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The Cochrane Database of Systematic... Apr 2019Hand eczema is an inflammation of the skin of the hands that tends to run a chronic, relapsing course. This common condition is often associated with itch, social... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Hand eczema is an inflammation of the skin of the hands that tends to run a chronic, relapsing course. This common condition is often associated with itch, social stigma, and impairment in employment. Many different interventions of unknown effectiveness are used to treat hand eczema.
OBJECTIVES
To assess the effects of topical and systemic interventions for hand eczema in adults and children.
SEARCH METHODS
We searched the following up to April 2018: Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, AMED, LILACS, GREAT, and four trials registries. We checked the reference lists of included studies for further references to relevant trials.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) that compared interventions for hand eczema, regardless of hand eczema type and other affected sites, versus no treatment, placebo, vehicle, or active treatments.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane. Primary outcomes were participant- and investigator-rated good/excellent control of symptoms, and adverse events.
MAIN RESULTS
We included 60 RCTs, conducted in secondary care (5469 participants with mild to severe chronic hand eczema). Most participants were over 18 years old. The duration of treatment was short, generally up to four months. Only 24 studies included a follow-up period. Clinical heterogeneity in treatments and outcome measures was evident. Few studies performed head-to-head comparisons of different interventions. Risk of bias varied considerably, with only five studies at low risk in all domains. Twenty-two studies were industry-funded.Eighteen trials studied topical corticosteroids or calcineurin inhibitors; 10 studies, phototherapy; three studies, systemic immunosuppressives; and five studies, oral retinoids. Most studies compared an active intervention against no treatment, variants of the same medication, or placebo (or vehicle). Below, we present results from the main comparisons.Corticosteroid creams/ointments: when assessed 15 days after the start of treatment, clobetasol propionate 0.05% foam probably improves participant-rated control of symptoms compared to vehicle (risk ratio (RR) 2.32, 95% confidence interval (CI) 1.38 to 3.91; number needed to treat for an additional beneficial outcome (NNTB) 3, 95% CI 2 to 8; 1 study, 125 participants); the effect of clobetasol compared to vehicle for investigator-rated improvement is less clear (RR 1.43, 95% CI 0.86 to 2.40). More participants had at least one adverse event with clobetasol (11/62 versus 5/63; RR 2.24, 95% CI 0.82 to 6.06), including application site burning/pruritus. This evidence was rated as moderate certainty.When assessed 36 weeks after the start of treatment, mometasone furoate cream used thrice weekly may slightly improve investigator-rated symptom control compared to twice weekly (RR 1.23, 95% CI 0.94 to 1.61; 1 study, 72 participants) after remission is reached. Participant-rated symptoms were not measured. Some mild atrophy was reported in both groups (RR 1.76, 95% CI 0.45 to 6.83; 5/35 versus 3/37). This evidence was rated as low certainty.Irradiation with ultraviolet (UV) light: local combination ultraviolet light therapy (PUVA) may lead to improvement in investigator-rated symptom control when compared to local narrow-band UVB after 12 weeks of treatment (RR 0.50, 95% CI 0.22 to 1.16; 1 study, 60 participants). However, the 95% CI indicates that PUVA might make little or no difference. Participant-rated symptoms were not measured. Adverse events (mainly erythema) were reported by 9/30 participants in the narrow-band UVB group versus none in the PUVA group. This evidence was rated as moderate certainty.Topical calcineurin inhibitors: tacrolimus 0.1% over two weeks probably improves investigator-rated symptom control measured after three weeks compared to vehicle (14/14 tacrolimus versus 0/14 vehicle; 1 study). Participant-rated symptoms were not measured. Four of 14 people in the tacrolimus group versus zero in the vehicle group had well-tolerated application site burning/itching.A within-participant study in 16 participants compared 0.1% tacrolimus to 0.1% mometasone furoate but did not measure investigator- or participant-rated symptoms. Both treatments were well tolerated when assessed at two weeks during four weeks of treatment.Evidence from these studies was rated as moderate certainty.Oral interventions: oral cyclosporin 3 mg/kg/d probably slightly improves investigator-rated (RR 1.88, 95% CI 0.88 to 3.99; 1 study, 34 participants) or participant-rated (RR 1.25, 95% CI 0.69 to 2.27) control of symptoms compared to topical betamethasone dipropionate 0.05% after six weeks of treatment. The risk of adverse events such as dizziness was similar between groups (up to 36 weeks; RR 1.22, 95% CI 0.80 to 1.86, n = 55; 15/27 betamethasone versus 19/28 cyclosporin). The evidence was rated as moderate certainty.Alitretinoin 10 mg improves investigator-rated symptom control compared with placebo (RR 1.58, 95% CI 1.20 to 2.07; NNTB 11, 95% CI 6.3 to 26.5; 2 studies, n = 781) and alitretinoin 30 mg also improves this outcome compared with placebo (RR 2.75, 95% CI 2.20 to 3.43; NNTB 4, 95% CI 3 to 5; 2 studies, n = 1210). Similar results were found for participant-rated symptom control: alitretinoin 10 mg RR 1.73 (95% CI 1.25 to 2.40) and 30 mg RR 2.75 (95% CI 2.18 to 3.48). Evidence was rated as high certainty. The number of adverse events (including headache) probably did not differ between alitretinoin 10 mg and placebo (RR 1.01, 95% CI 0.66 to 1.55; 1 study, n = 158; moderate-certainty evidence), but the risk of headache increased with alitretinoin 30 mg (RR 3.43, 95% CI 2.45 to 4.81; 2 studies, n = 1210; high-certainty evidence). Outcomes were assessed between 48 and 72 weeks.
AUTHORS' CONCLUSIONS
Most findings were from single studies with low precision, so they should be interpreted with caution. Topical corticosteroids and UV phototherapy were two of the major standard treatments, but evidence is insufficient to support one specific treatment over another. The effect of topical calcineurin inhibitors is not certain. Alitretinoin is more effective than placebo in controlling symptoms, but advantages over other treatments need evaluating.Well-designed and well-reported, long-term (more than three months), head-to-head studies comparing different treatments are needed. Consensus is required regarding the definition of hand eczema and its subtypes, and a standard severity scale should be established.The main limitation was heterogeneity between studies. Small sample size impacted our ability to detect differences between treatments.
Topics: Calcineurin Inhibitors; Eczema; Emollients; Humans; Immunosuppressive Agents; Odds Ratio; Pruritus; Randomized Controlled Trials as Topic; Severity of Illness Index; Treatment Outcome
PubMed: 31025714
DOI: 10.1002/14651858.CD004055.pub2 -
The Cochrane Database of Systematic... Apr 2016This review is one of six looking at the primary medical management options for patients with chronic rhinosinusitis.Chronic rhinosinusitis is common and is... (Review)
Review
BACKGROUND
This review is one of six looking at the primary medical management options for patients with chronic rhinosinusitis.Chronic rhinosinusitis is common and is characterised by inflammation of the lining of the nose and paranasal sinuses leading to nasal blockage, nasal discharge, facial pressure/pain and loss of sense of smell. The condition can occur with or without nasal polyps. Topical (intranasal) corticosteroids are used with the aim of reducing inflammation in the sinonasal mucosa in order to improve patient symptoms.
OBJECTIVES
To assess the effects of different types of intranasal steroids in people with chronic rhinosinusitis.
SEARCH METHODS
The Cochrane ENT Information Specialist searched the ENT Trials Register; Central Register of Controlled Trials (CENTRAL 2015, Issue 7); MEDLINE; EMBASE; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 11 August 2015.
SELECTION CRITERIA
Randomised controlled trials (RCTs) with a follow-up period of at least three months comparing first-generation intranasal corticosteroids (e.g. beclomethasone dipropionate, triamcinolone acetonide, flunisolide, budesonide) with second-generation intranasal corticosteroids (e.g. ciclesonide, fluticasone furoate, fluticasone propionate, mometasone furoate, betamethasone sodium phosphate), or sprays versus drops, or low-dose versus high-dose intranasal corticosteroids.
DATA COLLECTION AND ANALYSIS
We used the standard methodological procedures expected by Cochrane. Our primary outcomes were disease-specific health-related quality of life (HRQL), patient-reported disease severity and the commonest adverse event - epistaxis (nosebleed). Secondary outcomes included general HRQL, endoscopic nasal polyp score, computerised tomography (CT) scan score and the adverse event of local irritation. We used GRADE to assess the quality of the evidence for each outcome; this is indicated in italics.
MAIN RESULTS
We included nine RCTs (911 participants), including four different comparisons. None of the studies evaluated our first primary outcome measure, disease-specific HRQL. Fluticasone propionate versus beclomethasone dipropionate We identified two small studies (56 participants with polyps) that evaluated disease severity and looked at the primary adverse effect: epistaxis , but no other outcomes. We cannot report any numerical data but the study authors reported no difference between the two steroids. The evidence was of very low quality. Fluticasone propionate versus mometasone furoate We identified only one study (100 participants with polyps) that evaluated disease severity (nasal symptoms scores), which reported no difference (no numerical data available). The evidence was of very low quality. High-dose versus low-dose steroidsWe included five studies (663 participants with nasal polyps), three using mometasone furoate (400 µg versus 200 µg in adults and older children, 200 µg versus 100 µg in younger children) and two using fluticasone propionate drops (800 µg versus 400 µg). We found low quality evidence relating to disease severity and nasal polyps size, with results from the high-dose and low-dose groups being similar. Although all studies reported more improvement in polyp score in the high-dose group, the significance of this is unclear due to the small size of the improvements.The primary adverse effect, epistaxis , was more common when higher doses were used (risk ratio (RR) 2.06, 95% confidence interval (CI) 1.20 to 3.54, 637 participants, moderate quality evidence). Most of the studies that contributed data to this outcome used a broad definition of epistaxis, which ranged from frank bleeding to bloody nasal discharge to flecks of blood in the mucus. Aqueous nasal spray versus aerosol spray We identified only one poorly reported study (unclear number of participants for comparison of interest, 91 between three treatment arms), in which there were significant baseline differences between the participants in the two groups. We were unable to draw meaningful conclusions from the data.
AUTHORS' CONCLUSIONS
We found insufficient evidence to suggest that one type of intranasal steroid is more effective than another in patients with chronic rhinosinusitis, nor that the effectiveness of a spray differs from an aerosol. We identified no studies that compared drops with spray.It is unclear if higher doses result in better symptom improvements (low quality evidence), but there was moderate quality evidence of an increased risk of epistaxis as an adverse effect of treatment when higher doses were used. This included all levels of severity of epistaxis and it is likely that the proportion of events that required patients to discontinue usage is low due to the low numbers of withdrawals attributed to it. If epistaxis is limited to streaks of blood in the mucus it may be tolerated by the patient and it may be safe to continue treatment. However, it may be a factor that affects compliance.There is insufficient evidence to suggest that the different types of corticosteroid molecule or spray versus aerosol have different effects. Lower doses have similar effectiveness but fewer side effects.Clearly more research in this area is needed, with specific attention given to trial design, disease-specific health-related quality of life outcomes and evaluation of longer-term outcomes and adverse effects.
Topics: Administration, Intranasal; Adult; Beclomethasone; Child; Chronic Disease; Fluticasone; Humans; Mometasone Furoate; Nasal Polyps; Nasal Sprays; Randomized Controlled Trials as Topic; Rhinitis; Sinusitis; Steroids
PubMed: 27115215
DOI: 10.1002/14651858.CD011993.pub2 -
The Cochrane Database of Systematic... Dec 2011Lichen sclerosus is a chronic, inflammatory skin condition that most commonly occurs in adult women, although it may also be seen in men and children. It primarily... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Lichen sclerosus is a chronic, inflammatory skin condition that most commonly occurs in adult women, although it may also be seen in men and children. It primarily affects the genital area and around the anus, where it causes persistent itching and soreness. Scarring after inflammation may lead to severe damage by fusion of the vulval lips (labia); narrowing of the vaginal opening; and burying of the clitoris in women and girls, as well as tightening of the foreskin in men and boys, if treatments are not started early. Affected people have an increased risk of genital cancers.
OBJECTIVES
To assess the effects of topical interventions for genital lichen sclerosus and adverse effects reported in included trials.
SEARCH METHODS
We searched the following databases up to 16 September 2011: the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE (from 2005), EMBASE (from 2007), LILACS (from 1982), CINAHL (from 1981), British Nursing Index and Archive (from 1985), Science Citation Index Expanded (from 1945), BIOSIS Previews (from 1926), Conference Papers Index (from 1982), and Conference Proceedings Citation Index - Science (from 1990). We also searched ongoing trial registries and scanned the bibliographies of included studies, published reviews, and papers that had cited the included studies.
SELECTION CRITERIA
Randomised controlled trials (RCTs) of topical interventions in genital lichen sclerosus.
DATA COLLECTION AND ANALYSIS
Two authors independently selected trials, extracted data, and assessed the risk of bias. A third author was available for resolving differences of opinion.
MAIN RESULTS
We included 7 RCTs, with a total of 249 participants, covering 6 treatments. Six of these RCTs tested the efficacy of one active intervention against placebo or another active intervention, while the other trial tested three active interventions against placebo.When compared to placebo in one trial, clobetasol propionate 0.05% was effective in treating genital lichen sclerosus in relation to the following outcomes: 'participant-rated improvement or remission of symptoms' (risk ratio (RR) 2.85, 95% confidence interval (CI) 1.45 to 5.61) and 'investigator-rated global degree of improvement' (standardised mean difference (SMD) 5.74, 95% CI 4.26 to 7.23).When mometasone furoate 0.05% was compared to placebo in another trial, there was a significant improvement in the 'investigator-rated change in clinical grade of phimosis' (SMD -1.04, 95% CI -1.77 to -0.31).Both trials found no significant differences in reported adverse drug reactions between the corticosteroid and placebo groups. The data from four trials found no significant benefit for topical testosterone, dihydrotestosterone, and progesterone. When used as maintenance therapy after an initial treatment with topical clobetasol propionate in another trial, topical testosterone worsened the symptoms (P < 0.05), but the placebo did not.One trial found no differences between pimecrolimus and clobetasol propionate in relieving symptoms through change in pruritus (itching) (SMD -0.33, 95% CI -0.99 to 0.33) and burning/pain (SMD 0.03, 95% CI -0.62 to 0.69). However, pimecrolimus was less effective than clobetasol propionate with regard to the 'investigator-rated global degree of improvement' (SMD -1.64, 95% CI -2.40 to -0.87). This trial found no significant differences in reported adverse drug reactions between the pimecrolimus and placebo groups.
AUTHORS' CONCLUSIONS
The current limited evidence demonstrates the efficacy of clobetasol propionate, mometasone furoate, and pimecrolimus in treating genital lichen sclerosus. Further RCTs are needed to determine the optimal potency and regimen of topical corticosteroids, examine other topical interventions, assess the duration of remission or prevention of flares, evaluate the reduction in the risk of genital squamous cell carcinoma or genital intraepithelial neoplasia, and examine the efficacy in improving the quality of the sex lives of people with this condition.
Topics: Adult; Anti-Inflammatory Agents; Child; Clobetasol; Dermatologic Agents; Dihydrotestosterone; Female; Genital Diseases, Male; Humans; Lichen Sclerosus et Atrophicus; Male; Mometasone Furoate; Pregnadienediols; Randomized Controlled Trials as Topic; Tacrolimus; Testosterone Propionate; Vulvar Lichen Sclerosus
PubMed: 22161424
DOI: 10.1002/14651858.CD008240.pub2 -
Annals of Family Medicine 2012Acute sinusitis is a common condition in ambulatory care, where it is frequently treated with antibiotics, despite little evidence of their benefit. Intranasal... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Acute sinusitis is a common condition in ambulatory care, where it is frequently treated with antibiotics, despite little evidence of their benefit. Intranasal corticosteroids might relieve symptoms; however, evidence for this benefit is currently unclear. We performed a systematic review and meta-analysis of the effects of intranasal corticosteroids on the symptoms of acute sinusitis.
METHODS
We searched MEDLINE, EMBASE, the Cochrane Central register of Controlled Trials (CENTRAL), and Centre for Reviews and Dissemination databases until February 2011 for studies comparing intranasal corticosteroids with placebo in children or adults having clinical symptoms and signs of acute sinusitis or rhinosinusitis in ambulatory settings. We excluded chronic/allergic sinusitis. Two authors independently extracted data and assessed the studies' methodologic quality.
RESULTS
We included 6 studies having a total of 2,495 patients. In 5 studies, antibiotics were prescribed in addition to corticosteroids or placebo. Intranasal corticosteroids resulted in a significant, small increase in resolution of or improvement in symptoms at days 14 to 21 (risk difference [RD] = 0.08; 95% CI, 0.03-0.13). Analysis of individual symptom scores revealed most consistently significant benefits for facial pain and congestion. Subgroup analysis by time of reported outcomes showed a significant beneficial effect at 21 days (RD = 0.11; 95% CI, 0.06-0.17), but not at 14 to 15 days (RD = 0.05; 95% CI, -0.01 to 0.11). Meta-regression analysis of trials using different doses of mometasone furoate showed a significant dose-response relationship (P=.02).
CONCLUSIONS
Intranasal corticosteroids offer a small therapeutic benefit in acute sinusitis, which may be greater with high doses and with courses of 21 days' duration. Further trials are needed in antibiotic-naïve patients.
Topics: Acute Disease; Administration, Intranasal; Adrenal Cortex Hormones; Adult; Anti-Bacterial Agents; Child; Dose-Response Relationship, Drug; Humans; Regression Analysis; Sinusitis
PubMed: 22585889
DOI: 10.1370/afm.1338 -
Medicine Jul 2019This study aims to systematically explore the efficacy and safety of mometasone furoate (MTF) for patients with nasal polyps (NP).
BACKGROUND
This study aims to systematically explore the efficacy and safety of mometasone furoate (MTF) for patients with nasal polyps (NP).
METHODS
We will search MEDLINE, Cochrane Library, PubMed, Springer, Web of Science, Ovid, Wangfang and Chinese Biomedical Literature Database from their inception to April 30, 2019 without language restrictions. All randomized controlled trials (RCTs) of MTF for the treatment of NP will be considered for inclusion. RevMan 5.3 software will be used for data synthesis, subgroup analysis, sensitivity analysis, as well as the meta-analysis.
RESULTS
Primary outcomes include change in symptom scores (as measured by any symptom scores), and polyp size (as assessed by any Polyp size scores or tools). Secondary outcomes consist of polyp recurrence, change in nasal air flow, quality of life outcomes (as measured by any quality of life scales, such as Short Form Health Survey is a 36-item), and adverse events.
CONCLUSION
This study will provide evidence for judging whether MTF is an effective and safe treatment for NP or not.
PROSPERO REGISTRATION NUMBER
PROSPERO CRD42019134037.
Topics: Administration, Intranasal; Anti-Inflammatory Agents; Humans; Mometasone Furoate; Nasal Polyps; Quality of Life; Randomized Controlled Trials as Topic; Recurrence; Research Design
PubMed: 31348314
DOI: 10.1097/MD.0000000000016632 -
The Cochrane Database of Systematic... Jul 2014Inhaled corticosteroids (ICS) are the first-line treatment for children with persistent asthma. Their potential for growth suppression remains a matter of concern for... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Inhaled corticosteroids (ICS) are the first-line treatment for children with persistent asthma. Their potential for growth suppression remains a matter of concern for parents and physicians.
OBJECTIVES
To assess whether increasing the dose of ICS is associated with slower linear growth, weight gain and skeletal maturation in children with asthma.
SEARCH METHODS
We searched the Cochrane Airways Group Specialised Register of trials (CAGR) and the ClinicalTrials.gov website up to March 2014.
SELECTION CRITERIA
Studies were eligible if they were parallel-group randomised trials evaluating the impact of different doses of the same ICS using the same device in both groups for a minimum of three months in children one to 17 years of age with persistent asthma.
DATA COLLECTION AND ANALYSIS
Two review authors ascertained methodological quality independently using the Cochrane Risk of bias tool. The primary outcome was linear growth velocity. Secondary outcomes included change over time in growth velocity, height, weight, body mass index and skeletal maturation.
MAIN RESULTS
Among 22 eligible trials, 17 group comparisons were derived from 10 trials (3394 children with mild to moderate asthma), measured growth and contributed data to the meta-analysis. Trials used ICS (beclomethasone, budesonide, ciclesonide, fluticasone or mometasone) as monotherapy or as combination therapy with a long-acting beta2-agonist and generally compared low (50 to 100 μg) versus low to medium (200 μg) doses of hydrofluoroalkane (HFA)-beclomethasone equivalent over 12 to 52 weeks. In the four comparisons reporting linear growth over 12 months, a significant group difference was observed, clearly indicating lower growth velocity in the higher ICS dose group of 5.74 cm/y compared with 5.94 cm/y on lower-dose ICS (N = 728 school-aged children; mean difference (MD)0.20 cm/y, 95% confidence interval (CI) 0.02 to 0.39; high-quality evidence): No statistically significant heterogeneity was noted between trials contributing data. The ICS molecules (ciclesonide, fluticasone, mometasone) used in these four comparisons did not significantly influence the magnitude of effect (X(2) = 2.19 (2 df), P value 0.33). Subgroup analyses on age, baseline severity of airway obstruction, ICS dose and concomitant use of non-steroidal antiasthmatic drugs were not performed because of similarity across trials or inadequate reporting. A statistically significant group difference was noted in unadjusted change in height from zero to three months (nine comparisons; N = 944 children; MD 0.15, 95% CI -0.28 to -0.02; moderate-quality evidence) in favour of a higher ICS dose. No statistically significant group differences in change in height were observed at other time points, nor were such differences in weight, bone mass index and skeletal maturation reported with low quality of evidence due to imprecision.
AUTHORS' CONCLUSIONS
In prepubescent school-aged children with mild to moderate persistent asthma, a small but statistically significant group difference in growth velocity was observed between low doses of ICS and low to medium doses of HFA-beclomethasone equivalent, favouring the use of low-dose ICS. No apparent difference in the magnitude of effect was associated with three molecules reporting one-year growth velocity, namely, mometasone, ciclesonide and fluticasone. In view of prevailing parents' and physicians' concerns about the growth suppressive effect of ICS, lack of or incomplete reporting of growth velocity in more than 86% (19/22) of eligible paediatric trials, including those using beclomethasone and budesonide, is a matter of concern. All future paediatric trials comparing different doses of ICS with or without placebo should systematically document growth. Findings support use of the minimal effective ICS dose in children with asthma.
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Androstadienes; Anti-Asthmatic Agents; Asthma; Beclomethasone; Budesonide; Child; Dose-Response Relationship, Drug; Fluticasone; Growth; Growth Disorders; Humans; Mometasone Furoate; Pregnadienediols; Pregnenediones; Randomized Controlled Trials as Topic
PubMed: 25030199
DOI: 10.1002/14651858.CD009878.pub2 -
Health Technology Assessment... Nov 2004To assess the clinical and cost-effectiveness of once-daily use of topical corticosteroids versus more frequent use of same-potency topical corticosteroids in the... (Review)
Review
Clinical and cost-effectiveness of once-daily versus more frequent use of same potency topical corticosteroids for atopic eczema: a systematic review and economic evaluation.
OBJECTIVES
To assess the clinical and cost-effectiveness of once-daily use of topical corticosteroids versus more frequent use of same-potency topical corticosteroids in the treatment of people with atopic eczema.
DATA SOURCES
Electronic databases. Bibliographies of included studies and related papers. Experts in the field. Manufacturer submissions to the National Institute for Clinical Excellence.
REVIEW METHODS
Studies were assessed for inclusion according to predefined criteria by two reviewers. Data extraction and quality assessment were undertaken by one reviewer and checked by a second reviewer. Clinical effectiveness data were synthesised through a narrative review with full tabulation of results.
RESULTS
One RCT comparing moderately potent corticosteroids, eight RCTs comparing potent corticosteroids and one RCT comparing very potent corticosteroids were included. No RCTs or CCTs of mild corticosteroids were eligible. Most RCTs were of poor methodological quality, although two were judged to be of good quality. The only study that compared moderately potent corticosteroids found no significant difference between once- and twice-daily application. For potent corticosteroids, some statistically significant differences in numbers of patients responding to treatment were identified favouring twice-daily treatment, but these were inconsistent between physician and patient assessment and outcomes selected for analysis. Two studies found a significant improvement in some symptoms with once-daily mometasone furoate compared with twice-daily application of a different active compound, while a third study found no significant differences. One good-quality study favoured twice-daily application of fluticasone propionate ointment, while other studies found no significant difference or an improvement in one symptom but not others. The only study comparing very potent corticosteroids found a statistically significant difference in comparative clinical response in favour of three-times daily treatment, but no difference in number of patients with at least a good response. There appears to be little difference in the frequency or severity of short-term events, however data are limited. No published economic evaluations were identified. Given findings on clinical effectiveness, where outcomes from the comparators are similar, the relative cost-effectiveness of once-daily versus more frequent application of topical corticosteroids becomes a case of cost-minimisation, where the least-cost alternative should be favoured, all else being equal. Topical corticosteroid products included in this review have a wide variation in price; the cost per 30 g/30 ml varies between GBP0.60 and GBP4.88. Specific decisions on the least-cost alternative, between once-daily and more frequent application of products, will be determined by the relative price of the products being compared. Where patients can be appropriately prescribed once-daily treatment of a similarly priced product, a reduction in the quantity of topical corticosteroid used will be expected. However, issues related to pack size for prescribed products and subsequent waste (unused product) could easily erode any potential saving. The potential cost-savings on prescribed products are very small at a patient level; although given the large numbers of patients with atopic eczema, cost savings in theory could be substantial. The presence of specifically marketed 'once-daily' topical corticosteroids, which are relatively expensive (per unit price), may result in additional costs should there be a general recommendation in favour of once-daily use of topical corticosteroids, compared to more frequent use.
CONCLUSIONS
The literature is very limited; that available indicates the clinical effectiveness of once-daily and more frequent application of potent topical corticosteroids is very similar, but it does not offer a basis for favouring either option. The cost-effectiveness of once-daily versus more frequent use will depend on the generalisability of the findings to the specific treatment decision and the relative product prices. The trials included in this review generally refer to moderate to severe atopic eczema, whereas most patients have mild disease, and furthermore most of the included trials report on potent topical corticosteroids (eight of 10 RCTs); therefore the generalisability of the findings is limited. Further research is required on the clinical and cost-effectiveness of once-daily versus more frequent use of same potency corticosteroids, specifically on mild potency products for mild to moderate atopic eczema. Outcomes should include quality of life and compliance.
Topics: Administration, Topical; Adolescent; Adrenal Cortex Hormones; Adult; Child; Child, Preschool; Cost-Benefit Analysis; Dermatitis, Atopic; Drug Administration Schedule; Humans; Infant; Prevalence; Randomized Controlled Trials as Topic; Severity of Illness Index; Treatment Outcome; United Kingdom
PubMed: 15527669
DOI: 10.3310/hta8470 -
The Cochrane Database of Systematic... May 2015Asthma is the most common chronic medical condition among children and is one of the most common causes of hospitalisation and medical visits. Poorly controlled asthma... (Review)
Review
BACKGROUND
Asthma is the most common chronic medical condition among children and is one of the most common causes of hospitalisation and medical visits. Poorly controlled asthma often leads to preventable exacerbations that require additional medications, hospital stays, or treatment in the emergency department.Long-acting beta2-agonists (LABA) are the preferred add-on treatment for children with asthma whose symptoms are not well controlled on inhaled corticosteroids (ICS). The US Food and Drug Administration has issued a 'black box' warning for LABA in asthma, and now recommends that they be used "for the shortest duration of time required to achieve control of asthma symptoms and discontinued, if possible, once asthma control is achieved".
OBJECTIVES
To compare the effect on asthma control and adverse effects of stepping down to inhaled corticosteroids (ICS)-only therapy versus continuing ICS plus LABA in children whose asthma is well controlled on combined ICS and LABA therapy.
SEARCH METHODS
We searched the Cochrane Airways Group Specialised Register, and also searched www.ClinicalTrials.gov, www.who.int/ictrp/en/, reference lists of primary studies and existing reviews, and manufacturers' trial registries (GlaxoSmithKline and AstraZeneca). We searched all databases from their inception to the present, and imposed no restriction on language of publication. The most recent search was done in April 2015.
SELECTION CRITERIA
We looked for parallel randomised controlled trials of at least eight weeks' duration, available as published full text, abstract only, or unpublished data. We excluded studies including participants with other chronic respiratory comorbidities (for example bronchiectasis).We looked for studies in which children (18 years or younger) whose asthma was well controlled on any dose of ICS and LABA combination therapy were randomised to: a) step-down therapy to ICS alone or b) continued use of ICS and LABA.We included any dose of LABA (formoterol, salmeterol, vilanterol) and any dose of ICS (beclomethasone, budesonide, ciclesonide, mometasone, flunisolide, fluticasone propionate, fluticasone furoate, triamcinolone) delivered in a combination inhaler or in separate inhalers.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened all records identified in the searches. We used a data extraction tool in Microsoft Excel to manage searches and document reasons for inclusion and exclusion, and to extract descriptive and numerical data from trials meeting the inclusion criteria.The prespecified primary outcomes were exacerbations requiring oral steroids, asthma control, and all-cause serious adverse events.
MAIN RESULTS
Despite conducting extensive searches of electronic databases, trial registries and manufacturers' websites we identified no trials matching the inclusion criteria.After removing duplicates, we screened 1031 abstracts, and assessed 43 full-text articles for inclusion. We identified several adult studies, which will be summarised in a separate review (Ahmad 2014). The most common reasons for exclusion after viewing full texts were 'wrong comparison' (n = 22) and 'adult population' (n = 18).Some adult studies recruited adolescents from age 15, but none reported data separately for those under 18.
AUTHORS' CONCLUSIONS
There is currently no evidence from randomised trials to inform the discontinuation of LABAs in children once asthma control is achieved with ICS plus LABA. It is disappointing that such an important issue has not been studied, and a randomised double-blind trial recruiting children who are controlled on ICS plus LABA is warranted. The study should be large enough to assess children of different ages, and to measure the important safety and efficacy outcomes suggested in this review over at least six months.The only randomised evidence for stopping LABA has been conducted in adults; it will be summarised in a separate review.
Topics: Administration, Inhalation; Adolescent; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Asthma; Child; Humans; Withholding Treatment
PubMed: 25997166
DOI: 10.1002/14651858.CD011316.pub2 -
The Cochrane Database of Systematic... Apr 2021Asthma is characterised by chronic inflammation of the airways and recurrent exacerbations with wheezing, chest tightness, and cough. Treatment with inhaled steroids and... (Meta-Analysis)
Meta-Analysis
Regular treatment with formoterol and an inhaled corticosteroid versus regular treatment with salmeterol and an inhaled corticosteroid for chronic asthma: serious adverse events.
BACKGROUND
Asthma is characterised by chronic inflammation of the airways and recurrent exacerbations with wheezing, chest tightness, and cough. Treatment with inhaled steroids and bronchodilators can result in good control of symptoms, prevention of further morbidity, and improved quality of life. However, an increase in serious adverse events with the use of both regular formoterol and regular salmeterol (long-acting beta₂-agonists) compared with placebo for chronic asthma has been demonstrated in previous Cochrane Reviews. This increase was statistically significant in trials that did not randomise participants to an inhaled corticosteroid, but not when formoterol or salmeterol was combined with an inhaled corticosteroid. The confidence intervals were found to be too wide to ensure that the addition of an inhaled corticosteroid renders regular long-acting beta₂-agonists completely safe; few participants and insufficient serious adverse events in these trials precluded a definitive decision about the safety of combination treatments.
OBJECTIVES
To assess risks of mortality and non-fatal serious adverse events in trials that have randomised patients with chronic asthma to regular formoterol and an inhaled corticosteroid versus regular salmeterol and an inhaled corticosteroid.
SEARCH METHODS
We searched the Cochrane Airways Register of Trials, CENTRAL, MEDLINE, Embase, and two trial registries to identify reports of randomised trials for inclusion. We checked manufacturers' websites and clinical trial registers for unpublished trial data, as well as Food and Drug Administration (FDA) submissions in relation to formoterol and salmeterol. The date of the most recent search was 24 February 2021.
SELECTION CRITERIA
We included controlled clinical trials with a parallel design, recruiting patients of any age and severity of asthma, if they randomised patients to treatment with regular formoterol versus regular salmeterol (each with a randomised inhaled corticosteroid) and were of at least 12 weeks' duration.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected trials for inclusion in the review, extracted outcome data from published papers and trial registries, and applied GRADE rating for the results. We sought unpublished data on mortality and serious adverse events from study sponsors and authors. The primary outcomes were all cause mortality and non-fatal serious adverse events. We chose not to calculate an average result from all the formulations of formoterol and inhaled steroid, as the doses and delivery devices are too diverse to assume a single class effect.
MAIN RESULTS
Twenty-one studies in 11,572 adults and adolescents and two studies in 723 children met the eligibility criteria of the review. No data were available for two studies; therefore these were not included in the analysis. Among adult and adolescent studies, seven compared formoterol and budesonide to salmeterol and fluticasone (N = 7764), six compared formoterol and beclomethasone to salmeterol and fluticasone (N = 1923), two compared formoterol and mometasone to salmeterol and fluticasone (N = 1126), two compared formoterol and fluticasone to salmeterol and fluticasone (N = 790), and one compared formoterol and budesonide to salmeterol and budesonide (N = 229). In total, five deaths were reported among adults, none of which was thought to be related to asthma. The certainty of evidence for all-cause mortality was low, as there were not enough deaths to permit any precise conclusions regarding the risk of mortality on combination formoterol versus combination salmeterol. In all, 201 adults reported non-fatal serious adverse events. In studies comparing formoterol and budesonide to salmeterol and fluticasone, there were 77 in the formoterol arm and 68 in the salmeterol arm (Peto odds ratio (OR) 1.14, 95% confidence interval (CI) 0.82 to 1.59; 5935 participants, 7 studies; moderate-certainty evidence). In the formoterol and beclomethasone studies, there were 12 adults in the formoterol arm and 13 in the salmeterol arm with events (Peto OR 0.94, 95% CI 0.43 to 2.08; 1941 participants, 6 studies; moderate-certainty evidence). In the formoterol and mometasone studies, there were 18 in the formoterol arm and 11 in the salmeterol arm (Peto OR 1.02, 95% CI 0.47 to 2.20; 1126 participants, 2 studies; moderate-certainty evidence). One adult in the formoterol and fluticasone studies in the salmeterol arm experienced an event (Peto OR 0.05, 95% CI 0.00 to 3.10; 293 participants, 2 studies; low-certainty evidence). Another adult in the formoterol and budesonide compared to salmeterol and budesonide study in the formoterol arm had an event (Peto OR 7.45, 95% CI 0.15 to 375.68; 229 participants, 1 study; low-certainty evidence). Only 46 adults were reported to have experienced asthma-related serious adverse events. The certainty of the evidence was low to very low due to the small number of events and the absence of independent assessment of causation. The two studies in children compared formoterol and fluticasone to salmeterol and fluticasone. No deaths and no asthma-related serious adverse events were reported in these studies. Four all-cause serious adverse events were reported: three in the formoterol arm, and one in the salmeterol arm (Peto OR 2.72, 95% CI 0.38 to 19.46; 548 participants, 2 studies; low-certainty evidence).
AUTHORS' CONCLUSIONS
Overall, for both adults and children, evidence is insufficient to show whether regular formoterol in combination with budesonide, beclomethasone, fluticasone, or mometasone has a different safety profile from salmeterol in combination with fluticasone or budesonide. Five deaths of any cause were reported across all studies and no deaths from asthma; this information is insufficient to permit any firm conclusions about the relative risks of mortality on combination formoterol in comparison to combination salmeterol inhalers. Evidence on all-cause non-fatal serious adverse events indicates that there is probably little to no difference between formoterol/budesonide and salmeterol/fluticasone inhalers. However events for the other formoterol combination inhalers were too few to allow conclusions. Only 46 non-fatal serious adverse events were thought to be asthma related; this small number in addition to the absence of independent outcome assessment means that we have very low confidence for this outcome. We found no evidence of safety issues that would affect the choice between salmeterol and formoterol combination inhalers used for regular maintenance therapy by adults and children with asthma.
Topics: Administration, Inhalation; Adolescent; Adult; Anti-Asthmatic Agents; Asthma; Beclomethasone; Bronchodilator Agents; Budesonide; Child; Chronic Disease; Drug Therapy, Combination; Fluticasone; Formoterol Fumarate; Glucocorticoids; Humans; Mometasone Furoate; Randomized Controlled Trials as Topic; Salmeterol Xinafoate
PubMed: 33852162
DOI: 10.1002/14651858.CD007694.pub3 -
The Cochrane Database of Systematic... Jul 2014Treatment guidelines for asthma recommend inhaled corticosteroids (ICS) as first-line therapy for children with persistent asthma. Although ICS treatment is generally... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Treatment guidelines for asthma recommend inhaled corticosteroids (ICS) as first-line therapy for children with persistent asthma. Although ICS treatment is generally considered safe in children, the potential systemic adverse effects related to regular use of these drugs have been and continue to be a matter of concern, especially the effects on linear growth.
OBJECTIVES
To assess the impact of ICS on the linear growth of children with persistent asthma and to explore potential effect modifiers such as characteristics of available treatments (molecule, dose, length of exposure, inhalation device) and of treated children (age, disease severity, compliance with treatment).
SEARCH METHODS
We searched the Cochrane Airways Group Specialised Register of trials (CAGR), which is derived from systematic searches of bibliographic databases including CENTRAL, MEDLINE, EMBASE, CINAHL, AMED and PsycINFO; we handsearched respiratory journals and meeting abstracts. We also conducted a search of ClinicalTrials.gov and manufacturers' clinical trial databases to look for potential relevant unpublished studies. The literature search was conducted in January 2014.
SELECTION CRITERIA
Parallel-group randomised controlled trials comparing daily use of ICS, delivered by any type of inhalation device for at least three months, versus placebo or non-steroidal drugs in children up to 18 years of age with persistent asthma.
DATA COLLECTION AND ANALYSIS
Two review authors independently performed study selection, data extraction and assessment of risk of bias in included studies. We conducted meta-analyses using the Cochrane statistical package RevMan 5.2 and Stata version 11.0. We used the random-effects model for meta-analyses. We used mean differences (MDs) and 95% CIs as the metrics for treatment effects. A negative value for MD indicates that ICS have suppressive effects on linear growth compared with controls. We performed a priori planned subgroup analyses to explore potential effect modifiers, such as ICS molecule, daily dose, inhalation device and age of the treated child.
MAIN RESULTS
We included 25 trials involving 8471 (5128 ICS-treated and 3343 control) children with mild to moderate persistent asthma. Six molecules (beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone propionate and mometasone furoate) [corrected] given at low or medium daily doses were used during a period of three months to four to six years. Most trials were blinded and over half of the trials had drop out rates of over 20%.Compared with placebo or non-steroidal drugs, ICS produced a statistically significant reduction in linear growth velocity (14 trials with 5717 participants, MD -0.48 cm/y, 95% CI -0.65 to -0.30, moderate quality evidence) and in the change from baseline in height (15 trials with 3275 participants; MD -0.61 cm/y, 95% CI -0.83 to -0.38, moderate quality evidence) during a one-year treatment period.Subgroup analysis showed a statistically significant group difference between six molecules in the mean reduction of linear growth velocity during one-year treatment (Chi² = 26.1, degrees of freedom (df) = 5, P value < 0.0001). The group difference persisted even when analysis was restricted to the trials using doses equivalent to 200 μg/d hydrofluoroalkane (HFA)-beclomethasone. Subgroup analyses did not show a statistically significant impact of daily dose (low vs medium), inhalation device or participant age on the magnitude of ICS-induced suppression of linear growth velocity during a one-year treatment period. However, head-to-head comparisons are needed to assess the effects of different drug molecules, dose, inhalation device or patient age. No statistically significant difference in linear growth velocity was found between participants treated with ICS and controls during the second year of treatment (five trials with 3174 participants; MD -0.19 cm/y, 95% CI -0.48 to 0.11, P value 0.22). Of two trials that reported linear growth velocity in the third year of treatment, one trial involving 667 participants showed similar growth velocity between the budesonide and placebo groups (5.34 cm/y vs 5.34 cm/y), and another trial involving 1974 participants showed lower growth velocity in the budesonide group compared with the placebo group (MD -0.33 cm/y, 95% CI -0.52 to -0.14, P value 0.0005). Among four trials reporting data on linear growth after treatment cessation, three did not describe statistically significant catch-up growth in the ICS group two to four months after treatment cessation. One trial showed accelerated linear growth velocity in the fluticasone group at 12 months after treatment cessation, but there remained a statistically significant difference of 0.7 cm in height between the fluticasone and placebo groups at the end of the three-year trial.One trial with follow-up into adulthood showed that participants of prepubertal age treated with budesonide 400 μg/d for a mean duration of 4.3 years had a mean reduction of 1.20 cm (95% CI -1.90 to -0.50) in adult height compared with those treated with placebo.
AUTHORS' CONCLUSIONS
Regular use of ICS at low or medium daily doses is associated with a mean reduction of 0.48 cm/y in linear growth velocity and a 0.61-cm change from baseline in height during a one-year treatment period in children with mild to moderate persistent asthma. The effect size of ICS on linear growth velocity appears to be associated more strongly with the ICS molecule than with the device or dose (low to medium dose range). ICS-induced growth suppression seems to be maximal during the first year of therapy and less pronounced in subsequent years of treatment. However, additional studies are needed to better characterise the molecule dependency of growth suppression, particularly with newer molecules (mometasone, ciclesonide), to specify the respective role of molecule, daily dose, inhalation device and patient age on the effect size of ICS, and to define the growth suppression effect of ICS treatment over a period of several years in children with persistent asthma.
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Androstadienes; Anti-Asthmatic Agents; Asthma; Beclomethasone; Budesonide; Child; Child, Preschool; Fluocinolone Acetonide; Fluticasone; Growth; Growth Disorders; Humans; Mometasone Furoate; Patient Dropouts; Pregnadienediols; Pregnenediones
PubMed: 25030198
DOI: 10.1002/14651858.CD009471.pub2