What do Cochrane systematic reviews say about congenital vascular anomalies and hemangiomas? A narrative review

ABSTRACT BACKGROUND: Congenital vascular anomalies and hemangiomas (CVAH) such as infantile hemangiomas, port-wine stains and brain arteriovenous malformations (AVMs) impair patients’ lives and may require treatment if complications occur. However, a great variety of treatments for those conditions exist and the best interventions remain under discussion. OBJECTIVE: To summarize Cochrane systematic review (SR) evidence on treatments for CVAH. DESIGN AND SETTING: Review of SRs conducted in the Division of Vascular and Endovascular Surgery of Universidade Federal de São Paulo, Brazil. METHODS: A broad search was conducted on March 9, 2021, in the Cochrane Database of Systematic Reviews to retrieve any Cochrane SRs that assessed treatments for CVAH. The key characteristics and results of all SRs included were summarized and discussed. RESULTS: A total of three SRs fulfilled the inclusion criteria and were presented as a qualitative synthesis. One SR reported a significant clinical reduction of skin redness by at least 20%, with more pain, among 103 participants with port-wine stains. One SR reported that propranolol improved the likelihood of clearance 13 to 16-fold among 312 children with hemangiomas. One SR reported that the relative risk of death or dependence was 2.53 times greater in the intervention arm than with conservative management, among 218 participants with brain AVMs. CONCLUSION: Cochrane reviews suggest that treatment of port-wine stains with pulsed-dye laser improves redness; propranolol remains the best option for infantile hemangiomas; and conservative management seems to be superior to surgical intervention for treating brain AVMs.

treatment. However, infantile hemangiomas may need treatment when they follow a course that involves some complications, such as functional impairment, potential disfigurement or ulceration. 5 In summary, vascular anomalies are a set of complex and heterogeneous pathological conditions, with regard to both their clinical presentation and their natural course. Because these lesions are usually located in visible areas, there are considerable chances that not only will systemic alterations appear, but also they will have great potential for psychosocial involvement in both the patient's life and also the lives of the whole family. In fact, a multidisciplinary team is needed for treating these anomalies, and the treatment should be aimed towards better management of symptoms and complications, considering that the healing of these injuries is difficult and that resurgence of lesions occurs frequently. Hence, evidence concerning congenital vascular anomalies and hemangiomas is needed in order to improve the understanding of these diseases and the benefits of different types of treatment.

OBJECTIVE
The aim of this review was to identify and summarize the evidence from Cochrane systematic reviews (SRs) regarding congenital vascular anomalies and hemangiomas, in order to establish better clinical decision-making.

Design and setting
This was a review of Cochrane SRs conducted in the Division of Vascular and Endovascular Surgery, Universidade Federal de São Paulo, Brazil.

Types of participants
The participants included children and adults (both males and females) who had been diagnosed with congenital vascular anomalies or hemangiomas, without any restrictions regarding the site affected.

Types of interventions
We considered SRs that assessed any pharmacological intervention (e.g. beta-blocker agents) or non-pharmacological intervention (e.g. transdermal laser) for treating congenital vascular anomalies or hemangiomas. The focus of the studies included was to analyze different types of interventions for treating congenital vascular anomalies and hemangiomas, and the respective improvements. The main types of treatment referred to were pulsed-dye laser therapy, oral propranolol, oral prednisolone and conservative management.

Types of outcomes
We did not predefine the outcomes of interest. Rather, we considered all outcomes as reported in the SRs included.

Types of studies
All Cochrane SRs published thus far, about congenital vascular anomalies or hemangiomas, without restrictions regarding date of publication, were included. Withdrawn or outdated versions of SRs and protocols for SRs were considered not relevant.

Search for reviews
We conducted a systematic search in the Cochrane Database of Systematic Reviews on March 9, 2021. We used the following MeSH terms and related variants in the titles, abstracts and keywords: "Vascular malformations", "Lymphatic abnormalities" and "Hemangioma". The detailed search strategy is presented in Table 1.

Selection of reviews
Two researchers (HJGN and LCUN) independently evaluated the titles and abstracts to analyze whether the SRs fulfilled the inclusion criteria. Any disagreement was resolved by consulting other authors (DABK, RLGF, JCCBS and JEA). A total of three reviews fulfilled the inclusion criteria. The SRs were selected and summarized by two authors (HJGN and DABK) using previously developed forms to extract data from SRs, which had already been used in previous narrative reviews with this purpose. 5 We extracted the following study characteristics: • Participants: N randomized, N lost to follow-up/withdrawn, N analyzed, N of interest, mean age, age range, gender, condition of interest, inclusion criteria and exclusion criteria.
• Interventions: intervention and comparison characteristics, level of experience of the person carrying out the procedure, concomitant medications and medications excluded. Cochrane reviews of intervention • Outcomes: primary and secondary outcomes specified and collected, and time points reported.
• Study methods: primary study design, number of primary studies and location, study setting and date of study.

Presentation of results
The results from the search and the SRs included were presented as a qualitative synthesis (descriptive approach).

Ethics
No ethics committee approval was necessary since this was not a primary study and we did not deal directly with patients.

Search results
Our search strategy retrieved 156 references and, after screening the titles and abstracts, five SRs were preselected. After assessing the full texts, three reviews were found to fulfill the criteria for inclusion and were assessed in a qualitative synthesis (Figure 1).

Reviews included
The latest versions of all the SRs included were published between 2011 and 2019. [13][14][15] Details regarding the characteristics of interventions, comparisons, outcomes and certainty of evidence are presented in Table 2.
Lasers or light sources for treating port-wine stains 13 The aim of this SR was to study participant satisfaction with treatment of port-wine stains by means of laser and light sources, and the clinical efficacy and adverse events of this treatment. Five randomized clinical trials (RCTs) were identified, involving a total of 103 participants. The interventions and outcomes varied among the primary studies and therefore, could not be combined for numerical analysis.

Main findings
All of the primary studies described the participants' level of satisfaction at less than six months after treatments with the pulseddye laser, intense pulsed light and Nd:YAG laser, and reported that the participants' satisfaction was good or excellent, with regard to the degree of improvement attained.
Participant preference was analyzed in three of the five studies included, and most of the participants preferred pulsed-dye laser over intense pulsed light. The participants also preferred treatment with pulsed-dye laser in association with cooling, over treatment solely with pulsed-dye laser.
There was a significant clinical change of at least 20% in all the SRs regarding reduction of skin redness. All the studies determined the level of reduction in redness at one to three months after the final treatment. All five trials used the pulsed-dye laser, and, depending upon the setting, this resulted in more than 25% reduction in redness. The results reported were achieved after one to three sessions for up to six months postoperatively, in 50% to 100% of the participants. Adverse effects were considered in terms of their cosmetic aspect and were determined as either permanent or lasting longer than six months.

Complications
Few studies described short-term adverse effects occurring only in the first two weeks. Two primary studies reported that treatment with pulsed-dye laser alone was more painful than with pulsed-dye laser combined with cryogenic cooling. Three trials reported pigmentary complications in 3%-24% of the participants, such that the highest percentage occurred among Chinese participants with darker skin types. One case of scarring of the skin caused by high-dose laser was also reported. The trials included reported short-term side-effects such as pain, crusting and blistering in the first two weeks after the intervention.

Conclusion
Treatment of port-wine stains with pulsed-dye laser has clinical ben-

Interventions for infantile hemangiomas of the skin 14
This SR focused on assessing the effects of interventions for managing infantile hemangiomas in children. Twenty-eight primary SRs = systematic reviews.   tion. The quality of the evidence relating to the primary and secondary outcomes was assessed using the GRADE system.  of oral propranolol and placebo, at any doses. Also, there were no differences between these two different approaches, with regard to redness improvement, the proportion of parents who considered that their children still had a problem, the proportion of children who considered that they still had a problem, esthetic appearance or requirement for surgical correction.

Main findings and complications
Comparison of topical timolol and placebo treatments proved that there was no significant difference between them, with regard to clearance, subjective measurements of improvement or adverse events. One study demonstrated that volume reduction after use of topical timolol maleate was 5.21 times greater than after placebo there was no significant difference between dual therapy and oral prednisolone, regarding size reduction.

Conclusion
Propranolol remains the standard treatment for infantile hemangiomas and is probably beneficial, in terms of clearance and reduction of hemangioma volume, compared with placebo.

Interventions for treating brain arteriovenous malformations in adults 15
The objective of this review was to determine the effectiveness and safety of different interventions, alone or in combination, for treating brain AVMs in adults, compared against each other, or with conservative management, in RCTs. The primary outcome was death or dependence due to any cause. The secondary outcomes included symptomatic intracranial hemorrhage, epilepsy, symptomatic radiation necrosis and quality of life. Only one study fulfilled the inclusion criteria for this review.

Main findings
The primary and secondary outcomes were available for 218 participants. During the first year, the relative risk of death or dependence for participants randomized to interventional treatment was 2.53 greater than for participants randomized to conservative management (RR = 2.53; 95% CI = 1.28-4.98). The total number of participants with symptomatic intracranial hemorrhage was also higher in the group with intervention (RR = 6.75; 95% CI = 2.07-21.96).
In terms of epilepsy, comparison between the study arm that underwent the intervention and the arm that was treated with conservative management demonstrated a RR of 1.14 (95% CI = 0.63-2.06).

Conclusion
Although the quality of evidence of this study was considered moderate, conservative management was superior to intervention with regard to functional outcome and symptomatic intracranial hemorrhage, over one year after randomization.

DISCUSSION
Overall, there is a great variety of treatments for congenital vascular abnormalities and infantile hemangiomas and yet there is no consensus about which one is better. 5,6,8,11 Each technique has its benefits and risks and the type of treatment should be based not only on the characteristics of the lesion, but also on the participant's profile.
The first review described in this study suggested that treatment of port-wine stains with pulsed-dye laser improves the redness of these lesions. Pulsed-dye laser is considered to be the gold-standard treatment for port-wine stains, 16 but the response to this treatment varies according to the patient's age, lesion location, the frequency used and the intervals between sessions. 17 Some studies have suggested that port-wine stains located proximally to the limbs tend to have better results than those that are distal to the limbs, from treatment with pulsed-dye laser. 18 The SR described above included a small number of studies and, therefore, it was not possible to properly analyze these factors or compare different types of treatment.
The second SR compared a number of types of treatment and suggested that propranolol remains the standard treatment for infantile hemangiomas and is probably beneficial in terms of clearance and reduction of hemangioma volume. Although this review suggested that there were no significant differences in terms of improvement and adverse events, in comparing the use of propranolol at 1 mg/kg/day and 3 mg/kg/day with use of placebo, some reports in the literature have suggested that there is higher incidence of adverse events related to propranolol when it is administered at higher doses. 19 Perhaps the number of participants included was not enough to compare the effects of propranolol at different doses.
Regarding treatment of brain AVMs, our study suggested that conservative management was superior to intervention. However, there is no consensus about this. There is evidence from different studies suggesting that conservative management may be associated with worse outcomes. [20][21] The major limitation of this review was the small number of SRs included. There were also the facts that a great variety of