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Current management of complicated infantile hemangiomas: 
Atenolol or Propranolol? 

Ivan David Lozada-Martinez %°:*\, Claudia Marcela Castafieda-Moreno ©‘, Juan Pablo 
Duran-Tabera 4“, Gloria Patricia Crecian-Pérez ° 

° Medical and Surgical Research Center, Future Surgeons Chapter, Colombian Surgery Association, Bogota, Colombia 

> Grupo Prometheus y Biomedicina Aplicada a las Ciencias Clinicas, School of Medicine, Universidad de Cartagena, Cartagena, Colombia 
‘Department of Medicine, Universidad Cooperativa de Colombia, Villavicencio, Colombia 

4 Department of Medicine, Universidad del Quindio, Armenia, Colombia 

© Department of Medicine, Universidad Libre, Barranquilla, Colombia 


Article history: Keywords: 

Received 04 June 2022 Hemangioma Adolescent 

Received in revised form 28 June 2022 Infant Adrenergic Beta- 
Accepted 01 July 2022 Child antagonists 

© 2022 The Authors. Published by Iberoamerican Journal of Medicine. This is an open access article under the CC BY license 

Manejo actual de los hemangiomas infantiles complicados: ;Atenolol o Propranolol? 


Historia del articulo: Palabras clave: 

Recibido 04 Junio 2022 Hemangioma Adolescente 

Recibido en forma revisada 28 Junio 2022 Infante Antagonista Beta- 
Aceptado 01 Julio 2022 Nifio adrenérgico 

© 2022 Los Autores. Publicado por Iberoamerican Journal of Medicine. Este es un articulo en acceso abierto bajo licencia CC BY 
(http://creativecommons. org/licenses/by/4.0/). 

HOW TO CITE THIS ARTICLE: Lozada-Martinez ID, Castafieda-Moreno CM, Duran-Tabera P, Crecian-Pérez GP. Current 
management of complicated infantile hemangiomas: Atenolol or Propranolol? Iberoam J Med. 2022;4(3):133-135. doi: 

* Corresponding author. 
E-mail address: ilozadam 
ISSN: 2695-5075 / © 2022 The Authors. Published by Iberoamerican Journal of Medicine. This is an open access article under the CC BY license 
(http://creativecommons. org/licenses/by/4.0/). 


Infantile hemangiomas are the most common vascular tumor 
in childhood, occurring in more than 10% of infants in their 
first year of life [1, 2]. The vast majority appear weeks after 
birth as telangiectatic patches, which grow rapidly and 
diffusely until before the age of 6 months, until they become 
reddish, delimited, dome-shaped protuberances in deep 
areas [3]. They are mainly located on the face and neck. 
From the age of one year, these lesions grow parallel to the 
child's development. The regression of the lesions is almost 
100% at 10 years of life [1]. However, depending on the 
evolution and expansion of the lesions, they can become 
complicated and bleed uncontrollably, ulcerate and cause 
pain, disfigure the face, hinder activities of daily living, 
compromise the child's functional ability and substantially 
influence mental health [2]. This is not to mention that 
hemangiomas are associated with certain syndromes such as 
the PHACES (Posterior 
malformations/Hemangiomas/Arterial anomalies/Cardiac 
defects/Eye abnormalities/Sternal — cleft/Supraumbilical 
raphe syndrome) or PELVIS/SACRAL/LUMBAR (Perineal 
hemangioma/External genitalia 
abnormalities/Imperforate anus/Skin tag), which hinder the 
management and make the recovery process less tolerable 

For these complicated hemangiomas, the use of beta- 
blockers has been described as effective, but not entirely 
safe. [3-6]. Atenolol and propranolol have been two agents 
frequently studied in the last decade in the control of this 
condition, and although no significant differences have been 
found between the two, there is much discussion at present 
about which drug to use [4-6]. Propranolol is a non-selective 
beta-blocker, which has been associated with several 


adverse effects, mainly in those with respiratory system 
disorders [4, 6]. Atenolol is a cardioselective beta-blocker, 
which can significantly affect patients with abnormalities of 
the cardiovascular system (mainly those with PHACES 
syndrome, who are at increased risk of heart defects) [4, 6]. 
Therefore, there is a need to study in depth and be very 
critical in the therapeutic plan of those patients with 
complicated infantile hemangiomas. 

Abarztia-Araya et al [4] published in 2014 one of the first 
and most representative clinical trials to compare Atenolol 
and Propranolol in uncomplicated infantile hemangiomas. 
Although the authors found that Propranolol was more 
effective than Atenolol in terms of complete response 
(lesion resolution over time: 60% vs. 53.8%), these results 
were not significant (p= 0.68). However, a very strong 
limitation was the study sample, only 23 patients [4]. 
Therefore, up to that date, the problem question remained 

unresolved. Recently, in 2021, a trial was published with a 
more representative sample (337 participants), where 
Propranolol vs Atenolol was evaluated in the management 
of complicated infantile hemangiomas, 
outcome was the response or non-response at 6 months [6]. 

whose main 

The average age of the patients was 10 weeks and more than 
70% were women. After 6 months, Propranolol and 
Atenolol response were 93.7% and 92.5%, respectively. The 
hemangioma activity score was similar at 1 week and 4 
weeks after treatment (OR 1.03; 95% CI, 0.886 - 1.206) [6]. 
Although there were no significant differences in quality of 
life, ulcer healing time or rebound rate, the presence of 
adverse events was more frequent in the Propranolol group 
(70.0% vs. 44.4%). The complete response rate was similar 
at 24 months (82.1% vs 79.7%) [6]. Thus, it was concluded 
that Atenolol has an equally effective response as 
Propranolol, but is safer. 

Only one month after the aforementioned trial was 
published, Mufioz-Garza et al [5], who evaluated the impact 
of Timolol vs. placebo in the early proliferative phase of 
uncomplicated infantile hemangioma, published another 
Spanish trial. Although there were only 69 patients, with an 
average age of 48 days, there was no evidence of superiority 
compared to placebo with respect to complete resolution at 
24 weeks (42% vs. 36%, p= 0.37), nor to variation in tumor 
size. The only favorable finding was an improvement in 
color and the absence of systemic adverse effects [5]. The 
most recent systematic review that has studied the effects of 
certain interventions in the management of infantile 
hemangiomas (laser, beta-blockers, radiation therapy and 
steroids) was done by Novoa et al [3] and published in 2018. 
The authors included 28 containing 1,728 
participants, from various countries and ranging in age from 
12 weeks to 13 years of age. Among the outcomes evaluated, 
the favorable result of propranolol vs. placebo on tumor 
volume reduction (RR 16.61; 95% CI, 4.22 - 65.34) and 
clearance (45.9%; 95% CI, 11.60 - 80.20) was highlighted 
[3]. No serious short- or long-term adverse effects were 
evident (RR 1.05; 95% CI, 0.33 - 3.39). However, the latter 
finding was not significant, and had a low level of quality. 
The use of topical Timolol (0.5% gel) vs. placebo showed a 
reduction in redness (RR 8.11; 95% CI, 1.09 - 60.09), with 
no adverse events reported [3]. When comparing topical 
Timolol vs. oral Propranolol with respect to the impact on 


tumor size, no significant differences were observed (RR 
1.13; 95% CI, 0.64 - 1.97). However, effects that are more 
adverse were reported in the Propranolol group [3]. It should 
be noted that the authors reported that the quality of the 
outcomes evaluated and of the studies was moderate to low, 
the heterogeneity of the population studied was high (the age 


range was very wide), and the available studies that have 
evaluated efficacy and safety between drugs are almost 
nonexistent [3]. 

At present, there are no clinical trials from Latin America or 
from low- and middle-income countries of similar regions. 
In order to comply with global health objectives [7], which 
establish the search for entities that affect early childhood 
and the control of the burden of pediatric diseases. It is 
necessary to encourage the design and systematization of 
data regarding the approach and outcome of infants and 
adolescents with complicated infantile hemangioma, to 
facilitate the resolution and ensure that there are no sequelae 
of any kind [8]. In addition, due to current barriers in low- 
and middle-income countries, such as timely access to 
specialize health care, it is imperative to design policies or 
groups that can reach hard-to-reach areas to identify or rule 
out these types of tumors, if they are mistaken for other 
[8, 9]. Genomic 
characterize the behaviour of these tumors in regions where 
complicated infantile hemangiomas have not been studied in 
depth, to identify new therapeutic targets for a context- 
specific stratification of each population, according to their 

conditions studies are needed to 

needs [9, 10]. These tumors, because they resolve at 
approximately 10 years of age in the vast majority of cases 
[1, 2], can entail a high catastrophic expense for a very long 
period of time, which can affect the development of the child 
and the functionality of his family. 

To date, there is no sufficiently effective, efficient and safe 
therapeutic agent that is superior to other therapeutic tools 
designed for the management of complicated infantile 
hemangiomas. Although Propranolol has been shown to be 
superior to Atenolol in terms of efficacy, itis associated with 
numerous adverse events. Atenolol has been shown to be 
similar to Propranolol and other agents such as Timolol, 
with an acceptable safety profile. However, the current 
evidence is heterogeneous and of low quality. In this order 
of ideas, the therapeutic plan for complicated infantile 
hemangiomas should be multidisciplinary and personalized. 


The authors have no conflict of interest to declare. The 
authors declared that this study has received no financial 


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