Discussion
This study investigated the current use of Hemangiol® in 94 children
with proliferating IH. It provided new tolerance data on this treatment
and the value of systematic cardiac screening before treatment.
Moreover, the safety of a rapid initiation protocol was evaluated.
Overall, the population treated with Hemangiol® in this study is similar
to previous reports8 and our cohort is representative
of the usually described population of IH, with a predominant female
representation21. However, more subjects with preterm
birth and low birth weight were present in our cohort, considering they
were previously described as risk factors for IH2,22.
The cases with PHACES or LUMBAR syndromes included in the study
underwent screening evaluation of clinical and radiological associated
anomalies, as recommended in children with large segmental haemangiomas
of the upper and lower body10,12. The main indications
for treatment of our cohort were IH with a functional threat, ulcerated
haemangiomas and IH with an aesthetic prognosis, as recommended in the
current guidelines13. Children of our study were
treated for an average of 7 months, which is moderately longer than in
the initial trial (e.g. 6 months)18. However, recent
studies have suggested treatment for 6 to 12 months due to a greater IH
rebound growth in shorter treatment duration23,24.
Indeed, treatment duration is mostly dependent on clinical complete
lesion regression25. Off-label use of Hemangiol® was
rare in this study. Two neonates <5 weeks of age were treated
with a good tolerance during initiation and no reported adverse event
during follow-up, which confirms a previous study on the safety of oral
propranolol for IH in the neonatal period 26. Late
Hemangiol® initiations >5 months of age concerned 29
subjects in our study. Usually, late treatment initiations are related
to a delayed referral to the specialist, especially for superficial
IH27.
The safety analysis found AEs in 26.6% patients, which is consistent
with previous studies on oral propranolol, which reported AEs rates from
19.6%28 to 38.2%29. Sleep
disturbances, wheezing and digestive side effects were the most
frequently reported AEs in our cohort, as described in the previous
studies, however peripheral coldness was not reported in our cohort28,29. SAEs were found in 8.5% patients, exclusively
severe hypoglycaemia and uncontrolled bronchial hyperreactivity, which
is higher than previous reported SAEs rates, ranging from
2.6%30 to 4.8%29. Cardiac SAEs,
such as atrioventricular block, bradycardia and symptomatic hypotension,
were not found in our cohort, as opposed to previous
studies29,30 and despite a systematic paediatric
cardiology pretherapeutic and follow-up assessment. Nevertheless, the
causality of propranolol for cardiovascular SAEs in the literature
remains unclear and suggests pre-existing conditions or incidental
discovery29,31. Of note, SAEs occurred in two
prematurely born children, who may be more prone to hypoglycaemia and
bronchial hyperreactivity as previously reported32.
Therefore, low dose of Hemangiol® (2mg/kg/day) could be of interest in
such high-risk children23,28, however the dosage of
3mg/kg/day has been more investigated in pharmacokinetics and
pharmacodynamics studies33,34 based on the
manufacturer’s clinical trial18.
For all SAEs, causality scores concluded to possible to strong relation
to Hemangiol®. As severe hypoglycaemia and uncontrolled bronchial
hyperreactivity are well known SAEs, variability of causality scores
came from intrinsic causation with variable chronological criteria (time
to onset after taking the treatment, or evolution after lowering the
dosage or stopping treatment) and the presence of confounding factors
(i.e. infectious for bronchospasms). As a result, SAEs with high
causality scores (4 or 5) in our study were patients with complete
description of the event, compatible time to onset, regression of AE
after stopping treatment, and no confounding factor. Previous studies
did not provide any details on the causality between such SAEs and
treatment with Hemangiol®.
From a general perceptive, those findings emphasize the importance of
parental therapeutic education about these potential risks and how to
manage them. During the treatment initiation period, oral information
supported by an educational pack should be provided to parents, in order
to identify symptoms potentially related to SAEs35.
For example, parents should be fully aware that Hemangiol® needs to be
temporarily suspended in case of food intolerance or limited food intake
in their child, in order to avoid hypoglycaemia36.
Similarly, bronchial hyperreactivity reactions were often related to
respiratory tract infections and therefore require appropriate parental
supervision29,37.
Overall, the cardiac tolerance was good. No AE, serious or not, was
reported during drug initiation at the hospital, whatever the protocol
used, as well as during the follow-up. No significant decrease in
systolic blood pressure was observed, and the initial decrease in heart
rate and diastolic blood pressure was moderate and not clinically
relevant, as in the literature38–40. Similarly,
previous studies have reported the safety of oral propranolol for the
treatment of IH41 and suggested not to extend cardiac
monitoring beyond initiation period except for heart rate during
following consultations42. In light of these results,
an outpatient Hemangiol® initiation protocol could be considered in
selected and non-at risk patients, as suggested by Puttgen and
al.43.
This study supports the absence of relevance for a systematic
pre-therapeutic paediatric cardiology consultation. Indeed, all cardiac
findings observed in this cohort were mostly non-significant and did not
result in any contraindication for betablockers. Therefore, a simple
physical examination made by the IH expert seems sufficient to identify
patients at risk. Based on our cohort, children with IH requiring
cardiological assessment are those with clinical symptoms (cardiac
murmur), abnormal blood pressure or heart rate, syndromic forms
(PHACES), high risk of heart failure (hepatic, military haemangiomas),
or off-label use (preterm birth, neonate period).
These results are
consistent with previous studies reporting that systematic
echocardiography44,45 or
ECG40,46before propranolol
initiation are not relevant in terms of contraindication assessment and
correlation with SAE occurrence47.
Most patients (81%) underwent a conventional initiation protocol with a
3-week titration phase in day care hospital. This protocol seems safe
and adapted to most children with IH, as reported in cost-effectiveness
studies48. Nevertheless, a 3-week delay to reach the
maintenance dose of 3 mg/kg/day may not be appropriate in a therapeutic
emergency situation, such as in IH involving any vital risk,
uncontrolled bleeding, ulceration, pain or infectious risk. In our
study, nearly 20% of patients with severe proliferative IH underwent a
rapid initiation protocol, with a 48-hour dose escalation in
conventional hospitalization in paediatric cardiology. This rapid
protocol was well tolerated and facilitated the prescription of strong
analgesics and local treatment, as in ulcerated IH. In both conventional
and rapid protocols, Hemangiol® was well tolerated in terms of blood
pressure and heart rate adaptation.