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Comment on “Topical timolol as adjunct therapy to shorten oral propranolol therapy for infantile hemangiomas”

To the Editor, With no doubt, oral propranolol is the first choice of treatment for alarming infantile hemangiomas (IHs). The use of topically applied beta‐blockers for nonalarming IHs is debated, and controversy really exists on the potential for concomitant or sequential oral and topical therapy. Therefore, the effect of sequential timolol after propranolol is worth investigating. Mannschreck et al1 conducted a retrospective chart review of children with IHs treated with topical timolol and/or oral proprano‐ lol. They grouped the patients by treatment sequence: propranolol, timolol, propranolol followed by timolol (PT), timolol followed by pro‐ pranolol (TP), and timolol to propranolol to timolol (TPT). The pro‐ pranolol monotherapy group received a median of 2.2 months more propranolol compared with the PT group, and 13% required propran‐ olol reinitiation. The authors concluded that sequential oral to topical beta‐blockers can shorten exposure to propranolol, thereby minimiz‐ ing its adverse effects. However, several methodologic concerns limit the interpretabil‐ ity of the study. First, the study was conducted in a tertiary center that likely has more severe IHs (selection bias). Second, the propran‐ olol group had the highest baseline hemangioma severity scale (HSS) scores, indicating more severe IHs that likely warranted longer pro‐ pranolol treatment and/or precluded switching to timolol. The PT group had slightly lower HSS scores, indicating milder IHs that may have allowed for earlier termination of propranolol and switching to timolol (confounding by indication). As such, it may be incorrect to conclude that less propranolol was needed when timolol was used. Third, the review included patients from 2008 to 2018. Since pro‐ pranolol was approved by the US Food and Drug Administration in 2014, it is unclear if all patients received the same dosage of pro‐ pranolol throughout the study period. Fourth, loss to follow‐up was substantial (25%, 3%, and 18% for the propranolol, PT, and TPT groups, respectively). Many of the children in the propranolol group could have been lost to follow‐up because of complete IH clearance with treatment. The lower rates of loss to follow‐up in the PT group could actually suggest that the PT patients required longer treat‐ ment than the propranolol group with need for ongoing follow‐up. Finally, Figure 2C still showed some swelling during/after treatment, which may be fibrofatty tissue.2 However, if there is still IH tissue, propranolol should have been continued because timolol has no ef‐ fect on deeper IHs as shown earlier.3 I agree that in some cases, timolol may add value after propran‐ olol cessation. However, the significant study limitations limit any conclusions on the benefits of sequential timolol therapy.