “Immunization schedules would also be disrupted, as live virus vaccines cannot be given while on and for four weeks after steroid treatment. Routine immunizations given during steroid therapy may also need to be repeated.”

Risks from long-term steroids

Infants on long-term steroids are also at risk of hypertension and cardiomyopathy. A 2008 publication in the New England Journal of Medicine reported two patients with cardiac complications on steroids that were subsequently treated with propranolol, “actually led to the observation of the beneficial effect of propranolol on infantile hemangiomas,” Dr. Morel says.

In the current study, all patients started on propranolol were admitted to the hospital for three days. “Today, unless there are risk factors, the majority of patients are started on propranolol with a two-hour period of monitoring in the outpatient office,” Dr. Morel says. 

Dr. Morel says the strength of the study was that it was performed in a randomized fashion. An obvious limitation was the small size of the small study. 

REFERENCES

Kim KH, Choi TH, Choi Y, et al. "Comparison of Efficacy and Safety Between Propranolol and Steroid for Infantile Hemangioma: A Randomized Clinical Trial," JAMA Dermatology. June 1, 2017. DOI:10.1001/jamadermatol.2017.0250

Christine Léauté-Labrèze, M.D., Peter Hoeger, M.D., Juliette Mazereeuw-Hautier, M.D., et al. "A Randomized, Controlled Trial of Oral Propranolol in Infantile Hemangioma," NEJM. Feb. 19, 2015. DOI: 10.1056/NEJMoa1404710

Christine Léauté-Labrèze, M.D., Eric Dumas de la Roque, M.D., Thomas Hubiche, M.D., Franck Boralevi, M.D., Ph.D. "Propranolol for Severe Hemangiomas of Infancy," NEJM. June 12, 2008. DOI: 10.1056/NEJMc0708819