-
JAMA Dermatology May 2021Treatment of infantile hemangioma (IH) with topical timolol in the first 2 months of life (early proliferative phase) may prevent further growth and the need for... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Treatment of infantile hemangioma (IH) with topical timolol in the first 2 months of life (early proliferative phase) may prevent further growth and the need for treatment with oral propranolol. To our knowledge, no studies have determined whether beginning early treatment with timolol for IH is better than in other proliferative stages.
OBJECTIVE
To evaluate the efficacy and safety of timolol maleate solution, 0.5%, for the early treatment of IH in infants younger than 60 days.
DESIGN, SETTING, AND PARTICIPANTS
This multicenter, randomized, double-blind, placebo-controlled, phase 2a pilot clinical trial included patients aged 10 to 60 days with focal or segmental hemangiomas (superficial, deep, mixed, or minimal/arrested growth). Patients were randomly assigned to treatment with topical timolol maleate solution, 0.5%, or placebo twice daily for 24 weeks. Changes in lesion size (volume, thickness) and color were evaluated from photographs taken at 2, 4, 8, 12, 24, and 36 weeks. Vital signs and adverse effects were recorded at each visit. The study was carried out from November 2015 to January 2017, and data analyses were completed in September 2019.
MAIN OUTCOMES AND MEASURES
The primary outcome of complete or nearly complete IH resolution and the secondary outcomes of changes in lesion thickness, volume, and color were evaluated by a blinded investigator.
RESULTS
Of the 69 patients recruited, the mean (SD) age was 48.4 (10.6) days; 55 (80%) were female; and 51 (74%), 11 (16%), 6 (9%), and 1 (1%) had superficial, mixed, abortive, or deep IHs, respectively. The IHs were localized, segmental, or indeterminate in 60 (87%), 7 (10%), and 2 (3%) patients, respectively. The IHs were located on the head and/or neck (n = 23 [33%]) or other body sites (n = 46 [67%]). The study was completed by 26 of 33 (79%) patients receiving timolol and 31 of 36 (86%) receiving placebo. There were no significant differences between timolol and placebo for complete or nearly complete IH resolution at 24 weeks (n = 11 [42%] vs n = 11 [36%]; P = .37). The odds ratio of complete or almost complete response vs no response at week 24 was 1.33 (95% CI, 0.45-3.89). There were no between-group differences in IH size (volume, thickness). An improvement in color was observed at week 4 in the timolol group, and timolol was well tolerated with no systemic adverse effects.
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial, results demonstrated that topical timolol is well tolerated for the treatment of early proliferative IH but provides limited benefit in lesion resolution when given during the early proliferative stage.
TRIAL REGISTRATION
EudraCT Identifier: 2013-005199-17.
Topics: Administration, Topical; Adrenergic beta-Antagonists; Double-Blind Method; Drug Administration Schedule; Female; Hemangioma, Capillary; Humans; Infant; Infant, Newborn; Male; Pilot Projects; Prospective Studies; Skin Neoplasms; Timolol; Treatment Outcome
PubMed: 33825828
DOI: 10.1001/jamadermatol.2021.0596 -
Journal of Ocular Pharmacology and... Apr 2022Data are presented from ophthalmology clinics in Spain participating in the VISIONARY study, examining the effectiveness, tolerability, and safety of the... (Observational Study)
Observational Study
Treatment of Open-Angle Glaucoma and Ocular Hypertension with Preservative-Free Tafluprost/Timolol Fixed-Dose Combination Therapy: Results from the VISIONARY Study Population in Spain.
Data are presented from ophthalmology clinics in Spain participating in the VISIONARY study, examining the effectiveness, tolerability, and safety of the preservative-free tafluprost (0.0015%) and timolol (0.5%) fixed-dose combination (PF tafluprost/timolol FC) in the treatment of OAG and OHT. An observational, multicenter prospective study examined treatment outcomes following a switch to PF tafluprost/timolol FC in adult OAG/OHT patients demonstrating insufficient response to beta-blocker or prostaglandin analog (PGA) monotherapy. Primary end point was mean change in intraocular pressure (IOP) from baseline at month 6. Changes in the severity of ocular signs and symptoms were also assessed. Overall, 92 patients (51.1% female) were included. Mean (standard deviation) age was 68.3 (12.1) years. Mean IOP was reduced from 21.9 mmHg at baseline to 16.7 mmHg at month 6 (22.3% decrease; < 0.0001). Significant IOP reductions were observed at weeks 4 and 12 ( < 0.0001). Baseline PGA and beta-blocker users demonstrated mean month 6 IOP reductions of 5.5 mmHg (23.5%; < 0.001) and 3.5 mmHg (14.6%; = 0.029), respectively. Severity of conjunctival hyperemia, dry eye, irritation, itching, foreign body sensation, and eye pain was significantly reduced. Three treatment-related adverse events were reported, all were nonserious and mild/moderate in severity. In real-world clinical practice, PF tafluprost/timolol FC treatment provided significant IOP reductions over 6 months and was well tolerated among OAG/OHT patients showing poor response to PGA or beta-blocker monotherapy. IOP-lowering efficacy and improvements in ocular signs and symptoms were evident from week 4 and maintained over the 6-month study period. Trial Registration: European Union electronic Register of Post-Authorisation Studies (EU PAS) register number EUPAS22204.
Topics: Adult; Aged; Antihypertensive Agents; Drug Combinations; Female; Glaucoma; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Ocular Hypertension; Preservatives, Pharmaceutical; Prospective Studies; Prostaglandins; Prostaglandins A; Prostaglandins F; Prostaglandins, Synthetic; Spain; Timolol
PubMed: 35230148
DOI: 10.1089/jop.2021.0099 -
Acta Ophthalmologica Mar 2013ABSTRACT.:
UNLABELLED
ABSTRACT.:
PURPOSE
Malfunction of retinal blood flow or oxygenation is believed to be involved in various diseases. Among them are retinal vessel occlusions, diabetic retinopathy and glaucoma. Reliable, non-invasive technology for retinal oxygen measurements has been scarce and most of the knowledge on retinal oxygenation comes from animal studies. This thesis describes human retinal oximetry, performed with novel retinal oximetry technology. The thesis describes studies on retinal vessel oxygen saturation in (1) light and dark in healthy volunteers, (2) central retinal vein occlusion, (3) branch retinal vein occlusion, (4) central retinal artery occlusion, (5) diabetic retinopathy, (6) patients undergoing glaucoma surgery and (7) patients taking glaucoma medication.
METHODS
The retinal oximeter (Oxymap ehf., Reykjavik, Iceland) is based on a fundus camera. An attached image splitter allows the simultaneous capture of four images of the same area of the fundus. Two images are used for further analysis, one acquired with 586 nm light and one with 605 nm light. Light absorbance of retinal vessels is sensitive to oxygen saturation at 605 nm but not at 586 nm. Measurement of reflected light at these wavelengths allows estimation of oxygen saturation in the main retinal vessels. This is performed with custom-made analysis software.
RESULTS
LIGHT AND DARK: After 30 min in the dark, oxygen saturation in retinal arterioles of healthy volunteers was 92 ± 4% (mean ± SD, n = 15). After 5 min in 80 cd/m(2) light, the arteriolar saturation was 89 ± 5%. The decrease was statistically significant (p = 0.008). The corresponding values for retinal venules were 60 ± 5% in the dark and 55 ± 10% in the light (p = 0.020). Similar results were found after alternating 5 min periods of darkness and light. In a second experiment (n = 19), a significant decrease in retinal vessel oxygen saturation was found in 100 cd/m(2) light compared with darkness but 1 and 10 cd/m(2) light had no significant effect. CENTRAL RETINAL VEIN OCCLUSION: In patients with central retinal vein occlusion, the mean saturation in affected retinal venules was 49 ± 12%, while the mean value for venules in the fellow eye was 65 ± 6% (mean ± SD, p = 0.003, n = 8). The retinal arteriolar saturation was the same in affected (99 ± 3%) and the unaffected (99 ± 6%) eyes. The venous oxygen saturation showed much variation between affected eyes. BRANCH RETINAL VEIN OCCLUSION: Median oxygen saturation in venules affected by branch retinal vein occlusion was 59% (range, 12-93%, n = 22), while it was 63% (23-80%) in unaffected venules in the affected eye and 55% (39-80%) in venules in the fellow eye. The difference was not statistically significant (p > 0.05). There was a significant difference between affected arterioles (median 101%; range, 89-115%) and unaffected arterioles (95%, 85-104%) in the affected eye (p < 0.05, n = 18). CENTRAL RETINAL ARTERY OCCLUSION: In a patient with a day's history of central retinal artery occlusion due to temporal arteritis, the mean arteriolar saturation was 71 ± 9% and 63 ± 9% in the venules. One month later, after treatment with prednisolone, the mean arteriolar saturation was 100 ± 4% and the venous saturation 54 ± 5%. DIABETIC RETINOPATHY: When compared with healthy volunteers (n = 31), patients with all categories of diabetic retinopathy had on average 7-10 percentage points higher saturation in retinal arterioles (p < 0.05 for all categories, n = 6-8 in each category). In venules, the saturation was 8-12 percentage points higher (p < 0.05 for all categories). GLAUCOMA SURGERY: Oxygen saturation in retinal arterioles increased by 2 percentage points on average (p = 0.046, n = 19) with surgery, which lowered intraocular pressure from 23 ± 7 mmHg (mean ± SD) to 10 ± 4 mmHg (p < 0.0001). No other significant changes were found (p ≥ 0.35). DORZOLAMIDE: A significant reduction of 3 percentage points was found in arterioles (p < 0.01) and venules (p < 0.05) when patients with glaucoma or ocular hypertension changed from dorzolamide-timolol combination eye drops to timolol alone (n = 6). No change was found in patients, who started on timolol and switched to the combination therapy (p > 0.05, n = 7).
CONCLUSIONS
Dual wavelength oximetry can be used to non-invasively measure retinal vessel oxygen saturation in health and disease. The results indicate that retinal vessel oxygen saturation is (1) increased in the dark, (2) lower in venules affected by central retinal vein occlusions, (3) variable in branch retinal vein occlusion, (4) lower in retinal arterioles in central retinal artery occlusion, (5) increased in diabetic retinopathy, (6-7) mildly affected by glaucoma surgery or dorzolamide.
Topics: Adolescent; Adult; Aged; Antihypertensive Agents; Case-Control Studies; Dark Adaptation; Diabetic Retinopathy; Drug Combinations; Female; Glaucoma; Humans; Light; Male; Middle Aged; Oximetry; Oxygen; Regional Blood Flow; Retinal Artery Occlusion; Retinal Vein Occlusion; Retinal Vessels; Sulfonamides; Thiophenes; Timolol; Young Adult
PubMed: 23470088
DOI: 10.1111/aos.12086 -
Advances in Therapy Apr 2020A non-interventional, multicenter, European, prospective evaluation of the effectiveness, tolerability, and safety of a topical preservative-free tafluprost (0.0015%)... (Observational Study)
Observational Study
INTRODUCTION
A non-interventional, multicenter, European, prospective evaluation of the effectiveness, tolerability, and safety of a topical preservative-free tafluprost (0.0015%) and timolol (0.5%) fixed-dose combination (PF tafluprost/timolol FC) in adults with open-angle glaucoma (OAG) and ocular hypertension (OHT) demonstrating insufficient response to topical beta-receptor blockers or prostaglandin analogue (PGA) monotherapy.
METHODS
Mean intraocular pressure (IOP) change from baseline was measured at study visits following a switch to PF tafluprost/timolol FC. Primary endpoint was absolute mean IOP change at month 6. Change from baseline concerning ocular signs and symptoms was also explored.
RESULTS
Analyses included 577 patients (59.6% female). Mean age (SD) was 67.8 (11.67) years. Mean (SD) IOP reduction from baseline was significant at all study visits; 5.4 (3.76) mmHg (23.7%) at week 4, 5.9 (3.90) mmHg (25.6%) at week 12, and 5.7 (4.11) mmHg (24.9%) at month 6 (p < 0.0001 for all visits). At month 6, 69.2%, 53.6%, 40.0%, and 25.8% were responders based on ≥ 20%, ≥ 25%, ≥ 30%, and ≥ 35% cutoff values for mean IOP, respectively. Significant reductions were observed concerning corneal fluorescein staining (p < 0.0001), dry eye symptoms, irritation, itching, and foreign body sensation (p < 0.001 for each parameter). Conjunctival hyperemia was significantly reduced at all study visits (p < 0.0001 at each visit). Overall, 69 treatment-related adverse events (AEs) were reported, one of which was serious (status asthmaticus). Most AEs were mild to moderate in severity, and the majority had resolved or were resolving at the end of the study period.
CONCLUSION
In clinical practice, PF tafluprost/timolol FC provided statistically and clinically significant IOP reductions in patients with OAG and OHT insufficiently controlled on or intolerant to PGA or beta-receptor blocker monotherapy. The full IOP reduction appeared at week 4 and was maintained over the 6-month study period. Key symptoms of ocular surface health improved.
TRIAL REGISTRATION
European Union electronic Register of Post-Authorisation Studies (EU PAS) register number, EUPAS22204.
Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Drug Combinations; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Middle Aged; Ocular Hypertension; Preservatives, Pharmaceutical; Prospective Studies; Prostaglandins F; Prostaglandins, Synthetic; Timolol; Tonometry, Ocular
PubMed: 32072493
DOI: 10.1007/s12325-020-01239-8 -
Advances in Therapy Jan 2021The key clinical attributes of preserved dorzolamide/timolol fixed combination (DTFC) and the emerging potential of preservative-free (PF) DTFC are reviewed with... (Review)
Review
The key clinical attributes of preserved dorzolamide/timolol fixed combination (DTFC) and the emerging potential of preservative-free (PF) DTFC are reviewed with published evidence and clinical experience. The indications and role of DTFC in current glaucoma management are critically discussed. Preserved DTFC became the first intraocular pressure (IOP)-lowering fixed combination (FC) approved by the US Food and Drug Administration (FDA) and remains one of most commonly used medications worldwide. The pharmacological properties of DTFC reflect those of its two time-tested constituents, i.e., the carbonic anhydrase inhibitor dorzolamide and the non-selective beta-blocker timolol. In regulatory studies DTFC lowers IOP on average by 9 mmHg (32.7%) at peak and by 7.7 mmHg (27%) at trough. In trials DTFC shows equivalence to unfixed concomitant therapy, but in real-life practice it may prove superior owing to enhanced convenience, elimination of the washout effect from the second drop, improved tolerability, and better adherence. PF DTFC became the first PF FC approved, first in unit-dose pipettes, and more recently in a multidose format. Cumulative evidence has confirmed that PF DTFC is at least equivalent in efficacy to preserved DTFC and provides a tangible clinical benefit to patients with glaucoma suffering from ocular surface disease by improving tolerability and adherence. Finally, we identify areas that warrant further investigation with preserved and PF DTFC.
Topics: Antihypertensive Agents; Carbonic Anhydrase Inhibitors; Drug Combinations; Humans; Intraocular Pressure; Ocular Hypertension; Sulfonamides; Thiophenes; Timolol; Tonometry, Ocular
PubMed: 33108623
DOI: 10.1007/s12325-020-01525-5 -
Chirurgia (Bucharest, Romania : 1990) 2020Hemangiomas are the most common benign tumors in infancy and the uncontrolled increase in size can cause serious complications, requiring treatment in specialized...
Hemangiomas are the most common benign tumors in infancy and the uncontrolled increase in size can cause serious complications, requiring treatment in specialized centers. Despite their high frequency and possible complications, there is currently no consensus on optimal treatment. The strategy may vary from simple observation to the involvement of several medical, radiological and surgical specialties, requiring both pharmacological and surgical treatment. Aim: The current study analyzes the results of the treatment of hemangiomas performed in a tertiary hospital in Romania, in order to compare the data with those in the recent literature. In our retrospective study we analyzed the data of 142 patients treated in our tertiary hospital for a period of approximately 2 years. Demographics, localization of hemangiomas, duration of hospitalization and treatment, and complications were statistically analyzed. We achieved favourable outcomes in over 80-90% of cases by combining propranolol treatment with bleomycin injections, topical application of timolol and surgical excision, depending on the location and complexity of the hemangioma, and the age of the patient. The goal of hemangioma therapy is to stop hemangioma growth in its tracks, and has to provide relief and reassurance to patients and families. Such therapies might consist of combinations of drugs given concurrently or perhaps sequentially to target cells that are most active in the proliferating phase.
Topics: Antineoplastic Agents; Bleomycin; Child; Hemangioma; Humans; Infant; Propranolol; Retrospective Studies; Romania; Timolol; Treatment Outcome
PubMed: 33138909
DOI: 10.21614/chirurgia.115.5.643 -
BMC Ophthalmology Apr 2022Treatment of open angle glaucoma (OAG) and/or ocular hypertension (OHT) focuses on achievement of target intraocular pressure (IOP), with the objective of slowing...
BACKGROUND
Treatment of open angle glaucoma (OAG) and/or ocular hypertension (OHT) focuses on achievement of target intraocular pressure (IOP), with the objective of slowing disease progression. However, ocular surface health is an important consideration in the optimization of treatment. We report 6 patient cases in which enhanced IOP control was achieved following appropriate management of ocular surface inflammation and a therapeutic switch to the preservative-free (PF) tafluprost (0.0015%)/timolol (0.5%) fixed-dose combination (FC).
CASE PRESENTATION
Six patient cases, aged 48-74 years, presented with OAG or OHT. Each patient had signs and symptoms of ocular surface disease (OSD). Cases 1-3 were each receiving maximal medical therapy for OAG; regimens comprising prostaglandin analogue (PGA), β-blocker, carbonic anhydrase inhibitor (CAI) and α-2 agonist agents (including treatments containing preservative agent). Cases 1 and 2 reported IOP values ≥23 mmHg in each eye, and wide IOP fluctuations were identified when reviewing patient data concerning case 3 (11-20 mmHg). Maximal therapy was ceased and PF tafluprost/timolol FC was initiated, after which the signs and symptoms of OSD were improved and IOP was reduced (≤18 mmHg for cases 1-3) and stabilized. Cases 4 and 5 were diagnosed with OAG and case 6 had OHT. Each had symptoms and signs of OSD and were treated with a preserved PGA monotherapy (latanoprost 0.005% or bimatoprost 0.03%). At presentation, IOP was 24 mmHg in both eyes (case 4), ≥18 mmHg (case 5) and ≥ 22 mmHg (case 6). Following a switch to the PF tafluprost/timolol FC, OSD symptoms were improved and IOP was 14 mmHg (both eyes; case 4), ≤14 mmHg (case 5) and 16 mmHg (both eyes; case 6).
CONCLUSIONS
In addition to IOP-lowering efficacy, approaches to the management of OAG and OHT should consider the impact of treatment tolerability and the susceptibility of these patients to OSD. The presence of ocular surface inflammation appears to be detrimental to adherence and therefore to the effectiveness of topical medications. Addressing OSD through the use of PF FC formations, such as the PF tafluprost/timolol FC, reduces exposure to potentially toxic agents and facilitates improvements in IOP control.
Topics: Aged; Antihypertensive Agents; Glaucoma, Open-Angle; Humans; Middle Aged; Ocular Hypertension; Prostaglandins F; Timolol
PubMed: 35366846
DOI: 10.1186/s12886-022-02361-7 -
Advances in Therapy Jun 2021Reducing intraocular pressure (IOP), the only modifiable risk factor for open-angle glaucoma (OAG), is important for the preservation of vision and slowing of disease... (Observational Study)
Observational Study
Treatment of Open-Angle Glaucoma and Ocular Hypertension with Preservative-Free Tafluprost/Timolol Fixed-Dose Combination Therapy: UK and Ireland Results from the VISIONARY Study.
INTRODUCTION
Reducing intraocular pressure (IOP), the only modifiable risk factor for open-angle glaucoma (OAG), is important for the preservation of vision and slowing of disease progression. Preservative-free tafluprost (0.0015%)/timolol (0.5%) fixed combination (PF Taf-T FC) is an approved combination therapy for OAG treatment. The VISIONARY study aimed to evaluate the effectiveness and tolerability of PF Taf-T FC in real-world clinical settings. Here, we present the results from the United Kingdom (UK) and Ireland.
METHODS
This observational, multicentre, European, prospective study recorded data during routine clinic appointments on the use of PF Taf-T FC for the treatment of OAG and ocular hypertension (OHT) in patients whose disease was insufficiently controlled on a prostaglandin analogue (PGA) or beta blocker monotherapy or who did not tolerate these medications. Mean change in IOP, symptom severity, changes in clinical signs, and tolerability were investigated over 6 months.
RESULTS
Eighty-two patients were recruited in the UK and Ireland. After 6 months of PF Taf-T FC treatment, mean IOP was significantly reduced from 22.0 to 16.2 mmHg in the UK group and from 18.6 to 14.1 mmHg in the Ireland group. In the UK (65 patients), 49 adverse events (AEs) were reported, of which 3 were serious. No AEs were reported in the Ireland group (17 patients). Overall, 91.9% of UK physicians reported PF Taf-T FC treatment to be the same or better than prior medication for improving clinical signs; 90.0% of UK patients reported PF Taf-T FC treatment to have good or very good tolerability.
CONCLUSIONS
Treatment with PF Taf-T FC resulted in significant reductions in mean IOP over 6 months. Patients and physicians reported that treatment was well tolerated. These data demonstrate real-world efficacy of PF Taf-T FC for the treatment of OAG and OHT in routine clinical practice in the UK and Ireland.
TRIAL REGISTRATION
European Union electronic Register of Post-Authorisation Studies (EU PAS) register number, EUPAS22204.
Topics: Antihypertensive Agents; Drug Combinations; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Ireland; Ocular Hypertension; Prospective Studies; Prostaglandins F; Timolol; United Kingdom
PubMed: 33886093
DOI: 10.1007/s12325-021-01725-7 -
Clinical Medicine & Research Dec 2019Timolol is a commonly-used topical antiglaucoma medication and has proven to be highly efficacious for most recipients. Among the reported adverse events, the... (Review)
Review
Timolol is a commonly-used topical antiglaucoma medication and has proven to be highly efficacious for most recipients. Among the reported adverse events, the neuropsychiatric spectrum has been cited, albeit for a small proportion of those treated. This review summarizes the cumulative published experience of such side effects and assesses the quality of evidence. As for other beta-blockers, whether orally or topically administered, various central nervous systems dysfunctions have been detailed in either case reports or larger patient series. The adverse event commonly resolves following drug termination. Rigorous and more definitive studies of causation are lacking, and to some, such paucity has reduced the belief of a cause and effect relationship. Until otherwise proven, deference should be afforded to the potential for topical timolol to cause neuropsychiatric side effects, and at-risk patients should be closely monitored when they are prescribed this pharmacological agent.
Topics: Administration, Topical; Adrenergic beta-Antagonists; Central Nervous System; Central Nervous System Diseases; Glaucoma; Global Health; Humans; Incidence; Mental Disorders; Ophthalmic Solutions; Timolol
PubMed: 31462538
DOI: 10.3121/cmr.2019.1486 -
The Cochrane Database of Systematic... Apr 2018Infantile haemangiomas (previously known as strawberry birthmarks) are soft, raised swellings of the skin that occur in 3% to 10% of infants. These benign vascular... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Infantile haemangiomas (previously known as strawberry birthmarks) are soft, raised swellings of the skin that occur in 3% to 10% of infants. These benign vascular tumours are usually uncomplicated and tend to regress spontaneously. However, when haemangiomas occur in high-risk areas, such as near the eyes, throat, or nose, impairing their function, or when complications develop, intervention may be necessary. This is an update of a Cochrane Review first published in 2011.
OBJECTIVES
To assess the effects of interventions for the management of infantile haemangiomas in children.
SEARCH METHODS
We updated our searches of the following databases to February 2017: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, AMED, LILACS, and CINAHL. We also searched five trials registries and checked the reference lists of included studies for further references to relevant trials.
SELECTION CRITERIA
Randomised controlled trials (RCTs) of all types of interventions, versus placebo, active monitoring, or other interventions, in any child with single or multiple infantile haemangiomas (IHs) located on the skin.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane. The primary outcome measures were clearance, a subjective measure of improvement, and adverse events. Secondary outcomes were other measures of resolution; proportion of parents or children who consider there is still a problem; aesthetic appearance; and requirement for surgical correction. We used GRADE to assess the quality of the evidence for each outcome; this is indicated in italics.
MAIN RESULTS
We included 28 RCTs, with a total of 1728 participants, assessing 12 different interventions, including lasers, beta blockers (e.g. propranolol, timolol maleate), radiation therapy, and steroids. Comparators included placebo, an active monitoring approach, sham radiation, and interventions given alone or in combination.Studies were conducted in a number of countries, including China, Egypt, France, and Australia. Participant age ranged from 12 weeks to 13.4 years. Most studies (23/28) included a majority of females and different types of IHs. Duration of follow-up ranged from 7 days to 72 months.We considered most of the trials as at low risk of random sequence generation, attrition bias, and selective reporting bias. Domains such as allocation concealment and blinding were not clearly reported in general. We downgraded evidence for issues related to risk of bias and imprecision.We report results for the three most important comparisons, which we chose on the basis of current use. Outcome measurement of these comparisons was at 24 weeks' follow-up.Oral propranolol versus placeboCompared with placebo, oral propranolol 3 mg/kg/day probably improves clinician-assessed clearance (risk ratio (RR) 16.61, 95% confidence interval (CI) 4.22 to 65.34; 1 study; 156 children; moderate-quality evidence) and probably leads to a clinician-assessed reduction in mean haemangioma volume of 45.9% (95% CI 11.60 to 80.20; 1 study; 40 children; moderate-quality evidence). We found no evidence of a difference in terms of short- or long-term serious adverse events (RR 1.05, 95% CI 0.33 to 3.39; 3 studies; 509 children; low-quality evidence), nor in terms of bronchospasm, hypoglycaemia, or serious cardiovascular adverse events. The results relating to clearance and resolution for this comparison were based on one industry-sponsored study.Topical timolol maleate versus placeboThe chance of reduction of redness, as a measure of clinician-assessed resolution, may be improved with topical timolol maleate 0.5% gel applied twice daily when compared with placebo (RR 8.11, 95% CI 1.09 to 60.09; 1 study; 41 children;low-quality evidence). Regarding short- or long-term serious cardiovascular events, we found no instances of bradycardia (slower than normal heart rate) or hypotension in either group (1 study; 41 children; low-quality evidence). No other safety data were assessed, and clearance was not measured.Oral propranolol versus topical timolol maleateWhen topical timolol maleate (0.5% eye drops applied twice daily) was compared with oral propranolol (via a tablet taken once per day, at a 1.0 mg/kg dose), there was no evidence of a difference in haemangioma size (as a measure of resolution) when measured by the proportion of patients with a clinician-assessed reduction of 50% or greater (RR 1.13, 95% CI 0.64 to 1.97; 1 study; 26 participants; low-quality evidence). Although there were more short- or long-term general adverse effects (such as severe diarrhoea, lethargy, and loss of appetite) in the oral propranolol group, there was no evidence of a difference between groups (RR 7.00, 95% CI 0.40 to 123.35; 1 study; 26 participants; very low-quality evidence). This comparison did not measure clearance.None of our key comparisons evaluated, at any follow-up, a subjective measure of improvement assessed by the parent or child; proportion of parents or children who consider there is still a problem; or physician-, child-, or parent-assessed aesthetic appearance.
AUTHORS' CONCLUSIONS
We found there to be a limited evidence base for the treatment of infantile haemangiomas: a large number of interventions and outcomes have not been assessed in RCTs.Our key results indicate that in the management of IH in children, oral propranolol and topical timolol maleate are more beneficial than placebo in terms of clearance or other measures of resolution, or both, without an increase in harms. We found no evidence of a difference between oral propranolol and topical timolol maleate with regard to reducing haemangioma size, but we are uncertain if there is a difference in safety. Oral propranolol is currently the standard treatment for this condition, and our review has not found evidence to challenge this. However, these results are based on moderate- to very low-quality evidence.The included studies were limited by small sample sizes and risk of bias in some domains. Future trials should blind personnel and participants; describe trials thoroughly in publications; and recruit a sufficient number of children to deduce meaningful results. Future trials should assess patient-reported outcomes, as well as objective outcomes of benefit, and should report adverse events comprehensively. Propranolol and timolol maleate require further assessment in RCTs of all types of IH, including those considered problematic, as do other lesser-used interventions and new interventions. All treatments should be compared against propranolol and timolol maleate, as beta blockers are approved as standard care.
Topics: Adrenal Cortex Hormones; Adrenergic beta-Antagonists; Antineoplastic Agents; Bleomycin; Child, Preschool; Hemangioma, Capillary; Humans; Infant; Lasers, Dye; Methylprednisolone; Photochemotherapy; Prednisolone; Propranolol; Radiotherapy; Randomized Controlled Trials as Topic; Remission Induction; Skin Neoplasms; Timolol
PubMed: 29667726
DOI: 10.1002/14651858.CD006545.pub3