Effectiveness and Safety of Oral Propranolol versus Other Treatments for Infantile Hemangiomas: A Meta-Analysis

Background Epidemiological studies evaluating treatments for infantile hemangiomas have produced inconsistent results. A meta-analysis of published data was conducted to investigate the effectiveness and safety of oral propranolol versus other treatments for infantile hemangiomas. Methods A meta-analysis was conducted based on literature (published from 1960 to December 1, 2014) found on the PubMed, EMBASE, and OVID search engines. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for the outcome measures. Heterogeneity, publication bias and subgroup analysis were performed. Results A total of 61 studies involving 5,130 participants met the inclusion criteria. Propranolol was found to be a more effective modality in treating IHs (ORs = 0.92; 95%CI, 0.89–0.95) and had fewer complications compared to the other treatments including systemic steroids (ORs = 0.68; 95% CI, 0.59–0.76); laser ablation (ORs = 0.55; 95% CI, 0.43–0.67); other beta-adrenergic blockers (ORs = 0.56; 95% CI, 0.50–0.61) and surgery (ORs = 0.55; 95% CI, 0.28–0.81). A subgroup analysis of propranolol showed that a dose of 2 mg/kg/day or more yielded better outcomes (ORs = 0.92; 95% CI, 0.88–0.95; ORs = 0.95; 95% CI, 0.89–1.00), and IHs that had not been previously treated had better responses to propranolol treatment (ORs = 0.95; 95% CI, 0.91–0.98). Conclusions The meta-analysis demonstrated that propranolol was more effective and safer than other therapies in treating IHs. It provides strong evidence for supporting the use of propranolol as a first-line therapy for IHs.


Introduction
Infantile hemangiomas (IHs) are the most common type of benign tumor, affecting approximately 10% of children [1]. Although, most IHs have a self-limiting course, some may result in residual telangiectasias or redundant skin. Therefore, early intervention is indicated for IHs [2].
Systemic corticosteroids used to be the first-line treatment for IHs. However, long term use tends to result in serious side effects such as hypertension, adrenal cortical insufficiency, and delayed of growth [3].
Other treatment modalities including laser ablation, interferon-á, vincristine and surgical excision are reserved as second-or third-line therapy for IHs because of their inconsistent efficacy, multiple complications and potential toxicity [4].
In 2008, propranolol, a nonselective beta-blocker, was serendipitously discovered to be effective for treating IHs. Leaute-Lamberer et al. successfully treated 11 children with oral propranolol and observed tumor color regression in all cases soon after the treatment. Since then, large clinical studies have confirmed the efficacy and safety of propranolol [5].
Recently, other nonselective beta-blockers such as atenolol and timolol have also been found to be useful in treating IHs [6].
The aim of this meta-analysis was to systematically review the existing published data regarding the treatment of IHs, and to compare the effectiveness and safety of propranolol with other therapies. A subgroup analysis was also performed to evaluate the relationship between the effectiveness of propranolol and factors including location, dosage and previous treatment.

Materials and Methods
The study protocol was in accordance with the PRISMA guidelines (S1 PRISMA Checklist) [7].

Search strategy
A literature search was performed by searching the PubMed, EMBASE, and OVID databases through December 2014. Combinations of the following terms were used in the search (1) outcome terms: hemangiomas, infantile hemangiomas and complicated hemangiomas; and (2) therapeutic terms: propranolol, systemic steroids, beta-blocker, laser ablation, vincristine, and surgical intervention. The review articles were assessed for relevant references.

Selection criteria
The studies were evaluated by two independent reviewers (XHL and XHQ). To avoid bias, discrepancies were resolved by a third reviewer (JWZ) through a discussion. To avoid the issue of missing data in certain studies, the respective authors were contacted and asked to provide relevant information.
Studies that met the following criteria were included in the meta-analysis: (1) infantile population; (2) study sample size≧20(the timolol/atenolol sample size was≧10); (3) retrospective studies, prospective studies or RCT; (4) clear description of the therapy (propranolol, systemic steroids, laser ablation, etc.); and (5) well-reported outcome measures (including explicit reporting of the response rate). The studies that did not meet the inclusion criteria were excluded during the initial review.

Data extraction and quality assessment
Two reviewers (XHL and XHQ) independently extracted the data based on a standard data collection form. A third reviewer (JWZ) resolved any discrepancies by discussing and consulting on the original articles. For each identified study, the following data were collected: last name of the first author, publication year, country, study design, number of cases, participants' sex and age, location of the IHs, previous treatments, dosage of treatment, response rate and complications.

Data synthesis and statistical analysis
Odds ratios (ORs) and 95% CIs that reflected a degree of control for potential confounders were extracted from the selected studies for analysis [8]. In this meta-analysis, either a random-effects model (DerSimonian-Laird method) or a fixed-effects model (Mantel-Haenszel method) was used for analysis. Heterogeneity among the studies was evaluted by using I 2 statistics. I 2 values of 25%, 50% and 75% were defined as low, moderate, and high, respectively [9]. A subgroup analysis was conducted to identify associations between the efficiency of propranolol and relevant study characteristics (location of IHs, geographical location of patients, mean dosage of treatment and prior therapy). Funnel plot asymmetry measured by Egger's and Begg's tests, was used to assess publication bias [10,11]. Probability values <0.05 were considered statistically significant [12]. Data analysis was performed using R software 2.13.0, package (meta package metaprop and forest functions).

Eligible studies and study characteristics
A total of 61 studies  were selected from 1097 potential articles for the meta-analysis (Fig 1). The characteristics of the selected articles are listed in Tables 1 and 2. The analysis included 5,130 IH cases from the 61 studies; of these cases, 3761 were located in the head and neck, 216 were located in the trunk, and 160 were located in the extremities. Of the included studies, 30 studies chose propranolol as the definitive treatment; 31 studies used other treatments (15 studies used systemic steroids, 7 studies used laser ablation, 2 studies used surgery, 3 studies used atenolol and 4 studies used timolol). The average age of the patients was 6.2 months. Evaluation of the outcomes was based on visual measurements, photograph scoring, Doppler ultrasonography or MRI.

Propranolol for treating IHs
A total of 30 studies , which included 1893 individuals reported the response and sideeffects of propranolol for treating IHs. The pooled odd ratio (OR) for effectiveness was 0.92 (95% CI, 0.89-0.95), and a high heterogeneity was observed between the studies (P heterogeneity < 0.0001; I 2 = 87.1%) (Fig 2a). Of the included studies, 25 studies with 286 cases reported complications of propranolol treatment including hypotension (n = 33), hypoglycemia (n = 10), insomnia (n = 75), diarrhea (n = 26), and respiratory disorder (n = 28), among others (Table 3). Sensitivity analysis confirmed that excluding any of the studies from the pooled analysis did not influence the results.

Subgroup analysis of propranolol for treating IHs
In the subgroup analysis, possible sources of heterogeneity such as location of the IHs, geographical distribution of the patients, mean dosage of the treatment and previous therapy (or not) were examined ( Table 4). The results showed that the mean treatment dosage and previous therapy (or not) influenced the effectiveness of propranolol in treating the IHs. A propranolol dosage of 2 mg/kg/day or more resulted in better outcomes. The OR was 0.92 (95% CI, 0.88-0.95; P heterogeneity < 0.0001; I 2 = 86.8%) for the 2mg/kg/day dose and 0.95 (95%CI, 0.88-1.00; P heterogeneity < 0.0001; I 2 = 89%) for doses that exceeded 2 mg/kg/day; in comparison, for doses that were less than 2 mg/kg/day, the OR was 0.90 (95% CI, 0.79-1.00; P heterogeneity < 0.001; I 2 = 89%). The patients with severe or intractable IHs, which did not respond to previous treatment, received subsequent oral propranolol. The effectiveness of propranolol therapy among these cases was inferior to that among the cases without previous treatment. The ORs was 0.88 (95%CI, 0.83-0.93; P heterogeneity < 0.0001; I 2 = 86.5%) for the 15 studies that used some other form of treatment prior to propranolol administration; this was much lower

Discussion
Our analysis of the 61 studies demonstrats that propranolol was more effective and safer in treating IHs than the other therapies. A subgroup analysis showed that the prefered dose of propranolol treatment was 2 mg/kg/day or more. In addition, the patients who had received previous treatments did not respond as well to propranolol treatment. Steroids used to be the first-line treatment for IHs over the past several decades. It could be administered either locally or systemically and had a response rate of 78.05% [43][44][45][46][47][48][49][50][51][52][53][54][55][56][57]. Longterm steroid usage, however, tended to cause serious side effects [3]. Laser ablation, vincristine and surgical intervention have also been used to treat IHs but with varied efficiency and safety concerns [74].
Propranolol was first reported as a treatment for IHs by Lèautè-Labrère et al. in 2008 [5]. In this meta-analysis, propranolol showed a better effectiveness, with a response rate as high as 88.75%, which is 1.19 times higher than other treatments . It is also a safer therapy, with fewer side effects [75,76]. According to Labrèze et al., diarrhea (28/101), sleep-disorder (22/101), bronchitis (17/101) and cold hands and feet (10/101) were the common events [77]. The present study showed that propranolol treatment was more effective at a doses of 2 mg/kg/ day or more [13]. However, because there is a lack in dose response studies, the optimal dose of propranolol remains to be investigated.
Recently, other beta-adrenergic blocker agents such as timolol and atenolol were reported to treating IHs. They appeared to be as effective as propranolol but with fewer side effects. Given the small number of cases reported in the literature, conclusions cannot be reached at present.
This meta-analysis is advantageous in two respects. First, a substantial number of participants were included. A meta-analysis by Peridis et al. included 13 studies, but none of them included more than 20 participants [78]. Lou et al. examined included 35 studies, but only 6 of them included more than 20 participants [79]. In this meta-analysis, 61 studies were included, and 59 of the studies had more than 20 participants. Second, data extraction, data analysis, and quality assessment were performed independently by two investigators, and consistency was achieved by a third reviewer, which enhanced the accuracy and reliability of the findings.
However, there are several limitations that should be addressed. First, the outcome measures varied across the studies, which weakened the strength of the identified association. Some of the studies used visual methods alone, while others used objective methods such as Doppler ultrasonography, MRI and endoscopy to evaluate the treatment outcomes. This discrepancy may lead to inevitable bias in the estimated ORs. Second, methodological differences among the studies may have also resulted in heterogeneity, as high I 2 values were observed in this meta-analysis. A subgroup analysis was performed to explore the possible heterogeneity of the studies.
Based on the findings of this analysis, a few questions remain to be answered. First, the patients with previous treatments did not respond as well to propranolol treatment. Thus, do previous IH treatments influence the effectiveness of propranolol? Second, due to the lack of dose response studies, the optimal dose of propranolol and other treatment modalities for treating IHs remains unknown. To answer these questions, further well-designed RCT studies are need to be performed.
In conclusion, propranolol is a more effective and safer treatment for IHs, and can be used as the first-line therapy for complicated IHs cases.