Controlled Trial of Budesonide-Formoterol as Needed for Mild Asthma.

BACKGROUND: In double-blind, placebo-controlled trials, budesonide-formoterol used on an as-needed basis resulted in a lower risk of severe exacerbation of asthma than as-needed use of a short-acting ß2-agonist (SABA); the risk was similar to that of budesonide maintenance therapy plus as-needed SABA. The availability of data from clinical trials designed to better reflect clinical practice would be beneficial. METHODS: We conducted a 52-week, randomized, open-label, parallel-group, controlled trial involving adults with mild asthma. Patients were randomly assigned to one of three treatment groups: albuterol (100 µg, two inhalations from a pressurized metered-dose inhaler as needed for asthma symptoms) (albuterol group); budesonide (200 µg, one inhalation through a Turbuhaler twice daily) plus as-needed albuterol (budesonide maintenance group); or budesonide-formoterol (200 µg of budesonide and 6 µg of formoterol, one inhalation through a Turbuhaler as needed) (budesonide-formoterol group). Electronic monitoring of inhalers was used to measure medication use. The primary outcome was the annualized rate of asthma exacerbations. RESULTS: The analysis included 668 of 675 patients who underwent randomization. The annualized exacerbation rate in the budesonide-formoterol group was lower than that in the albuterol group (absolute rate, 0.195 vs. 0.400; relative rate, 0.49; 95% confidence interval [CI], 0.33 to 0.72; P<0.001) and did not differ significantly from the rate in the budesonide maintenance group (absolute rate, 0.195 in the budesonide-formoterol group vs. 0.175 in the budesonide maintenance group; relative rate, 1.12; 95% CI, 0.70 to 1.79; P = 0.65). The number of severe exacerbations was lower in the budesonide-formoterol group than in both the albuterol group (9 vs. 23; relative risk, 0.40; 95% CI, 0.18 to 0.86) and the budesonide maintenance group (9 vs. 21; relative risk, 0.44; 95% CI, 0.20 to 0.96). The mean (±SD) dose of inhaled budesonide was 107±109 µg per day in the budesonide-formoterol group and 222±113 µg per day in the budesonide maintenance group. The incidence and type of adverse events reported were consistent with those in previous trials and with reports in clinical use. CONCLUSIONS: In an open-label trial involving adults with mild asthma, budesonide-formoterol used as needed was superior to albuterol used as needed for the prevention of asthma exacerbations. (Funded by AstraZeneca and the Health Research Council of New Zealand; Novel START Australian New Zealand Clinical Trials Registry number, ACTRN12615000999538.).

The ICS/Formoterol Reliever Therapy Regimen in Asthma: A Review.

The Global Initiative for Asthma recommends that low-dose inhaled corticosteroid (ICS)/formoterol be preferred to short-acting beta2-agonists as reliever therapy in adolescents and adults with asthma, across the range of asthma severity. This recommendation represents the most fundamental change in asthma management for many decades. In this commentary, we review the rationale for combination ICS/formoterol therapy, the evidence on which this recommendation has been made, the limitations in the evidence, the practical issues relevant to the implementation of ICS/formoterol reliever-based regimens in clinical practice, and the emerging evidence for the efficacy and safety of combination ICS/salbutamol reliever therapy regimens.

Patterns of Asthma Medication Use in New Zealand After Publication of National Asthma Guidelines.

BACKGROUND: In June 2020, the New Zealand (NZ) adolescent and adult asthma guidelines recommended budesonide/formoterol, taken as maintenance and/or reliever therapy, as the preferred therapeutic approach. OBJECTIVE: To investigate whether these recommendations were associated with changes in clinical practice indicated by asthma medication use trends. METHODS: NZ national dispensing data for inhaler medications from January 2010 to December 2021 were reviewed. Monthly "dispensings" of inhaled budesonide/formoterol, inhaled corticosteroid (ICS), other ICS/long-acting ß2-agonists (LABA), and inhaled short-acting ß2-agonists (SABA), for the 12+ age group, were displayed graphically with piecewise regression used to produce plots of rates by time with a July 1, 2020, break point. The number of dispensings in the last 6 months that data were available (July-December 2021) was compared with the corresponding period, July-December 2019. RESULTS: Budesonide/formoterol dispensing increased markedly after July 1, 2020 (regression coefficient 41.1 inhalers dispensed/100,000 population per month [95% confidence interval (CI): 36.3-45.6, P < .0001]; 64.7% increase in the number of dispensings between July-December 2019 and July-December 2021), in contrast to "other ICS/LABA" (regression coefficient: -15.9 [95% CI: -22.2 to -9.6, P < .0001]; -1.7% decrease) and SABA (regression coefficient: -14.7 [95% CI: -29.7 to 0.3, P = .055]; -10.6% decrease), respectively. CONCLUSION: In NZ, a progressive increase in budesonide/formoterol dispensing, accompanied by a reduction in SABA and "other ICS/LABA" dispensing, occurred after publication of the 2020 NZ asthma guidelines. While acknowledging the limitations in the interpretation of temporal associations, these findings suggest that the transition to ICS/formoterol reliever-based therapy can be achieved if recommended and promoted as the preferred therapeutic approach in national guidelines.

What variables should inform needle length choice for deltoid intramuscular injection? A systematic review.

OBJECTIVES: (1) Assess the distribution of skin-to-deltoid-muscle distance (SDMD) at the deltoid intramuscular (IM) injection site; (2) its relationship with demographic and anthropometric variables and (3) Consider the findings in relation to clinical guidance on IM injection, such as COVID-19 vaccines. DESIGN: Systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. DATA SOURCES: MEDLINE, EMBASE, ClinicalTrials.gov, Cochrane Library, CINAHL and SCOPUS between June and July 2021 with no publication date limit. ELIGIBILITY CRITERIA: Studies reporting measurements of the SDMD in living adults aged 16 years and older, at the deltoid IM injection site, published in English were considered. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers performed each stage of screening, data extraction and quality assessments using the Joanna Briggs Institute Critical Appraisal Checklist for analytical cross sectional studies. RESULTS: 16 105 papers were identified, of which 11 studies were suitable for review, representing 1414 participants. Heterogeneity in the definition of the deltoid IM injection site, locations measured and methods of measurement precluded meta-analysis. Evidence from ultrasound SDMD measurements demonstrated some patients in all but 'underweight' body mass index (BMI) categories, may require needles longer than 25 mm for successful IM injection. Calliper measurements overestimated SDMD compared with ultrasound. Female sex, higher BMI categories and greater weight in women were associated with greater SDMD. CONCLUSIONS: The reviewed evidence was insufficient to inform definitive needle length 'cut points' for IM injection based on demographic or anthropomorphic variables. Contemporary clinical guidance currently based on this evidence, including the site of injection and choice of needle length, may result in subcutaneous administration in a small proportion of recipients, particularly if obese or of female sex. PROSPERO REGISTRATION NUMBER: CRD42021264625.

The Anti-Inflammatory Reliever (AIR) Algorithm Study: a protocol for a single-group study of an AIR stepwise approach to the treatment of adult asthma.

Background: The stepwise approach to long-term asthma management, which traditionally incorporates short-acting ß2-agonist reliever therapy, has been a core feature of asthma guidelines for over 30 years. There have been no studies, however, directly investigating the use of an entire guideline-recommended track. Recently, inhaled corticosteroid-formoterol has been recommended as the preferred reliever therapy in adult asthma, in accordance with a stepwise "Anti-Inflammatory Reliever" (AIR) treatment track. Objective: The aim of this study was to evaluate the AIR stepwise approach recommended by the New Zealand adolescent and adult asthma guidelines, in combination with a novel algorithm for transitioning between treatment steps. Methods: This 52-week, open-label, single-group study will recruit 100 adults aged 18 to 75 years with mild, moderate and moderate-severe asthma (ACTRN12620001010987). Participants will be allocated to budesonide-formoterol 200/6 µg, one actuation as needed (Step 1), one actuation twice daily and as needed (Step 2), or two actuations twice daily and one as needed (Step 3). Treatment steps will be adjusted throughout the study, in response to reliever use and asthma attacks, according to a stepwise AIR algorithm. Following a 26-week period of investigator-led transitions, participants will adjust their own treatment step. The primary outcome is participant satisfaction as measured by the Global Satisfaction score of the Treatment Satisfaction Questionnaire for Medication. Secondary outcomes will assess efficacy and safety, and describe patterns of medication use and participant flow through the treatment steps. Conclusion: This is the first trial to assess the AIR treatment track and algorithm. The results will provide knowledge to guide the clinical use of this approach.

Developing new portals to safety for domestic abuse survivors in the context of the pandemic.

This study examined the emergence and implementation of community touchpoints established in the UK during the COVID-19 pandemic for victims/survivors of domestic abuse (DA). Community touchpoints are designated places, both online and in accessible settings such as pharmacies and banks, where victims/survivors can seek confidential advice and be directed to expert DA services. The research adopted a case study approach and explored a range of perspectives through expert interviews, document analysis, consultation with survivors and stakeholders and a survey of DA co-ordinators. Four national community touchpoint schemes were identified and, of these, three were implemented rapidly and were available in 2020-2021 when the UK experienced lockdowns. Partnerships between Government/voluntary organisations and commercial businesses-assisted design and implementation. Some stakeholders considered that the schemes lacked responsivity to the local context and noted challenges in providing a confidential service in rural areas. Whilst pharmacies, banks and online spaces were identified as non-stigmatised and trusted places to seek advice, community touchpoints were judged less accessible for some groups including those experiencing digital poverty and victims whose movements were heavily scrutinised. Most of the touchpoint schemes targeted adults only. There were also concerns about whether frontline staff in commercial businesses received sufficient training. Whilst robust evidence of outcomes was limited, there were indications that the schemes had achieved good reach with some early evidence of take-up. Testimonials indicated that victims/survivors were using the touchpoints in flexible ways which met their needs. Moreover, the wide reach and visibility of these initiatives delivered in non-stigmatised settings may have served to raise public awareness of DA, reducing the silence that has traditionally surrounded it. Further research into the use and impact of these initiatives is required and there may be future potential to extend community touchpoints to include children and young people experiencing DA.

Asthma control with ICS-formoterol reliever versus maintenance ICS and SABA reliever therapy: a post hoc analysis of two randomised controlled trials.

BACKGROUND: In randomised controlled trials, as-needed inhaled corticosteroid (ICS)-formoterol reliever therapy reduces severe exacerbation risk compared with maintenance ICS plus short-acting beta2-agonist (SABA) reliever in adolescent and adult asthma, but results in slightly worse control of asthma symptoms, as measured by mean Asthma Control Questionnaire-5 (ACQ-5) score. OBJECTIVE: To assess the levels and changes in asthma control for as-needed budesonide-formoterol versus maintenance budesonide plus SABA in post hoc analyses from the Novel START and PRACTICAL clinical trials. METHODS: The number and proportion of participants at study end in each ACQ-5 category ('well-controlled', 'partly controlled' or 'inadequately controlled' symptoms), and in each responder category based on the minimal clinically important difference for ACQ-5 of 0.5 (improved, no change and worse) with as-needed budesonide-formoterol and maintenance budesonide plus SABA treatment were calculated. RESULTS: With last observation carried forwards, 189/214 (88.3%) and 354/434 (81.6%) of patients in the budesonide-formoterol group had 'well-controlled' or 'partly controlled' symptoms at the end of the study, vs 183/214 (85.5%) and 358/431 (83.1%) in the budesonide maintenance group, for Novel START and PRACTICAL, respectively. The proportion of patients whose symptom control was either improved or unchanged from baseline was 190/214 (88.8%) and 368/434 (84.8%) for budesonide-formoterol, vs 185/214 (86.4%) and 376/431 (87.2%) for maintenance budesonide, in Novel START and PRACTICAL respectively. CONCLUSIONS: There were no clinically important differences in the proportions of patients with 'well-controlled' or 'partly controlled' asthma symptoms, or proportions who improved or maintained their level of control, with as-needed budesonide-formoterol versus maintenance budesonide plus SABA.

Predictive value of blood eosinophils and exhaled nitric oxide in adults with mild asthma: a prespecified subgroup analysis of an open-label, parallel-group, randomised controlled trial.

BACKGROUND: Whether blood eosinophil counts and exhaled nitric oxide (FeNO) are associated with important outcomes in mild asthma is unclear. In this prespecified subgroup analysis of a previously published open-label clinical trial, we aimed to assess associations between blood eosinophil counts and FeNO with outcomes and response to asthma treatment. METHODS: In the previously reported 52-week, open-label, randomised controlled trial, people with mild asthma receiving only ß agonist reliever inhalers were enrolled at one of 16 clinical trials units in New Zealand, the UK, Italy, or Australia. Eligible participants were randomly assigned (1:1:1, stratified by country), to receive inhalers to take as-needed salbutamol (two inhalations of 100 µg in a pressurised metered dose inhaler), maintenance budesonide (200 µg twice per day by inhaler) plus as-needed salbutamol (two inhalations of 100 µg), or as-needed budesonide-formoterol (one inhalation of 200 µg budesonide and 6µg formoterol by inhaler). The primary outcome was the annual rates of asthma exacerbations per patient, and in this prespecified subgroup analysis, we assessed whether annual exacerbation rates in each treatment group were significantly different depending on levels of blood eosinophil count, FeNO, or a composite score of both. Analyses were done for patients with available biomarker measurements The study was registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12615000999538. FINDINGS: 675 participants were enrolled between March 17, 2016, and Aug 29, 2017, of whom 656 had results for blood eosinophil analysis and 668 had results for FeNO. Of the patients who received as-needed salbutamol, the proportion of patients having a severe exacerbation increased progressively with increasing blood eosinophil count (two [4%] of 49 participants with <0·15 × 109/L, six [6%] of 93 with 0·15 to <0·3 × 109/L, and 15 [19%] of 77 with ≥0·3 × 109/L; p=0·014). There were no significant interactions between blood eosinophil count or FeNO level and the effect of as-needed budesonide-formoterol compared with as-needed salbutamol for either exacerbations or severe exacerbations. However, there were significant interactions between blood eosinophil count subgroups and the effect of maintenance budesonide plus as-needed salbutamol compared with as-needed salbutamol, both for exacerbations (p=0·0006) and severe exacerbations (p=0·0007). Maintenance budesonide plus as-needed salbutamol was more effective than as-needed salbutamol in patients with blood eosinophil counts of 0·3 × 109/L or more, both for exacerbations (rate ratio 0·13 [95% CI 0·05-0·33]) and severe exacerbations (risk odds ratio 0·11 [0·03-0·45]). This difference was not seen for blood eosinophil counts of less than 0·15 × 109/L (1·15 [0·51-1·28] for exacerbations and 5·72 [0·97-33·60] for severe exacerbations). There was no consistent interaction between treatment response and FeNO or the composite score. INTERPRETATION: In patients with mild asthma, the effects of as-needed budesonide-formoterol on exacerbations are independent of biomarker profile, whereas the benefits of maintenance inhaled budesonide are greater in patients with high blood eosinophil counts than in patients with low counts. FUNDING: AstraZeneca, Health Research Council of New Zealand.