Epinephrine (adrenaline) compared to selective beta-2-agonist in adults or children with acute asthma: a systematic review and meta-analysis.

BACKGROUND: International asthma guidelines recommend against epinephrine (adrenaline) administration in acute asthma unless associated with anaphylaxis or angio-oedema. However, administration of intramuscular epinephrine in addition to nebulised selective ß2-agonist is recommended for acute severe or life-threatening asthma in many prehospital guidelines. We conducted a systematic review to determine the efficacy of epinephrine in comparison to selective ß2-agonist in acute asthma. METHODS: We included peer-reviewed publications of randomised controlled trials (RCTs) that enrolled children or adults in any healthcare setting and compared epinephrine by any route to selective ß2-agonist by any route for an acute asthma exacerbation. The primary outcome was treatment failure, including hospitalisation, need for intubation or death. RESULTS: Thirty-eight of 1140 studies were included. Overall quality of evidence was low. Seventeen studies contributed data on 1299 participants to the meta-analysis. There was significant statistical heterogeneity, I2=56%. The pooled Peto's OR for treatment failure with epinephrine versus selective ß2-agonist was 0.99 (0.75 to 1.32), p=0.95. There was strong evidence that recruitment age group was associated with different estimates of the odds of treatment failure; with studies recruiting adults-only having lower odds of treatment failure with epinephrine. It was not possible to determine whether epinephrine in addition to selective ß2-agonist improved outcomes. CONCLUSION: The low-quality evidence available suggests that epinephrine and selective ß2-agonists have similar efficacy in acute asthma. There is a need for high-quality double-blind RCTs to determine whether addition of intramuscular epinephrine to inhaled or nebulised selective ß2-agonist improves outcome. PROSPERO REGISTRATION NUMBER: CRD42017079472.

Budesonide-formoterol reliever therapy versus maintenance budesonide plus terbutaline reliever therapy in adults with mild to moderate asthma (PRACTICAL): a 52-week, open-label, multicentre, superiority, randomised controlled trial.

BACKGROUND: In adults with mild asthma, a combination of an inhaled corticosteroid with a fast-onset long-acting ß-agonist (LABA) used as reliever monotherapy reduces severe exacerbations compared with short-acting ß-agonist (SABA) reliever therapy. We investigated the efficacy of combination budesonide-formoterol reliever therapy compared with maintenance budesonide plus as-needed terbutaline. METHODS: We did a 52-week, open-label, parallel-group, multicentre, superiority, randomised controlled trial at 15 primary care or hospital-based clinical trials units and primary care practices in New Zealand. Participants were adults aged 18-75 years with a self-reported doctor's diagnosis of asthma who were using SABA for symptom relief with or without maintenance low to moderate doses of inhaled corticosteroids in the previous 12 weeks. We randomly assigned participants (1:1) to either reliever therapy with budesonide 200 µg-formoterol 6 µg Turbuhaler (one inhalation as needed for relief of symptoms) or maintenance budesonide 200 µg Turbuhaler (one inhalation twice daily) plus terbutaline 250 µg Turbuhaler (two inhalations as needed). Participants and investigators were not masked to group assignment; the statistician was masked for analysis of the primary outcome. Six study visits were scheduled: randomisation, and weeks 4, 16, 28, 40, and 52. The primary outcome was the number of severe exacerbations per patient per year analysed by intention to treat (severe exacerbations defined as use of systemic corticosteroids for at least 3 days because of asthma, or admission to hospital or an emergency department visit because of asthma requiring systemic corticosteroids). Safety analyses included all participants who had received at least one dose of study treatment. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12616000377437. FINDINGS: Between May 4, 2016, and Dec 22, 2017, we assigned 890 participants to treatment and included 885 eligible participants in the analysis: 437 assigned to budesonide-formoterol as needed and 448 to budesonide maintenance plus terbutaline as needed. Severe exacerbations per patient per year were lower with as-needed budesonide-formoterol than with maintenance budesonide plus terbutaline as needed (absolute rate per patient per year 0·119 vs 0·172; relative rate 0·69, 95% CI 0·48-1·00; p=0·049). Nasopharyngitis was the most common adverse event in both groups, occurring in 154 (35%) of 440 patients receiving as-needed budesonide-formoterol and 144 (32%) of 448 receiving maintenance budesonide plus terbutaline as needed. INTERPRETATION: In adults with mild to moderate asthma, budesonide-formoterol used as needed for symptom relief was more effective at preventing severe exacerbations than maintenance low-dose budesonide plus as-needed terbutaline. The findings support the 2019 Global Initiative for Asthma recommendation that inhaled corticosteroid-formoterol reliever therapy is an alternative regimen to daily low-dose inhaled corticosteroid for patients with mild asthma. FUNDING: Health Research Council of New Zealand.

What matters most to patients when choosing treatment for mild-moderate asthma? Results from a discrete choice experiment.

BACKGROUND: An as-needed combination preventer and reliever regimen was recently introduced as an alternative to conventional daily preventer treatment for mild asthma. In a subgroup analysis of the PRACTICAL study, a pragmatic randomised controlled trial of budesonide-formoterol reliever therapy versus maintenance budesonide plus terbutaline reliever therapy in adults with mild asthma, we recently reported that about two-thirds preferred as-needed combination preventer and reliever therapy. The aim of this study was to determine the relative importance of attributes associated with these two asthma therapies in this subgroup of participants who indicated their preferred treatment in the PRACTICAL study. METHODS: At their final study visit, a subgroup of participants indicated their preferred treatment and completed a discrete choice experiment using the Potentially All Pairwise RanKings of all possible Alternatives method and 1000minds software. Treatment attributes and their levels were selected from measurable study outcomes, and included: treatment regimen, shortness of breath, steroid dose and likelihood of asthma flare-up. RESULTS: The final analysis dataset included 288 participants, 64% of whom preferred as-needed combination preventer and reliever. Of the attributes, no shortness of breath and lowest risk of asthma flare-up were ranked highest and second highest, respectively. However, the relative importance of the other two attributes varied by preferred therapy: treatment regimen was ranked higher by participants who preferred as-needed treatment than by participants who preferred maintenance treatment. CONCLUSIONS: Knowledge of patient preferences for treatment attributes together with regimen characteristics can be used in shared decision-making regarding choice of treatment for patients with mild-moderate asthma. TRIAL REGISTRATION NUMBER: ACTRN12616000377437.

Self-titration of inhaled corticosteroid and ß2-agonist in response to symptoms in mild asthma: a pre-specified analysis from the PRACTICAL randomised controlled trial.

INTRODUCTION: In mild asthma, as-needed budesonide-formoterol is superior or noninferior to maintenance budesonide plus as-needed short-acting ß2-agonist in reducing severe exacerbations. In this pre-specified analysis, we investigated patterns of inhaled corticosteroid (ICS) and ß2-agonist use in PRACTICAL, a randomised controlled trial. METHODS: Participants were randomised 1:1 to as-needed budesonide-formoterol (200/6 µg Turbuhaler, one actuation) or maintenance budesonide (200 µg Turbuhaler, one actuation twice a day) with as-needed terbutaline (250 µg, two actuations) for 52 weeks. 110 participants had electronic monitors attached to their study inhalers which captured the time and date of every actuation. Key outcome measures were patterns of ICS and ß2-agonist use. One actuation of budesonide-formoterol was considered to be an equivalent bronchodilator dose as two actuations of terbutaline. RESULTS: Participants randomised to as-needed budesonide-formoterol had more days with no ICS use compared with maintenance budesonide (median total days of no use 156 versus 22 days, respectively), lower median daily budesonide dose (164 versus 328 µg, respectively) and a greater median number of days of ≥4 budesonide actuations (4 versus 1 days, respectively). Participants randomised to as-needed budesonide-formoterol took higher equivalent doses of ß2-agonist both overall (median number of actuations 0.8 versus 0.3 per day, respectively) and in response to worsening asthma (total number of "overuse days" of >8 or >16 actuations of budesonide-formoterol or terbutaline 33 versus 10 days, respectively). CONCLUSIONS: The timing of ICS dose when self-titrated to ß2-agonist use is more important than total ICS dose in reducing severe exacerbation risk in mild asthma, when associated with greater overall use of as-needed ß2-agonist.

Patient preferences for symptom-driven or regular preventer treatment in mild to moderate asthma: findings from the PRACTICAL study, a randomised clinical trial.

Symptom-driven low-dose inhaled corticosteroid-formoterol is safe and effective in mild asthma and has been recommended as one of the preferred treatment regimens at steps 1 and 2 in the 2019 update of the Global Initiative for Asthma. However, there are no data on patient preferences for this regimen.A subgroup of participants in the PRACTICAL study (ACTRN12616000377437), a randomised controlled trial comparing symptom-driven budesonide-formoterol with maintenance budesonide plus as-needed terbutaline completed a survey on treatment preferences, satisfaction, beliefs and experience at their final study visit.306 (75%) out of 407 eligible participants completed the survey. Regimen preference was strongly associated with randomised treatment, as were preferences for and beliefs about preventer inhaler use. Combination preventer and reliever as-needed therapy was preferred by 135 (90%, 95% CI 85.2-94.8%) out of 150 who were randomised to as-needed budesonide-formoterol, and by 63 (40%, 95% CI 32.7-48.1%) out of 156 who were randomised to maintenance budesonide. By contrast, twice-daily preventer inhaler with a reliever inhaler as required was preferred by 15 (10%) out of 150 of those randomised to as-needed budesonide-formoterol and 93 (60%) out of 156 of those randomised to maintenance budesonide. Satisfaction with all study inhalers was high. Of patients randomised to as-needed budesonide-formoterol 92% (n=138) were confident using it as a reliever at the end of the study.Although most participants preferred the regimen to which they had been randomised, this association was much stronger for those randomised to budesonide-formoterol as needed, indicating that most patients preferred as-needed corticosteroid-formoterol therapy if they had experienced it.

Treatable traits of chronic airways disease.

PURPOSE OF REVIEW: To describe the rationale on which the treatable traits approach to the management of airways disease is based and the issues that need to be considered for its implementation in clinical practice. RECENT FINDINGS: In clinical practice, treatable traits can be classified according to both endotypes and phenotypes, broadly grouped within pulmonary, extrapulmonary, environmental and behavioural factors. Specific investigations and treatments are undertaken for each of the traits rather than a 'one size fits all' stepwise approach to pharmacological treatment which currently represents the core of asthma and chronic obstructive pulmonary disease (COPD) guidelines. Although there is strong evidence of the benefit of the treatable traits approach to specific traits in asthma and/or COPD, there is uncertainty regarding the preferred method of implementation, efficacy and cost-effectiveness of multidimensional intervention programmes in clinical practice. It is likely that 'master protocols' for randomized controlled trials will be required to evaluate such multiple interventions in broad populations of patients with airways disease. SUMMARY: Current evidence suggests that the precision medicine approach based on the identification and treatment of treatable traits is preferable to a 'one-size-fits-all' stepwise approach to the treatment of airways disease, although high-quality evidence to guide the practical application of this multidimensional management strategy is now required. VIDEO ABSTRACT.

Physical rehabilitation for older people in long-term care.

BACKGROUND: The worldwide population is progressively ageing, with an expected increase in morbidity and demand for long-term care. Physical rehabilitation is beneficial in older people, but relatively little is known about effects on long-term care residents. This is an update of a Cochrane review first published in 2009. OBJECTIVES: To evaluate the benefits and harms of rehabilitation interventions directed at maintaining, or improving, physical function for older people in long-term care through the review of randomised and cluster randomised controlled trials. SEARCH METHODS: We searched the trials registers of the following Cochrane entities: the Stroke Group (May 2012), the Effective Practice and Organisation of Care Group (April 2012), and the Rehabilitation and Related Therapies Field (April 2012). In addition, we searched 20 relevant electronic databases, including the Cochrane Central Register of Controlled Trials (The Cochrane Library, 2009, Issue 4), MEDLINE (1966 to December 2009), EMBASE (1980 to December 2009), CINAHL (1982 to December 2009), AMED (1985 to December 2009), and PsycINFO (1967 to December 2009). We also searched trials and research registers and conference proceedings; checked reference lists; and contacted authors, researchers, and other relevant Cochrane entities. We updated our searches of electronic databases in 2011 and listed relevant studies as awaiting assessment. SELECTION CRITERIA: Randomised studies comparing a rehabilitation intervention designed to maintain or improve physical function with either no intervention or an alternative intervention in older people (over 60 years) who have permanent long-term care residency. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed risk of bias and extracted data. We contacted study authors for additional information. The primary outcome was function in activities of daily living. Secondary outcomes included exercise tolerance, strength, flexibility, balance, perceived health status, mood, cognitive status, fear of falling, and economic analyses. We investigated adverse effects, including death, morbidity, and other events. We synthesised estimates of the primary outcome with the mean difference; mortality data, with the risk ratio; and secondary outcomes, using vote-counting. MAIN RESULTS: We included 67 trials, involving 6300 participants. Fifty-one trials reported the primary outcome, a measure of activities of daily living. The estimated effects of physical rehabilitation at the end of the intervention were an improvement in Barthel Index (0 to 100) scores of six points (95% confidence interval (CI) 2 to 11, P = 0.008, seven studies), Functional Independence Measure (0 to 126) scores of five points (95% CI -2 to 12, P = 0.1, four studies), Rivermead Mobility Index (0 to 15) scores of 0.7 points (95% CI 0.04 to 1.3, P = 0.04, three studies), Timed Up and Go test of five seconds (95% CI -9 to 0, P = 0.05, seven studies), and walking speed of 0.03 m/s (95% CI -0.01 to 0.07, P = 0.1, nine studies). Synthesis of secondary outcomes suggested there is a beneficial effect on strength, flexibility, and balance, and possibly on mood, although the size of any such effect is unknown. There was insufficient evidence of the effect on other secondary outcomes. Based on 25 studies (3721 participants), rehabilitation does not increase risk of mortality in this population (risk ratio 0.95, 95% CI 0.80 to 1.13). However, it is possible bias has resulted in overestimation of the positive effects of physical rehabilitation. AUTHORS' CONCLUSIONS: Physical rehabilitation for long-term care residents may be effective, reducing disability with few adverse events, but effects appear quite small and may not be applicable to all residents. There is insufficient evidence to reach conclusions about improvement sustainability, cost-effectiveness, or which interventions are most appropriate. Future large-scale trials are justified.

New Zealand COPD Guidelines: Quick Reference Guide.

The purpose of the Asthma and Respiratory Foundation of New Zealand's COPD Guidelines: Quick Reference Guide is to provide simple, practical, evidence-based recommendations for the diagnosis, assessment, and management of chronic obstructive pulmonary disease (COPD) in clinical practice. The intended users are health professionals responsible for delivering acute and chronic COPD care in community and hospital settings, and those responsible for the training of such health professionals.

Combination budesonide/formoterol inhaler as sole reliever therapy in Maori and Pacific people with mild and moderate asthma.

AIM: In the PRACTICAL study, as-needed budesonide/formoterol reduced the rate of severe exacerbations compared with maintenance budesonide plus as-needed terbutaline. In a pre-specified analysis we analysed the efficacy in Maori and Pacific peoples, populations with worse asthma outcomes. METHOD: The PRACTICAL study was a 52-week, open-label, parallel group, randomised controlled trial of 890 adults with mild to moderate asthma, who were randomised to budesonide/formoterol Turbuhaler 200/6mcg one actuation as required or budesonide Turbuhaler 200mcg one actuation twice daily and terbutaline Turbuhaler 250mcg two actuations as required. The primary outcome was rate of severe exacerbations. The analysis strategy was to test an ethnicity-treatment interaction term for each outcome variable. RESULTS: Seventy-two participants (8%) identified as Maori, 36 participants (4%) as Pacific ethnicity. There was no evidence that ethnicity was an effect modifier for severe exacerbations (P interaction 0.70). CONCLUSION: The reduction in severe exacerbation risk with budesonide-formoterol reliever compared with maintenance budesonide was similar in Maori and Pacific adults compared with New Zealand European/Other.

Rehabilitation for older people in long-term care.

BACKGROUND: Examination of demographic trends indicates that the worldwide population is progressively ageing. It is expected that such longevity will be associated with an increase in morbidity and demand for long-term residential care. This review examines whether there is evidence that physical rehabilitation benefits older people in long-term care. OBJECTIVES: To evaluate physical rehabilitation interventions directed at improving physical function among older people in long-term care. SEARCH STRATEGY: We searched the trials registers of the following Cochrane entities: Stroke Group (searched March 2008), Effective Practice and Organisation of Care Group (searched August 2006) and the Rehabilitation and Related Therapies Field, (searched August 2006). In addition, we searched 17 relevant electronic databases including the Cochrane Central Register of Controlled Trials (The Cochrane Library 2007, Issue 3), MEDLINE (1966 to 1 October 2007), EMBASE (1980 to 1 October 2007), CINAHL (1982 to 1 October 2007), AMED (1985 to 1 October 2007), PsycINFO (1967 to 1 October 2007) and PEDro (searched 1 October 2007). We also searched trials and research registers and conference proceedings, checked reference lists, and contacted authors and researchers in the field and other relevant Cochrane entities. SELECTION CRITERIA: Randomised studies comparing a rehabilitation intervention designed to maintain or improve physical function with either no intervention or an alternative intervention in older people aged 60 years or over who have permanent long-term care residency. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. MAIN RESULTS: Forty-nine trials involving 3611 participants were included. On average, 74 (range 12 to 468) participants were randomised into trials at baseline. Of studies which reported age, the overall mean age was 82 years (range of 69 to 89). Most interventions lasted less than 20 weeks, and comprised approximately three 30 to 45-minute group sessions per week. Twelve trials conducted post-intervention follow up (maximum one year). Most often a 'usual care' control group was used, but social activity and alternative interventions also featured. The primary outcome, daily activity restriction, was reported by 38 trials. A range of secondary outcomes are also reported. AUTHORS' CONCLUSIONS: Provision of physical rehabilitation interventions to long-term care residents is worthwhile and safe, reducing disability with few adverse events.Most trials reported improvement in physical condition. However, there is insufficient evidence to make recommendations about the best intervention, improvement sustainability and cost-effectiveness.

Description of the protocol for the PRACTICAL study: a randomised controlled trial of the efficacy and safety of ICS/LABA reliever therapy in asthma.

INTRODUCTION: In adult asthma, combination inhaled corticosteroid (ICS)/fast-onset long-acting beta agonist (LABA) used solely as reliever therapy may represent an effective and safe alternative to ICS maintenance and short-acting beta agonist (SABA) reliever therapy. OBJECTIVE: To compare the efficacy and safety of ICS/fast-onset LABA reliever therapy with ICS maintenance and SABA reliever therapy in adults with asthma. METHODS AND ANALYSIS: A 52-week, open-label, parallel group, multicentre, phase III randomised controlled trial with 1:1 randomisation to either budesonide/formoterol Turbuhaler 200/6 µg, one actuation as required for symptom relief, or budesonide Turbuhaler 200 µg, one actuation twice daily and terbutaline Turbuhaler 250 µg, two actuations as required for symptom relief. 890 adults aged 18-75 years with asthma for whom maintenance ICS and SABA reliever therapy is indicated by current guidelines will be recruited in New Zealand. The primary outcome variable is the rate of severe exacerbations per patient per year. This study will investigate a novel treatment regimen that might lead to a paradigm shift in asthma management for adults for whom guidelines currently recommend maintenance ICS and SABA reliever therapy. ETHICS AND DISSEMINATION: Ethical approval has been granted (15/NTB/178). Study findings will be published according to Iinternational Committee of Medical Journal Editors' recommendations. TRIAL REGISTRATION NUMBER: ACTRN12616000377437; Pre-results.