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Efficacy and safety of maintenance and reliever combination budesonide-formoterol inhaler in patients with asthma at risk of severe exacerbations: A randomised controlled trial
Abstract
Background:
The Single combination budesonide-formoterol inhaler Maintenance And Reliever Therapy (SMART) regimen reduces severe asthma exacerbations in patients, but whether the high doses of corticosteroid and β agonist increase the risk of adverse effects with both short-term and cumulative exposure is not certain. Our aim was to investigate whether the SMART regimen would reduce the risk of overuse of β agonist, reduce the likelihood of patients to seek medical review when such episodes occurred, and if any reduction in severe asthma exacerbations would be at the cost of a higher burden of systemic corticosteroid.
Methods:
In this 24-week trial undertaken at four primary health-care practices and one hospital in New Zealand, patients (aged 16-65 years) with a recent asthma exacerbation were randomly assigned in a 1:1 ratio to the SMART or standard fixed-dose regimen. Treatment in the SMART group consisted of two actuations of budesonide-formoterol (200 μg and 6 μg, respectively, per actuation) twice daily, delivered through a combination metered dose inhaler (MDI), with one extra actuation as needed for relief of symptoms; treatment in the standard group consisted of two actuations of budesonide-formoterol (200 μg and 6 μg, respectively, per actuation) twice daily through a combination MDI with one to two actuations of salbutamol (100 μg per actuation) by MDI as needed for relief of symptoms. MDIs were monitored electronically to measure actual use of medication. The allocation sequence for randomisation was computer generated, with a block size of eight per site. Participants, investigators, and the statistician were not masked to group assignment. The primary outcome was the proportion of participants with at least one high-use episode of β agonist (more than eight actuations per day of budesonide-formoterol in addition to the four maintenance doses in the SMART group or more than 16 actuations per day of salbutamol in the standard group). Analysis was by intention to treat. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12610000515099.
Findings:
303 patients were randomly assigned to the SMART (n=151) or standard group (n=152). No significant difference was noted between the SMART and standard groups in the proportion of participants with at least one high-use episode of β agonist (84 [56%] vs 68 [45%], respectively, relative risk 1·24 [95% CI 0·99-1·56]; p=0·058). There were fewer days of high use in the SMART group (mean 5·1 days [SD 14·3] vs 8·9 days [20·9], relative rate 0·58 [0·39-0·88]; p=0·01). Of the patients who had at least one high-use episode, those in the SMART group had fewer days of high use without medical review (8·5 days [17·8] vs 18·3 days [24·8], 0·49 [0·31-0·75]; p=0·001). The SMART regimen resulted in higher inhaled corticosteroid exposure (943·5 μg budesonide per day [1502·5] vs 684·3 μg budesonide per day [390·5], respectively; ratio of means 1·22 [1·06-1·41]; p=0·006), but reduced oral corticosteroid exposure (77·5 mg prednisone [240·5] vs 126·6 mg prednisone [382·1], respectively; p=0·011), with no significant difference in composite systemic corticosteroid exposure (793·7 mg prednisone equivalent per year [893·1] vs 772·1 mg prednisone equivalent per year [1062·7], respectively; 1·03 [0·86-1·22]; p=0·76). Participants in the SMART group had fewer severe asthma exacerbations (35 [weighted mean rate per year 0·53] vs 66 [0·97]; relative rate 0·54 [0·36-0·82]; p=0·004).
Interpretation:
The SMART regimen has a favourable risk-to-benefit profile and can be recommended for use in adults at risk of severe asthma exacerbations.
Funding:
Health Research Council of New Zealand.
... However, poor generalisability from RCTs to severe asthma registries is also the case for RCTs of high dose ICS/long-acting β-agonist (LABA) plus short-acting β-agonist (SABA) reliever therapy. There are similar differences in average baseline severity between patients in the UKSAR database and participants in RCTs of high dose versus medium dose ICS/LABA plus SABA therapy, as with those in the MART studies (table 1) [3][4][5][6][7][8][9][10][11][12][13]. Of particular note, the MART study populations had an overall higher baseline rate of severe exacerbations, a marker of both severity and future exacerbation risk. ...
... 5) ICS/formoterol MART has better efficacy/safety profile than ICS/LABA plus SABA. In high risk asthma, medium dose ICS/formoterol MART reduced severe exacerbation risk by 46% (relative rate 0.54, 95% CI 0.36 to 0.82) versus medium dose maintenance ICS/LABA plus SABA [11]. The MART regimen also led to significant reductions in days with no ICS therapy, days with β-agonist overuse episodes, and β-agonist overuse episodes associated with delay in seeking medical review, all risk factors for asthma mortality [11]. ...
... In high risk asthma, medium dose ICS/formoterol MART reduced severe exacerbation risk by 46% (relative rate 0.54, 95% CI 0.36 to 0.82) versus medium dose maintenance ICS/LABA plus SABA [11]. The MART regimen also led to significant reductions in days with no ICS therapy, days with β-agonist overuse episodes, and β-agonist overuse episodes associated with delay in seeking medical review, all risk factors for asthma mortality [11]. ...
... Over the last two decades, low-dose ICS-FOR has been introduced as MART for moderate-severe asthma [2,9,12,63]. More recently, attempts have been made to present ICS-FOR as a useful reliever treatment for mild asthma [2,9,12,63]. ...
... Over the last two decades, low-dose ICS-FOR has been introduced as MART for moderate-severe asthma [2,9,12,63]. More recently, attempts have been made to present ICS-FOR as a useful reliever treatment for mild asthma [2,9,12,63]. The rationale for this approach is to guarantee administration of ICS, or a higher dose of ICS, at the time of an exacerbation, with the LABA FOR being used for symptom relief [9,64]. ...
... In 2019, GINA recommendations underwent major updates to incorporate emerging data, particularly from the SYGMA studies, on asneeded ICS-FOR use, and shifted to encourage ''as-needed low-dose ICS-FOR'' in place of SABA reliever in mild and moderate asthma [15,42,43,56,63,[65][66][67][68]. Among the cited studies is a 24-week trial of 303 patients that showed fewer severe asthma exacerbations were experienced with ICS-FOR maintenance therapy plus as-needed ICS-FOR, versus ICS-FOR maintenance therapy plus as-needed SABA (relative rate 0.54; 95% CI 0.36, 0.82; p = 0.004), potentially due to increased ICS exposure [63]. ...
Short-acting β2 agonists (SABAs) have been a mainstay of asthma treatment since the 1950s, and have been mainly recommended as-needed for symptom relief alongside daily inhaled corticosteroid (ICS)-based maintenance treatment for the past 30 years. However, patient adherence to regular ICS-based anti-inflammatory maintenance therapy is frequently poor, leading to SABA overuse for symptom relief and associated poor outcomes. At present, there is a lack of consensus between treatment guidelines on how SABA should be used, and as-needed ICS-formoterol is suggested by some as an alternative reliever therapy. Here, we examine the pharmacology and current use of inhaled SABAs, identify that regular dosing of ICS can encourage appropriate SABA use, and appraise the evidence used to support the changing reliever treatment recommendations. We conclude that SABA continues to play an important role in the asthma management landscape, and give our views on how it should be used in patients with mild–moderate asthma, to complement regular ICS-based maintenance treatment.
... In both the moderate (Fig. 4A) and moderate-to-severe asthma (Fig. 4B) scenarios, most studies with MART dosing [21,25,29,30,34,40,43] and most adherence simulations (BUD 400 lg and 800 lg, FP 500 lg) fell within the high airway efficacy/high systemic activity quadrant. All final data from the In the moderate asthma simulations, a C 1.5 doubling dose efficacy threshold was used (Fig. 4A), simulations of 100% adherence with BUD/FOR 800 lg, BUD/FOR 400 lg, and FP/SAL 500 lg offered maximum bronchoprotection (100.0%), ...
... Five of the clinical trials with a BUD/FOR MART 200/6 lg (two inhalations BID plus as-needed Fig. 3 Comparison of airway efficacy to systemic activity for BUD/FOR as-needed and regular ICS dosing regimens in mild asthma [8][9][10][11]. AEF airway efficacy, BID twice daily, BUD budesonide, DD doubling dose, FOR formoterol, FP fluticasone propionate, ICS inhaled corticosteroid, PRN as needed, SA systemic activity inhalations) treatment arm [21,25,30,34,40] fell in the high efficacy/high systemic activity quadrant in both the moderate asthma and moderate-to-severe asthma simulations. Bronchoprotection ranged from 91.1% to 92.4% and from 79.9% to 83.4% in the moderate and moderate-to-severe asthma simulations, respectively; cortisol suppression was similar in both models and ranged from 32.6% to 34.9%. ...
... Studies of BUD/FOR MART versus daily BUD/ FOR dosing (plus an as-needed SABA) also had mixed results. We identified studies wherein MART was associated with fewer severe exacerbations [30] and similar asthma control [29] compared with daily BUD/FOR regular dosing, and was associated with a high proportion of rescue-medication-free days [25]. Variations in the daily ICS dose were also reported: BUD/FOR MART had a lower ICS exposure compared with daily dosing with FP/SAL or BUD/FOR in some studies [34,37,40,43], but a similar exposure to FP/SAL daily dosing in another [21]. ...
... In both the moderate (Fig. 4A) and moderate-to-severe asthma (Fig. 4B) scenarios, most studies with MART dosing [21,25,29,30,34,40,43] and most adherence simulations (BUD 400 lg and 800 lg, FP 500 lg) fell within the high airway efficacy/high systemic activity quadrant. All final data from the In the moderate asthma simulations, a C 1.5 doubling dose efficacy threshold was used (Fig. 4A), simulations of 100% adherence with BUD/FOR 800 lg, BUD/FOR 400 lg, and FP/SAL 500 lg offered maximum bronchoprotection (100.0%), ...
... Five of the clinical trials with a BUD/FOR MART 200/6 lg (two inhalations BID plus as-needed Fig. 3 Comparison of airway efficacy to systemic activity for BUD/FOR as-needed and regular ICS dosing regimens in mild asthma [8][9][10][11]. AEF airway efficacy, BID twice daily, BUD budesonide, DD doubling dose, FOR formoterol, FP fluticasone propionate, ICS inhaled corticosteroid, PRN as needed, SA systemic activity inhalations) treatment arm [21,25,30,34,40] fell in the high efficacy/high systemic activity quadrant in both the moderate asthma and moderate-to-severe asthma simulations. Bronchoprotection ranged from 91.1% to 92.4% and from 79.9% to 83.4% in the moderate and moderate-to-severe asthma simulations, respectively; cortisol suppression was similar in both models and ranged from 32.6% to 34.9%. ...
... Studies of BUD/FOR MART versus daily BUD/ FOR dosing (plus an as-needed SABA) also had mixed results. We identified studies wherein MART was associated with fewer severe exacerbations [30] and similar asthma control [29] compared with daily BUD/FOR regular dosing, and was associated with a high proportion of rescue-medication-free days [25]. Variations in the daily ICS dose were also reported: BUD/FOR MART had a lower ICS exposure compared with daily dosing with FP/SAL or BUD/FOR in some studies [34,37,40,43], but a similar exposure to FP/SAL daily dosing in another [21]. ...
Inhaled corticosteroid (ICS)-containing therapies are the mainstay of pharmacological management of asthma. They can be administered alone or in combination with a long-acting bronchodilator, depending on asthma severity, and may also be supplemented with short-acting bronchodilators for as-needed rescue medication. Adherence to asthma therapies is generally poor and characterized by underuse of ICS therapies and over-reliance on short-acting bronchodilators, which leads to poor clinical outcomes. This article reviews efficacy versus systemic activity profiles for various dosing regimens of budesonide (BUD) and fluticasone propionate (FP). We performed a structured literature review of BUD and FP regular daily dosing, and BUD/formoterol (FOR) as-needed dosing, to explore the relationship between various dosing patterns of ICS regimens and the risk-benefit profile in terms of the extent of bronchoprotection and cortisol suppression. In addition, we explored how adherence could potentially affect the risk-benefit profile, in patients with mild, moderate, and moderate-to-severe asthma. With a specific focus on BUD or FP-containing treatments, we found that regular daily ICS and ICS/long-acting β2-agonist (LABA) dosing had a greater degree of bronchoprotection than as-needed BUD/FOR dosing or BUD/FOR maintenance and reliever therapy (MART) dosing, and still maintained low systemic activity. We also found that the benefits of regular daily ICS dosing regimens were diminished when adherence was low (50%); the shorter duration of bronchoprotection observed was similar to that seen with typical as-needed BUD/FOR usage. These findings have implications for aiding clinicians with selecting the most suitable treatment option for asthma management, and subsequent implications for the advice clinicians give their patients.
... One should note that SMART is thus different from the aforementioned concept of reliever-only usage of ICS-formoterol in mild asthma. SMART has shown clear superiority to traditional inhaler management paradigms in numerous randomized trials enrolling more than 20,000 patients over the last 20 years (Table 2) (22,54,(66)(67)(68)(69)(70)(71)(72)(73)(74)(75). A recent meta-analysis showed that simply switching a patient with uncontrolled moderate/severe asthma to SMART (as opposed to stepping up maintenance ICS dosage) resulted in a prolonged time to first severe exacerbation and an approximately 30% lower risk of a future severe exacerbation (hazard ratio, 0.71; 95% CI, 0.52-0.97) ...
... Notably, most studies of SMART (and all large studies of reliever-only budesonideformoterol in mild asthma) used a drypowder delivery device rather than a U.S.-available metered dose inhaler (MDI), which can affect the airway delivery of active medication (77,78). However, the safety and efficacy of SMART have also been demonstrated with U.S.-available budesonide-formoterol 160/4.5 μg MDI in one study (70). Although nearly all of the evidence supporting the benefits of SMART only enrolled patients at least 12 years old (60), SMART with ultra-low-dose budesonide-formoterol (80/4.5 μg one puff daily and for symptoms) was investigated in children (age 4-11 yr) and significantly reduced the rate of exacerbations in this population (79). ...
... Based on earlier studies, we assumed that about 80% of participants would experience at least one moderate or severe exacerbation during the one-year study. 14,15 With the chisquare test and the two-sided alpha risk set at 5%, 242 participants (121 in each group) were needed to obtain at least 80% power for detecting a 20% between-group difference (relative effect). Previous studies suggest a 25% decrease in unscheduled healthcare contacts for severe exacerbations when a WAP is supplied. ...
... Nevertheless, only about half the participants experienced exacerbations, whereas we expected a proportion of 80%, based on the literature. 14,15 This lower proportion may be ascribable to good asthma management throughout follow-up. The frequency of severe exacerbations in our study is consistent with that of two recent multicenter trials 17,18 and is well above the rate between 0.1 and 0.2 per patient per year in unselected populations of asthma patients. ...
... Пациентам с БА старше 18 лет из группы риска по развитию обострений рекомендуется комбинация низких доз будесонида + формотерол † или беклометазона + формотерол † в качестве поддерживающей терапии и для купирования симптомов -т. н. режим единого ингалятора [70][71][72][73][74]. ...
... У детей старше 5 лет на ступени 3 лечения БА в качестве базисной терапии рекомендуются низкие / средние дозы иГКС (см. Приложение Г11) или в комбинации с ДДБА или АЛТР [69,73,75,76]. ...
Bronchial asthma is a heterogeneous disease that requires identification of its phenotype and a personalized approach to therapy. At the same time, despite a wide range of therapeutic options, many patients with asthma cannot achieve control over the disease.
Methodology . The target audience of these clinical recommendations are general practitioners, therapists, pediatricians, allergologists-immunologists, pulmonologists, and functional diagnostics doctors. Each thesis-recommendation about diagnostic and therapeutic procedures has been scored according to the scales of classes of recommendations from 1 to 5 and A, B, C scale of the levels of evidence. The clinical recommendations also contain comments and explanations to the theses, algorithms for the diagnosis and treatment of bronchial asthma, and reference materials.
Conclusion . The presented clinical guidelines cover current information about the etiology and pathogenesis, classification, clinical manifestations, diagnosis, treatment, and prevention of bronchial asthma. These guidelines were approved by the Scientific and Practical Council of the Ministry of Health of the Russian Federation in 2021.
... The editorial references a network meta-analysis [2] which included a subset analysis of 10 MART studies in "moderate-severe" asthma, and a meta-analysis of five papers which focuses on selected participants within MART studies with persistent asthma symptoms (Asthma Control Questionnaire score >1.5) [3]. The baseline features of the cohorts included in these meta-analyses and the UKSAR population are outlined in table 1 [4][5][6][7][8][9][10][11][12][13][14][15][16]. ...
... 1 Uncontrolled asthma is associated with considerable burden of disease, including impaired lung function and exacerbations, high healthcare resource utilization (HCRU) and costs, and impaired health-related quality of life (HRQoL). 2 The goal of asthma management is, therefore, to achieve and maintain control of symptoms and activity levels, reduce air ow limitation, and limit the risk of future exacerbations. 1 The Global Initiative for Asthma (GINA) 2023 report recommends a low-dose inhaled corticosteroid/long-acting β 2 -agonist (ICS/LABA) combination (budesonide/formoterol or beclomethasone/formoterol) as-needed at GINA treatment Steps 1-2, and low-medium-dose ICS/LABA as maintenance and reliever therapy (MART) at GINA treatment Step 3 and above. 1 This approach is recommended as a preferred option over maintenance treatment with ICS/LABA plus as-needed short-acting β 2 -agonist (SABA). 1 This is based on evidence from clinical trials that ICS/LABA prescribed as MART can achieve the same or improved asthma control compared with ICS/LABA as maintenance therapy plus as-needed SABA, 3,4 as well as recent reports from observational studies indicating that a large proportion of patients with asthma are highly reliant on or overuse SABA. 5,6 Furthermore, despite limited real-world data for ICS/LABA prescribed as MART, a 2022 study analyzing the electronic medical records of Korean patients with asthma found that the risk of exacerbations and overall corticosteroid requirements were lower in patients with ICS/LABA MART versus those receiving ICS/LABA plus SABA. ...
Inhaled corticosteroids (ICS) plus long-acting β 2 -agonists (LABA) are recommended for maintenance-only or maintenance and reliever therapy (MART) in patients with asthma. However, real-world data on ICS/LABA as maintenance-only or MART are limited. This study characterized clinical, economic, and humanistic burdens of asthma in Canada, China, Europe, Japan, and the US, using data collected from patients and physicians via a cross-sectional survey (Asthma Disease Specific Programme). Patients were ≥18 years of age with physician-confirmed asthma and receiving fixed-dose ICS/LABA for ≥3 months. Mean physician-reported symptom-free days over the past 30 days ranged from 10.1–20.6 days, and 31.5–34.6% of ICS/LABA users self-reported not well-controlled asthma. SABA co-prescription was reported in 8.8–67.8% of patients. These findings highlight the continued disease burden among ICS/LABA users, with the high level of SABA co-prescription indicating potentially inappropriate prescribing of ICS/LABA as MART or detrimental reliance on SABA medication in addition to MART.
... [4] It reduces the risk of beta 2 -agonist overuse in the situation of worsening asthma and the associated delay in seeking medical review, both key risk factors for asthma mortality. [5] It allows titration of ICS use according to changes in asthma severity, through the vehicle of bronchodilator use, and ensures delivery of ICS therapy in patients not prescribed or non-adherent to maintenance ICS-based medication. It is simple to use, requiring only one inhaler device regardless of severity, and is the regimen preferred by most patients. ...
... The recommendations are based on evidence from several trials, which have demonstrated a significant reduction in exacerbations with budesonide-formoterol asneeded treatment in patients with mild 7,8 or moderate-to-severe asthma. 9,10 In China, asthma is generally underdiagnosed and undertreated due to the lack of appropriate primary-care services, especially in rural regions. ...
Objectives
The SABINA CHINA study aimed to determine prescription data for asthma medication with a focus on SABA and ICS in a representative population of patients with asthma in China.
Methods
SABINA China was a multicentre, observational, cross-sectional study with data collected retrospectively from a convenience sample of 25 tertiary centres across China. Patients (age ⩾ 12 years) with ⩾3 consultations/year were enrolled. Data were collected on clinical characteristics, asthma severity, and symptom control (as per GINA 2017), treatment and history of severe exacerbations over the past year. SABA over-prescription was defined as ⩾3 SABA canisters/year. Descriptive statistics are presented.
Results
Between March and August 2020, 498 patients were included in the outcome analysis. Mean (SD) age was 48.7 (15.0) years, 57.9% were female and 91% had moderate-to-severe asthma ( n = 453). Overall, 12.5% ( n = 62) and 26.4% ( n = 131) of patients had uncontrolled and partly controlled asthma, respectively. SABA add-on was prescribed to 20.3% ( n = 101) of patients; one patient with moderate-to-severe asthma was prescribed SABA-alone. SABA over-prescription in the overall population was 4.0% ( n = 20; all with moderate-to-severe asthma) and 19.8% (20/101) among those prescribed SABA add-on. In the mild asthma group, 50% ( n = 22) were prescribed ICS/LABA and 43.2% ( n = 19) were prescribed LTRA. Among those with moderate-to-severe asthma, 97.4% ( n = 441) were prescribed ICS/LABA and 55.0% ( n = 249) were prescribed LTRA. Approximately 30% of patients ( n = 149) experienced ⩾1% and 6.6% ( n = 33) ⩾3 severe exacerbations in the preceding year; mean annual number of severe exacerbation/patient was 0.6 (1.2). Among those prescribed SABA add-on, ICS/LABA and LTRA (non-mutually exclusive groups due to overlapping prescriptions), 54.5%, 29.9%, and 35.3% had ⩾1 severe exacerbations, respectively.
Conclusion
Among patients with predominantly moderate-to-severe asthma managed in tertiary care and were prescribed SABA, 1 in 5 received ⩾3 canisters/year. Fewer patients who received ICS/LABA prescriptions experienced annual exacerbations than those prescribed SABA add-on.
... 68,201 The ICS-formoterol maintenance and reliever regimen can be prescribed with low dose beclometasone-formoterol or budesonide-formoterol. In adult and adolescent patients with ≥1 exacerbation in the previous year, the ICS-formoterol maintenance and reliever regimen significantly reduces exacerbations and provides similar levels of asthma control at relatively low doses of ICS, compared with a fixed dose of ICS-LABA as maintenance treatment or a higher dose of ICS, both with as-needed SABA [202][203][204][205][206][207] (Evidence A). Low dose ICS-formoterol is the preferred reliever for patients prescribed the maintenance and reliever treatment regimen. ...
Hintergrund: Die chronische Rhinosinusitis mit Nasenpolypen (CRSwNP) ist eine multifaktorielle entzündliche Erkrankung der paranasalen Schleimhäute, der als Endotyp meistens eine Typ-2-Inflammation zugrunde liegt. Mittlerweile sind drei Antikörper (Dupilumab, Omalizumab und Mepolizumab) für die Therapie der schweren CRSwNP zugelassen. Eine Dokumentation der Erkrankungsschwere im Behandlungsverlauf ist unverzichtbar.
Methoden: In einer Literaturrecherche in Medline, Pubmed sowie den nationalen und internationalen Studien- und Leitlinienregistern und der Cochrane Library wurde die Immunologie der CRSwNP analysiert und die Evidenz zur Wirkung von Dupilumab, Omalizumab und Mepolizumab bei dieser Erkrankung ermittelt. Hieraus wurden drei Positionspapiere durch unsere Autorengruppe erstellt, die Grundlage dieser zusammenfassenden Übersichtsarbeit sind.
Ergebnisse: Basierend auf den Angaben aus der internationalen Literatur werden von einem Expertengremium Empfehlungen für die Anwendung von Dupilumab, Omalizumab und Mepolizumab bei CRSwNP im deutschen Gesundheitssystem gegeben.
Schlussfolgerung: Dupilumab, Omalizumab und Mepolizumab sind zugelassen für Patienten ab 18 Jahren mit schwerer CRSwNP als Zusatztherapie zu intranasalen Glukokortikosteroiden (INCS), wenn, bei Dupilumab und Mepolizumab, durch eine Therapie mit systemischen Glukokortikosteroiden und/oder chirurgischem Eingriff keine ausreichende Krankheitskontrolle erzielt werden kann. Eine Therapie mit Omalizumab ist angezeigt, wenn eine Therapie mit INCS keine suffiziente Kontrolle der Erkrankung ergibt. Es werden dezidierte Empfehlungen zur Dokumentation der Anwendung im Deutschen Gesundheitssystem gegeben, die auf den hierzu bereits publizierten Positionspapieren unserer Autorengruppe basieren.
Zitierweise: Klimek L, Förster-Ruhrmann U, Beule AG, Chaker AM, Hagemann J, Klimek F, Casper I, Huppertz T, Hoffmann TK, Dazert S, Deitmer T, Olze H, Strieth S, Wrede H, Schlenter W, Welkoborsky H-J, Wollenberg B, Bergmann C, Cuevas M, Beutner C, Gröger M, Becker S. Indicating biologics for chronic rhinosinusitis with nasal polyps (CRSwNP): Recommendations by German Allergy and ORL-societies AeDA and DGHNO for Dupilumab, Omalizumab and Mepolizumab. Allergo J Int 2022;31:149-60
https://doi.org/10.1007/s40629-022-00220-x
... The 2017 GINA report 17 (the version in effect during the study) recommended SABAs alone or with an ICS for patients with mild asthma, and ICS use rates observed in our dataset are within the range of the rates reported in other studies (10.9% 24 to 37%). 29 Of note, several recent large clinical studies found no increase in serious asthma-related side effects in patients using ICS/LABA compared with those using ICS monotherapy, [30][31][32] prompting a recommendation in the 2019 GINA update to use low-dose ICS/LABA combination therapy as needed for all therapeutic steps for breakthrough asthma symptoms in lieu of a SABA. 17 The evolution of management guidelines for pulmonary disease highlights the need to regularly revisit provider and patient knowledge surrounding therapeutic options and to pair education with other strategies that facilitate the adoption of evidence-based practices. ...
Limited data exist on asthma and chronic obstructive pulmonary disease (COPD) management-major drivers of healthcare resource utilization (HCRU) in the USA. We describe prevalence and exacerbation rates, therapeutic interventions, and HCRU for asthma and/or COPD within a large, integrated healthcare system. Patients with asthma, COPD, and asthma + COPD were identified from retrospective electronic health record data (2016-2018) of >1.7 million patients. Descriptive analysis of disease prevalence and exacerbation frequencies, pharmacotherapies, and HCRU was performed. Time-to-event analysis of time to first exacerbation was performed in patients with asthma and/or COPD. Exacerbation rates, pharmacotherapies, and HCRU were examined by exploratory analysis in an outpatient subset. Overall, 149,086 unique patients (8.6%) had encounters for asthma, COPD, or asthma + COPD. Acute care utilization was high, including emergency department visits (asthma, 52.9%; COPD, 35.1%) and hospitalizations (asthma, 26.7%; COPD, 65.7%). Many patients were prescribed short-acting therapies (asthma, 45.3%; COPD, 40.0%; asthma + COPD, 54.7%). Prescription rates for maintenance therapies were low (17.1%, 20.8%, 31.7%) and annual exacerbation rates were 0.65, 0.80, and 1.33. This analysis showed a substantive prevalence of pulmonary disease, variability between documented prescriptions and pharmacotherapy guidelines, and high HCRU. Appropriate tailoring of pharmacotherapies and management of asthma and COPD over a continuum are opportunities to improve patient care.
... Formoterol is acceptable for usage in this approach in conjunction with beclomethasone or budesonide as both managed and relief treatments because of its quick onset of action [43,44]. Various clinical trials and real-world research have looked into budesonide/formoterol sustaining and relief therapy [44][45][46]. Over 3 hours, it exhibits equal therapeutic effects and safety profile to salbutamol in the treatment of mild bronchial cell constriction in asthma patients; its bronchial cell dilation action is visible one minute after therapy. ...
Background: Asthma is a chronic airway inflammatory disease, in which the excessive mucus adheres to the airway tube and causes narrowing of the respiration tube which is responsible for the difficulty in breathing. Around 235 million persons are affected with severe asthma worldwide. Purpose: The purpose of this study is to investigate and review the mechanisms of treatment strategies for asthma and the benefits or complications of nutrition supplements used in asthma, and the role of international agencies which stands for the treatment and management of asthma. Method: We search the randomized clinical trial, case reports, clinical studies, and preclinical studies with the use of search keys like asthma exacerbation, treatment strategies involve in asthma, Preclinical studies of asthma, supplement support or management of asthma, etc. we search the total 311 studies and based upon the inclusion criteria total 123 studies are included. Conclusion: According to the findings corticosteroids and Leukotrienes are mainly used for the treatment of early stages of asthma, for severe inflammation, the add-on therapy for corticosteroids with SABA and LABA may effective. Some biological compounds like Omalizumab, Reslizumab, and Benralizumab are used to treat asthma.
... As-needed ICS/LABA or ICS/SABA showed a similar effect on the prevention of exacerbation with other low-dose ICS maintenance therapies (i.e., low-dose ICS, ICS/LABA, and low-dose SMART). The mechanism of the prevention of exacerbation by as-needed ICS would be similar to that of SMART-when patients experience exacerbated symptoms, they may temporarily increase the ICS use, thereby preventing exacerbation 46 . For the recently introduced as-needed ICS/LABA, a similar efficacy in exacerbation prevention was observed despite the smaller dose of total ICS 5 . ...
The comparative effectiveness of different inhaler therapies in mild-to-moderate asthma remains unclear. To assess this, we performed a systematic review and network meta-analysis of randomized controlled trials on the use of inhalers for mild-to-moderate asthma by searching PubMed, Cochrane, and Embase. A total of 29 trials including 43,515 patients and 12 types of inhaler therapies were included. For the prevention of severe and moderate-to-severe exacerbations, inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) as maintenance and reliever (SMART) showed the highest rank for effectiveness. As-needed ICS/LABA or short-acting β2-agonist (SABA) was similar to low-dose ICS and superior to as-needed SABA or LABA for the prevention of severe and moderate-severe exacerbations. As for lung function (FEV 1 ), low-dose ICS/LABA had the highest rank; as-needed ICS/LABA was inferior to regular low-dose ICS but superior to placebo. Higher-dose ICS had a superior effect on the Asthma Control Questionnaire (ACQ) scores, and as-needed ICS/LABA and as-needed SABA or LABA had lower ranks in p-rankogram than did the regular use of low-dose ICS. As-needed ICS with LABA or SABA was more effective than a similar dose of regular ICS for preventing exacerbation in mild-to-moderate asthma. As-needed ICS showed some weakness in improving lung function and controlling asthma symptoms.
... терапия одним ингалятором (фиксированной комбинации будесонид/формотерол) как регулярно 2 раза в день, так и по потребности. Данная рекомендация обоснована многочисленными исследованиями, в которых доказано, что терапия в режиме «SMART» позволяет уменьшить количество обострений в 1,7 раза по сравнению со стандартной терапией (ИКС/БАДД + БАКД по потребности), при сопоставимом контроле симптомов заболевания и значимом снижении суммарной дозы ИГКС [30,31,32,33]. ...
Among chronic respiratory diseases, asthma is one of the most common diseases. The current goal of asthma treatment is to achieve asthmacontrol. Despite the fact that, according to the data of randomized trials, this goal is achievable in most patients, in real clinical practice the proportion of patients who have achieved asthmacontrol does not exceed 42–49%. The article provides an analysis of these recommendations and a literature review of those studies that justify their changes. A key change in the new GINA recommendations is the rejection of shortacting beta2agonists as monotherapy in patients with mild stage I asthma.
The priority regimen of basic therapy at this stage of treatment is now a fixed combination of budesonide/formoterol, taken on demand. Such therapy, according to the literature, was significantlymoreeffectivethanshortactingbeta2 agonists monotherapy. In addition, budesonide/ formoterol is also considered as a priority drug for relieving symptoms on demand, and short acting beta2agonists is currently classified as an alternative drug.
The recommendation is based on the data of randomized trials, in which it was proved that the use of a fixed combination of budesonide/ formoterol on demand, significantly reduces the number of exacerbations of asthma compared with the use of shortacting beta2agonists on demand. The introduction of new GINA recommendations into practice will improve the effectiveness of basic therapy for asthma.
Introduction
Single maintenance and reliever therapy (SMART) with a combination inhaled corticosteroid‐formoterol inhaler is the preferred asthma treatment by the Global Initiative for Asthma and the National Asthma Education and Prevention Program guidelines. These recommendations have been slow to be implemented routinely into clinical practice.
Methods
This was an observational cohort study conducted in a family medicine residency program clinic. A clinical pharmacist‐led initiative to implement SMART, which included provider education and the development of clinical tools to facilitate SMART prescribing, was assessed. Year 1 (Y1; pre‐intervention) and year 2 (Y2; post‐intervention) were compared.
Outcomes
The primary outcome was to evaluate the impact of this initiative on the frequency of SMART (budesonide‐formoterol without albuterol) prescribing. Prescription frequencies for albuterol and budesonide‐formoterol were also compared separately. Secondary outcomes were Asthma Control Test (ACT) scores and prescribing frequencies among faculty and resident physicians.
Results
The total number of eligible patients in the clinic population was 807, and 459 of these patients met the inclusion criteria. There were more females than males, and the mean age was 39. About 24% had a language preference other than English and 22% required an interpreter. The percentage of patients who were prescribed SMART significantly increased from 0.44% to 11.5% ( p < 0.001). Budesonide‐formoterol prescriptions increased from 7.4% to 34.6% ( p < 0.001). Albuterol metered‐dose inhaler prescriptions decreased from 79.7% to 66.2% ( p < 0.001). Prescribing patterns were similar for patients of faculty physicians ( n = 258) and resident physicians ( n = 196). Only 164 (35.7%) patients had an ACT score in Y1 and Y2, and the mean ACT score was not significantly different between Y1 and Y2 ( p = 0.973).
Conclusion
A clinical pharmacist‐led SMART asthma prescribing initiative was associated with a significant increase in SMART prescribing, a significant increase in budesonide‐formoterol prescribing, and a significant decrease in albuterol prescribing.
Introduction:
The study aims to compare the real-world effectiveness and economy of the budesonide/formoterol reliever and maintenance therapy (SMART) with fixed-dose inhaled corticosteroids (ICS)/long-acting b-agonist (LABA) or ICS alone plus as-needed, short-acting β2 agonists (SABA) in pediatric patients.
Methods:
The outpatient data warehouse of a hospital in China was used. A total of 103 patients under 18 years old in the SMART group and 63 patients in the control group were included from January 1, 2020 to December 31, 2021. The effectiveness was assessed using asthma attacks and lung function at baseline, 6 months and 12 months follow-up. Cost-effectiveness analysis was performed with a three-state Markov model from the healthcare system perspective. One-way sensitivity analyses and probabilistic sensitivity analyses were performed to check the robustness of the results.
Results:
The SMART regimen was more effective than other strategies in reducing the risk of mild and severe attacks in the real-life management of childhood asthma. Patients in both groups showed significant improvement in lung function at 6 and 12 months in contrast to baseline. Compared with other strategies, the forced expiratory volume in 1 s (FEV1 ) level in the SMART group was markedly improved at 6 months. The total cost of outpatient service using the SMART regimen was lower than that of other strategies, while the drug costs were similar in different groups. Incremental cost-effectiveness analysis results showed that using the SMART regimen reduced the total cost by approximately CNY 10,516.11 per year with a 0.12 quality-adjusted life year (QALYs) increase. Sensitive analyses supported that the SMART regimen was the dominant choice at the willingness-to-pay threshold of CNY 85,698, per capita GDP in China.
Conclusions:
Collectively, our findings indicate that the real-world effectiveness and economy of the SMART regimen are superior to the traditional strategies in pediatric asthma patients.
Introduction of inhaled corticosteroids (ICS) has been the cornerstone of the long-term management of asthma. ICSs either alone or in combination with long-acting beta-2 agonists have been shown to be associated with favorable asthma outcomes. However, asthma control is still reported to be below expectations all around the world. Research in the last decades focusing on the use of ICS/formoterol both as maintenance and as needed (maintenance and reliever therapy approach) showed improved asthma outcomes. As a result of recent developments, Turkish Asthma Guidelines group aimed to revise asthma treatment recommendations. In general, we recommend physicians to consider the risk factors for poor asthma outcomes, patients’ compliance and expectations and then to determine “a personalized treatment plan.” Importantly, the use of short-acting beta-2 agonists alone as a symptom reliever in asthma patients not using regular ICS is no longer recommended. In stepwise treatment approach, we primarily recommend to use ICS-based controllers and initiate ICS as soon as possible. We define 2 different treatment tracks in stepwise approaches as maintenance and reliever therapy or fixed-dose therapy and equally recommend each track depending on the patient’s risks as well as decision of physicians in a personalized manner. For both tracks, a strong recommendation was made in favor of using add-on treatments before initiating phenotype-specific treatment in step 5. A strong recommendation was also made in favor of using biologic agents and/or aspirin treatment after desensitization in severe asthma when indicated.
The treatable traits approach is based on the recognition that the different clinical phenotypes of asthma and chronic obstructive airways disease (COPD) are a heterogeneous group of conditions with different underlying mechanisms and clinical manifestations, and that the identification and treatment of the specific clinical features or traits facilitates a personalised approach to management. Fundamentally, it recognises two important concepts. Firstly, that treatment for obstructive lung disease can achieve better outcomes if guided by specific clinical characteristics. Secondly, that in patients with a diagnosis of asthma, and/or COPD, poor respiratory health may also be due to numerous overlapping disorders that can present with symptoms that may be indistinguishable from asthma and/or COPD, comorbidities that might require treatment in their own right, and lifestyle or environmental factors that, if addressed, might lead to better control rather than simply increasing airways directed treatment. While these concepts are well accepted, how best to implement this personalised medicine approach in primary and secondary care within existing resource constraints remains uncertain. In this review, we consider the evidence base for this management approach and propose that the priority now is to assess different prototype templates for the identification and management of treatable traits in both asthma and COPD, in primary, secondary and tertiary care, to provide the evidence that will guide their use in clinical practice in different health care systems.
Background
The stepwise approach to long-term asthma management, which traditionally incorporates short-acting beta 2 -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
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 with mild, moderate, and moderate-severe asthma (ACTRN12620001010987). Participants will be allocated to budesonide-formoterol 200/6 mcg, 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, 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.
Zusammenfassung
Das Management von Asthma hat sich in den letzten Jahrzehnten fundamental gewandelt. Die vorliegende Leitlinie zur Diagnostik und Therapie von Asthma wurde für pneumologisch tätige Fachärztinnen und Fachärzte entwickelt, welche detaillierte und evidenzbasierte Informationen zu den neuen diagnostischen und therapeutischen Optionen von Asthma benötigen. Die Leitlinie zeigt die neue Bedeutung der Biomarker, insbesondere der Bluteosinophilen und des exhalierten NO (FeNO), in den diagnostischen Algorithmen von Asthma. Als erste Asthma-Leitlinie weltweit benennt die vorliegende Leitlinie die nachhaltige Symptomprävention und die Asthma-Remission als Asthma-Therapieziele, welche durch den Einsatz individuell angepasster, krankheitsmodifizierender Medikamente (wie inhalative Steroide, Allergenimmuntherapie oder Biologika) erreicht werden können. Die zentrale Bedeutung der Behandlung von typischen Asthma-Komorbiditäten wird zudem betont. Schließlich wird auch auf besondere Herausforderungen im Asthma-Management eingegangen, wie bspw. die Therapie von Asthma in der Schwangerschaft, die Behandlung von schwerem Asthma oder die Diagnostik und Therapie von arbeitsbedingten Asthma-Formen.
Background:
A "window of opportunity" has been proposed where anti-inflammatory therapy administration in response to symptoms could prevent exacerbation.
Objective:
To evaluate rescue and maintenance therapy claims surrounding a severe asthma exacerbation serious enough to require a face-to-face clinical encounter.
Methods:
Merative® MarketScan® research databases (US administrative claims 2011-2017) were analyzed for patients ≥4 years, with an asthma diagnosis code, who filled short-acting β2-agonist (SABA) and Global Initiative for Asthma Steps 3-5 maintenance therapies. Patients were indexed on a random SABA claim and had 12 months' continuous health-plan eligibility pre- and post-index. Serious exacerbations were severe exacerbations requiring systemic corticosteroids prescribed from an outpatient clinic, urgent-care or emergency department, or hospitalization for asthma. SABA and maintenance claims 30 days pre- and post-event were analyzed.
Results:
Of 319,342 patients (30% children 4-11 years; 70% adolescents/adults ≥12 years), 27.2% of children and 16.8% of adolescents/adults experienced ≥1 serious exacerbation (unadjusted odds ratio [OR] 1.85 [95% CI 1.81-1.88]). In the 30 days pre-event, 42.6% filled ≥1 SABA (children: 44.3%; adolescents/adults: 41.5%; OR 1.12 [1.09-1.16]) and 57.4% filled maintenance (children: 59.0%; adolescents/adults: 56.3%; OR 1.12 [1.08-1.15]). In the 30 days post-event, 61.4% filled SABA (children: 69.7%; adolescents/adults: 55.6%; OR 1.84 [1.78-1.90]) and 94.8% filled maintenance (children: 98.6%; adolescents/adults: 92.2%; OR 6.09 [5.45-6.81]).
Conclusion:
Many patients treated as having moderate-to-severe asthma escalate SABA claims before a serious exacerbation, but ∼40% have no anti-inflammatory maintenance fill, highlighting a "window of opportunity" to prevent exacerbations using inhaled corticosteroids concomitantly with SABA as rescue.
Asthma is a chronic inflammatory airway disease characterized by variable airflow obstruction. Korean Asthma Study Group in Korean Academy of Tuberculosis and Respiratory Diseases has updated Korean Asthma Guideline. This review summarized the updated Korean Asthma Guideline. Asthma prevalence is increasing worldwide and is also increasing in Korea. Variable airflow obstruction can be confirmed by bronchodilator response or other tests and should be established prior to the controller medication. A low-dose inhaled corticosteroid-formoterol is used to alleviate symptoms in all treatment step, and it can be used as a controller as well as reliever in steps 3-5. This approach is preferred because it reduces the risk of severe exacerbations compared to the use of short-acting β2-agonist as reliever. In severe asthma, phenotype/endotype based on the underlying inflammation should be evaluated. For type 2 severe asthma, biologics should be considered.
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 beta2-agonists (LABA), and inhaled short-acting beta2-agonists (SABA), for the 12+ age group, were displayed graphically with piecewise regression used to produce plots of rates by time with a 01 July 2020 break point. The number of dispensings in the last six months that data was available (July-December 2021) was compared with the corresponding period, July-December 2019.
Results:
Budesonide/formoterol dispensing increased markedly after 01 July 2020 (regression coefficient 41.1 inhalers dispensed/100,000 population/per month (95%CI: 36.3 to 45.6, P<0.0001); 64.7% increase in 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<0.0001); -1.7% decrease) and SABA (regression coefficient -14.7 (95%CI: -29.7 to 0.3, P=0.055); -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 following publication of the 2020 NZ asthma guidelines. While acknowledging the limitations in the interpretation of temporal associations, these findings suggest the transition to ICS/formoterol reliever-based therapy can be achieved if recommended and promoted as the preferred therapeutic approach in national guidelines.
Purpose of review:
Asthma is the most common chronic respiratory disorder, characterized by recurring, reversible airflow obstruction due to inflammation and airway hyperresponsiveness. Although biologics have provided significant advances in the treatment of asthma, they are expensive, and their use remains restricted to more severe asthma. Additional approaches in the management of moderate-to-severe asthma are necessary.
Recent findings:
ICS-formoterol as maintenance and reliever therapy in asthma and its effect on improved asthma control has been demonstrated in multiple cohorts of asthma. Although ICS-formoterol as maintenance and reliever therapy has been widely validated, there are significant design considerations including the requirement for exacerbation and bronchodilator response and the lack of evidence for effectiveness in patients who use nebulized reliever therapies, which may limit the use of this therapy in selected populations. More recent trials of as-needed ICS have demonstrated effectiveness in reducing asthma exacerbations and improvements in asthma control and may provide an additional therapeutic strategy for individuals with moderate-to-severe asthma.
Summary:
Both ICS-formoterol as a maintenance and a reliever as well as as-needed ICS have demonstrated significant improvements in the control of moderate-to-severe asthma. Future investigational work will be necessary to elucidate whether a strategy of ICS-formoterol as maintenance and reliever therapy or an as-needed ICS strategy demonstrates superiority in asthma control in the context of the cost to individual patients and health systems.
Background:
As-needed low-dose inhaled corticosteroid (ICS)-formoterol reliever is recommended in asthma patients prescribed maintenance ICS-formoterol. Clinicians often ask whether ICS-formoterol reliever can be used with other maintenance ICS-long-acting β2-agonists (LABAs).
Objective:
To evaluate safety and effectiveness of as-needed formoterol in patients taking maintenance ICS-formoterol or ICS-salmeterol from the RELIEF study.
Methods:
RELIEF (SD-037-0699) was a 6-month, open-label study that randomized 18,124 patients with asthma to as-needed formoterol 4.5μg or salbutamol 200μg on top of maintenance therapy. This post hoc analysis included patients on maintenance ICS-formoterol or ICS-salmeterol (n=5,436). The primary safety outcome was a composite of serious adverse events (SAEs) and/or adverse events leading to discontinuation (DAEs); the primary effectiveness outcome was time-to-first exacerbation.
Results:
For both maintenance groups and both relievers, similar numbers of patients had ≥1 SAE and/or DAE. In patients taking maintenance ICS-salmeterol, but not ICS-formoterol, significantly more non-asthma-related and non-serious DAEs occurred with as-needed formoterol versus as-needed salbutamol (p=0.0066 and p=0.0034, respectively). In patients taking maintenance ICS-formoterol, there was a significantly lower risk in time-to-first exacerbation with as-needed formoterol versus as-needed salbutamol (HR 0.82; 95% CI 0.70, 0.95; p=0.007). In patients taking ICS-salmeterol maintenance, time-to-first exacerbation was not significantly different between treatment arms (HR 0.95; 95% CI 0.84, 1.06; p=0.35).
Conclusions:
As-needed formoterol significantly reduced exacerbation risk compared with as-needed salbutamol when added to maintenance ICS-formoterol, but not to maintenance ICS-salmeterol. More DAEs were seen with ICS-salmeterol maintenance therapy plus as-needed formoterol. Further research is needed to assess whether this is relevant to as-needed combination ICS-formoterol.
Asthma is characterized by chronic airway inflammation, variable airway narrowing, and sensory nerve irritation, which manifest as wheezing, dyspnea, chest tightness, and cough. Longstanding asthma may result in airway remodeling and become intractable. Despite the increased prevalence of asthma in adults, asthma-associated deaths have decreased in Japan (0.94 per 100,000 people in 2020). The goals of asthma treatment include the control of symptoms and reduction of future risks. A functional partnership between physicians and patients is indispensable for achieving these goals. Long-term management with medications and the elimination of triggers and risk factors are fundamental to asthma treatment. Asthma is managed via four steps of pharmacotherapy ("controllers"), ranging from mild to intensive treatments, depending on disease severity; each step involves daily administration of an inhaled corticosteroid, which varies from low to high dosage. Long-acting β2 agonists, leukotriene receptor antagonists, sustained-release theophylline, and long-acting muscarinic antagonists are recommended as add-on drugs. Allergen immunotherapy is a new option that is employed as a controller treatment. Further, as of 2021, anti-IgE antibody, anti-IL-5 and anti-IL-5 receptor α-chain antibodies, and anti-IL-4 receptor α-chain antibodies are available for the treatment of severe asthma. Bronchial thermoplasty can be performed for asthma treatment, and its long-term efficacy has been reported. Algorithms for their usage have been revised. Comorbidities, such as allergic rhinitis, chronic rhinosinusitis, chronic obstructive pulmonary disease, and aspirin-exacerbated respiratory disease, should also be considered during the treatment of chronic asthma. Depending on the severity of episodes, inhaled short-acting β2 agonists, systemic corticosteroids, short-acting muscarinic antagonists, oxygen therapy, and other approaches are used as needed ("relievers") during exacerbation.
Background:
A written action plan (WAP) for managing asthma exacerbations is recommended.
Objective:
We compared the effect on unscheduled medical contacts (UMCs) of a digital action plan (DAP) accessed via a smartphone Web application (app) combined with a WAP on paper versus the same WAP alone.
Methods:
This randomized, unblinded, multicenter (offline recruitment in private offices and public hospitals by physicians), parallel-group trial included asthma patients who were either children (6-12 years) or adults (18-60 years) and who had experienced at least one severe exacerbation in the previous year. They were randomized to WAP or DAP+WAP in a 1:1 ratio. The DAP (fully automated) provided treatment advice according to the severity and previous pharmacotherapy of the exacerbation. The DAP was an algorithm that recorded three to nine clinical descriptors. When using the app, the participant first assessed severity of current symptoms on a 10-point scale then entered the symptom descriptors. Before the trial (DAP development) the wordings of these descriptors and their ordering were validated by 50 parents of children with asthma and 50 adults with asthma; the app was not modified during the trial. Participants were interviewed at three, six, nine, and 12 months to record exacerbations, UMCs, and WAP and DAP use, including the subjective evaluation (availability, usefulness) of the action plans, by a research nurse.
Results:
Two-hundred and eighty participants were randomized of whom 33 were excluded due to the absence of follow-up data after randomization, leaving 247 participants (93 children, 154 adults). The WAP group had 123 participants (45 children, mean age 8.3±2.0 years; and 78 adults, 36.3±12.7 years) and the DAP+WAP group 124 participants (48 children, 9.0±1.9 years; and 76 adults, 34.5±11.3 years). Overall, the annual severe exacerbation rate was 0.53 and was not different in the two groups of participants. The mean UMC number/year was 0.31±0.62 in the WAP group and 0.37±0.82 in the DAP+WAP group (mean difference, 0.06; 95% confidence interval, -0.12 to 0.24, P=.82). Use per patient with at least one moderate or severe exacerbation was higher for the WAP (33/65 versus 15/63 for the DAP, P=.002). Thus, participants were more likely to use the WAP as compared to the DAP despite non-significant difference for the subjective evaluation of both action plans. Median symptom severity of the exacerbation self-evaluated by the participants was 4/10 and was not significantly different from symptom severity assessed by the app.
Conclusions:
The DAP was used less often than the WAP and did not decrease the number of UMCs compared to the WAP alone, which does not call into question the interest of the action plan and its associated therapeutic education. The benefits of telehealthcare in asthma care remain to be demonstrated.
Clinicaltrial:
ClinicalTrials.gov Identifier: NCT02869958.
Pengobatan asma bertujuan untuk mencapai kontrol yang baik atas gejala dan untuk meminimalkan risiko eksaserbasi, morbiditas, dan mortalitas. Global Initiative for Asthma (GINA) menganjurkan pendekatan bertahap untuk mencapai kontrol gejala dan kontrol risiko yang terbaik. Pendekatan ini dibagi untuk 3 kelompok usia (5 tahun atau kurang, 6-11 tahun, dewasa atau remaja). Setiap langkah pengobatan mencakup obat utama (controller dan/atau reliever). Asthma treatment aims to achieve good symptom control and minimize the risk of exacerbations, morbidity, and mortality. Global Initiative for Asthma (GINA) recommends a phased treatment approach with several adjustable steps to achieve the best possible symptom and risk control. This stepped approach is divided into three age groups (5 years or less, 6-11 years, adults or adolescents). Each treatment step includes primary drug (controller and/or reliever).
The most recent recommendations from the 2020 National Asthma Education and Prevention Program (NAEPP) Update and Global Initiative for Asthma (GINA) 2021 guide evidence-based clinical decision making. However, given the present state of health disparities by age, income, and race, the equitable implementation and dissemination of these guidelines will be unlikely without further guidance. This workgroup report reviews the current state of the new asthma guideline implementation, presents updated evidence-based therapeutic options with attention to specific patient populations, and addresses barriers to the implementation of these guidelines in minoritized, marginalized, and under resourced communities. Allergists and immunologists can utilize practical ways to accomplish the goals of improved asthma care access and advanced asthma care across the lifespan, with specific considerations to historically marginalized populations. Modifiable barriers to guideline implementation include financial barriers, environmental factors, and allergy subspecialty access and care coordination. Various programs to improve access to guideline-based asthma care include community programs, school-based asthma programs, and digital health solutions, with an emphasis on reducing disparities by race.
Prevention of severe asthma exacerbations is a primary management goal for asthma across the severity spectrum. Inhaled corticosteroids (ICS) decrease the risk of asthma exacerbations, but patient adherence to ICS-containing medications as a daily maintenance therapy is poor, and many patients overuse short-acting beta2-agonist relievers; both are associated with increased risk of severe exacerbations and death. Airway inflammation also varies over time, influenced by exposures such as viral infections and allergen. As-needed ICS strategies, in which patients receive ICS (or additional ICS, if already taking controller therapy) whenever they take their reliever inhaler, empower patients to adjust their ICS intake in response to symptom fluctuation. These strategies can improve asthma morbidity outcomes, particularly by reducing severe exacerbations and reducing the risk of adverse effects of oral corticosteroids. In this review, the evidence for combination ICS-formoterol in a single inhaler, ICS and short-acting beta2-agonists in separate inhalers, and combination ICS-albuterol in a single inhaler is presented, along with practical considerations, evidence gaps, and implications for clinical practice for each strategy, presented by level of asthma severity and age group. Improving access to such strategies on a global scale is imperative in order to improve asthma outcomes and achieve equity across populations.
The vast array of inhaler devices can be overwhelming for patients with chronic obstructive pulmonary disease (COPD) or asthma. Matching the right inhaler features to patients’ needs is key to maximising adherence and achieving the best outcomes. During this symposium, leading global asthma and COPD experts took an in-depth look at the latest clinical data relating to inhaler satisfaction and clinical outcomes.
The Global Initiative for Asthma (GINA) recommends that low dose inhaled corticosteroid (ICS)/formoterol is preferred to short-acting beta2-agonists (SABA’s) 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.
A written asthma action plan is an important element of asthma self-management in children and adults. It provides patients instructions for managing both the acute and long-term aspects of asthma. Studies suggested that optimal asthma self-management and an action plan can improve asthma outcomes. These outcomes include reduction in asthma-related hospital admissions, emergency department visits, systemic corticosteroid use, short-acting β2 agonist use, nighttime symptoms, days off work or school, and the number of limited activity days. Evidence also supports the benefits of an asthma action plan on improving the quality of life (QOL) of asthma patients and their caregivers, and adherence to asthma medications. However, the majority of the studies did not investigate if the benefits are from the use of asthma action plan alone or due to other aspects of asthma self-management education combined. Nevertheless, it is recommended that all patients with asthma should have an action plan, especially in those with moderate or severe persistent asthma, a history of severe exacerbation, or poorly controlled asthma. Lack of an asthma action plan is considered one of the risk factors of asthma exacerbation and asthma death. A food allergy action plan should be provided to patients, caregivers, and school staff to implement emergency treatment in case of an allergic reaction due to exposure to food that an individual is allergic to. It can potentially help improve anaphylaxis outcomes by improving the use of epinephrine auto-injectors. Several asthma-related and food-related QOL assessment instruments are available for children, adults, and caregivers. Disease-specific QOL questionnaires can help provide a complete assessment of the impact of the disease on patients/caregivers and develop effective interventions that matter to the individuals, which can lead to the improvement of medication adherence, and hence, the disease outcomes.
The claimed functional basis for ICSs in asthma and COPD is airway selectivity, attained by inhaling a potent, lipophilic compound with long local dissolution/absorption time. The development has been empirically based, resulting in five widely used ICSs. Among them, budesonide (BUD) deviates by being less lipophilic, leading to a more rapid systemic uptake with plasma peaks with some systemic anti-inflammatory activity. By this, BUD fits less well into the current pharmacological dogma of optimal ICS profile.
In this review we compared the physicochemical, pharmacological and clinical properties of BUD, fluticasone propionate (FP) and fluticasone furoate (FF), representing different levels of lipophilicity, airway and systemic kinetics, focusing on their long-acting β2-agonist (LABA) combinations, in line with current GINA and GOLD recommendations. We are aware of the differences between formoterol (FORM) and the not rapid acting LABAs such as e.g. salmeterol and vilanterol but our comparisons are based on currently available combination products. A beclomethasone dipropionate (BDP)/FORM combination is also commented upon.
Based on clinical comparisons in asthma and COPD, we conclude that the BUD/formoterol (BUD/FORM) combination is as effective and safe as the FP and FF combinations, and is in some cases even better as it can be used as “maintenance plus reliever therapy” (MART) in asthma and as maintenance in COPD. This is difficult to explain by current views of required ICS's/LABAs pharmacokinetic profiles.
We propose that BUD achieves its efficacy by a combination of airway and systemic activity. The airway activity is dominating. The systemic activity contributes by plasma peaks, which are high enough for supportive anti-inflammatory actions at the blood and bone marrow levels but not sufficiently long to trigger a similar level of systemic adverse effects. This may be due to BUD's capacity to exploit a systemic differentiation mechanism as programmed for cortisol's various actions. This differentiation prospect can be reached only for an ICS with short plasma half-life. Here we present an alternative mode for an ICS to reach combined efficacy and safety, based on a poorly investigated and exploited physiological mechanism. A preference of this mode is broader versatility, due to that its straighter dose-response should allow a better adaptation to disease fluctuations, and that its rapid activity enables use as “anti-inflammatory reliever”.
The Global Initiative for Asthma has since 2019 recommended as-needed inhaled steroids (ICS)/formoterol either alone or in combination with ICS/long-acting β2-agonists (LABA) maintenance for mild to moderate asthma. This might give patients more adverse effects by using LABA instead of short-acting β2-agonists (SABA) and by using ICS as needed where the patient might not be able to wash their mouth after use. The objective of this study is through a literature review to investigate whether the new recommendations increase the incidence of adverse events. We included 15 randomized clinical trials. They showed no increase in adverse events with as-needed ICS/formoterol only compared with either as-needed SABA only or maintenance ICS and SABA as-needed, and even a small tendency to less adverse events. When comparing as-needed and maintenance ICS/formoterol with as-needed SABA and maintenance ICS/LABA a small increase was seen for some adverse events, especially candidiasis (1.4 vs. 0.7%) and dysphonia (1.5 vs. 1.0%). In conclusion, the new treatment with as-needed ICS/formoterol only is at least as safe as the previously recommended treatment, regarding adverse effects. ICS/formoterol used as needed and maintenance might give an increased risk of candidiasis and dysphonia, though the absolute risk remains low.
Objective
The objective of this review is to evaluate the effectiveness and practicality of SMART (single maintenance and reliever therapy) in the treatment of asthma exacerbation.
Data Sources
PubMed, MEDLINE, Cochrane, and Clinical Trial databases using the keywords SMART therapy, maintenance and reliever therapy, and budesonide and formoterol.
Study Selection
Articles were selected based on their relevance and applicability to this topic.
Results
Multiple studies have evaluated the efficacy of SMART in reducing asthma exacerbations in comparison to standard inhaled corticosteroid (ICS) maintenance and short-acting beta-agonist (SABA) rescue therapy. Most of the randomized trials demonstrated a reduction in asthma exacerbation with open-label studies revealing similar effectiveness in reducing asthma exacerbation. Previously, concerns have been raised regarding the administration of increased doses of long-acting beta-agonist that may potentially mask symptoms and delay appropriate medical attention. However, studies have not demonstrated an increase in morbidity or mortality. The primary concern regarding many of these trials is that they have been sponsored by pharmaceutical companies.
Conclusion
Although not all studies demonstrated the effectiveness of SMART, the majority revealed a significant reduction in asthma exacerbation frequency and severity.
Asthma is a chronic inflammatory lung disease that affects millions of Americans, with variable symptoms of bronchospasm and obstruction among individuals over time. The National Heart, Lung, and Blood Institute (NHLBI) published the 2020 Focused Updates to the Asthma Management Guidelines based on the latest research since the 2007 Expert Panel Report-3 (EPR-3). The following article reviews the 21 new recommendations on the six core topics in asthma: use of intermittent inhaled corticosteroids, long-acting muscarinic antagonist therapy, use of the fractional exhaled nitric oxide test in asthma diagnosis and monitoring, indoor allergen mitigation, immunotherapy, and bronchial thermoplasty. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to rate recommendations as strong or conditional based on the evidence. The recommendations were based on systematic reviews of the literature and focused on patient-centered critical outcomes of asthma exacerbations, asthma control, and asthma-related quality of life. Understanding the recommendations with consideration of individual values through shared decision-making may improve asthma outcomes.
Importance:
The Global Initiative for Asthma (GINA) recommends 2 alternative treatments for patients receiving treatment at steps 3 to 5: single inhaler combination inhaled corticosteroid-formoterol as both maintenance and reliever (SMART) or inhaled corticosteroid-long-acting β2-agonist as maintenance plus short-acting β2-agonist as reliever.
Objective:
To assess whether switching to SMART is associated with longer time to first severe asthma exacerbation compared with a step up or continuation of GINA treatment step with maintenance inhaled corticosteroid-long-acting β2-agonist plus short-acting β2-agonist reliever among patients with poorly controlled asthma.
Data sources:
For this systematic review and meta-analysis, the literature, internal study databases at AstraZeneca and the Medical Research Institute of New Zealand, and references from a previous systematic review and meta-analysis on SMART were searched to identify randomized clinical trials published from January 1990 to February 2018, that compared budesonide-formoterol by SMART with maintenance inhaled corticosteroid-long-acting β2-agonist plus short-acting β2-agonist reliever.
Study selection:
Trials of at least 24 weeks' duration were included if they reported baseline data on GINA treatment step, asthma control status, and efficacy measures of severe exacerbations. Included patients were adults and adolescents with asthma and baseline Asthma Control Questionnaire 5-item version scores of 1.5 or higher.
Data extraction and synthesis:
Patient-level data were identified by independent extraction, and analyses were performed using a fixed-effect model. Data analysis was performed from August 2018 to November 2021.
Main outcomes and measures:
The primary outcome was time to first severe asthma exacerbation associated with each treatment, analyzed by Cox proportional hazards regression.
Results:
Overall, 4863 patients were included (3034 [62.4%] female; mean [SD] age, 39.8 [16.3] years). Switching patients with uncontrolled asthma at GINA step 3 (n = 1950) to SMART at either step 3 or 4 was associated with a prolonged time to first severe asthma exacerbation, with a 29% reduced risk compared with stepping up to step 4 inhaled corticosteroid-long-acting β2-agonist maintenance plus short-acting β2-agonist reliever (hazard ratio, 0.71; 95% CI, 0.52-0.97). For patients with uncontrolled asthma at step 3 and step 4 (n = 2913), switching to SMART was associated with a prolonged time to first severe asthma exacerbation and a 30% reduced risk compared with remaining at the same treatment step (hazard ratio, 0.70; 95% CI, 0.58-0.85).
Conclusions and relevance:
In this systematic review and meta-analysis, for patients with poorly controlled asthma, SMART was associated with longer time to first severe asthma exacerbation compared with a step up or continuation of GINA step with maintenance inhaled corticosteroid-long-acting β2-agonist plus short-acting β2-agonist reliever. These findings suggest that if an adult or adolescent receiving treatment at GINA step 3 or 4 has poorly controlled asthma, it is preferable to switch to the SMART regimen rather than to step up or continue the GINA treatment step with maintenance inhaled corticosteroid-long-acting β2-agonist plus short-acting β2-agonist reliever therapy.
Purpose of review:
The 2020 focused updates to the asthma management guidelines by the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group advocate for inhaled corticosteroid (ICS)-formoterol combinations as single maintenance and reliever therapy (SMART) for patients with persistent asthma. We review the rationale, the evidence supporting SMART use in asthma, and barriers limiting its wide adoption in the United States.
Recent findings:
A growing body of evidence supports the use of SMART over the conventional use of controller medicaments with an as-needed short-acting β2 agonist for rescue therapy for the purpose of reducing the risk of asthma exacerbation and maintaining asthma control in adolescents and adults with persistent disease. Lack of US Food and Drug Administration approval, inconsistent insurance coverage, and limited options of ICS-formoterol combination available for use as SMART represent obstacles to wider integration of SMART in clinical practice.
Summary:
SMART represents a paradigm shift in asthma management. By identifying and addressing the current and anticipated barriers to implementing SMART, its adoption by providers is likely to increase in the United States.
A metal-carbon nano-polymer based sensor was constructed by combining platinum nanoparticles (PtNPs), acidified multi-walled carbon nanotubes (MWCNTs), and a ionic polymer of perfluorinated sulfonic resin (PFSE) for modifying on the surface of glassy carbon electrode (GCE), yielding PtNPs/MWCNTs-PFSE/GCE. The behaviors of cyclic voltammetry (CV) and differential pulse voltammetry (DPV) of four different modified electrodes such as bare GCE、MWCNTs-PFSE/GCE、PtNPs/GCE and PtNPs/MWCNTs-PFSE/GCE were investigated in detail, showing that the PtNPs/MWCNTs-PFSE composite exhibited significantly improved electrocatalytic activity to salbutamol (SAL, 1). An oxidation mechanism has been confirmed that the phenolic hydroxyl group of SAL (1) is oxidized involving one proton and one electron for a formation of a free radical, resulting in intermediate (2) via resonance, and then transform to a SAL dimmer (3) with a C-C bond formation via re-combination of the intermediate (2), showing an irreversible oxidation process. Under the optimum condition, the metal-carbon nano-polymer modified electrode showed excellent linear response to SAL in range of from 5.0×10-8 mol/L to 2.0×10-6 mol/L and a detection limit of 1.4×10-8 mol/L. The modified electrode possessed good selectivity, reproducibility, and stability. This has been successfully applied to determination of SAL content in pork meat and pork liver samples with recovery rates from 95.4% to 104.3%, indicating strong potential applications in food safety control. © 2022 The Authors. Published by ESG (www.electrochemsci.org). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/).
Asthma is a disorder of the respiratory system in which the passages that enable air to pass in and out of the lungs periodically becomes narrow, causing coughing, wheezing, and shortness of breath. This disorder makes the victim uncomfortable and sometimes exposed such a person to untimely death. Because of this reason, we want to determine the future occurrence of Asthma and also find out the age that is mostly affected with Asthma. Sample data were collected at Federal Medical Centre Jalingo. Markov chain model was used to solve the problem and maple 13 package was used to plot the graph of the sample data and that of the predicted transition probability which shows that as the year increases, there is an increase in the predicted transition probability which clearly shows that asthmatic patient increases along the years. It was also observed that there is likely more Asthmatic case at state 1 followed by state 3 and finally state 2.
Morbidity and mortality from asthma appear to be increasing, and it has been suggested that medications used to treat asthma are contributing to this trend. We investigated a possible association between death or near death from asthma and the regular use of beta 2-agonist bronchodilators.
Using linked health insurance data bases from Saskatchewan, Canada, we conducted a matched case-control study of subjects drawn from a cohort of 12,301 patients for whom asthma medications had been prescribed between 1978 and 1987. We matched 129 case patients who had fatal or near-fatal asthma with 655 controls (who had received medications for asthma but had not had fatal or near-fatal events) with respect to region of residence, age, receipt of social assistance, and previous hospitalization for asthma.
The use of beta-agonists administered by a metered-dose inhaler was associated with an increased risk of death from asthma (odds ratio, 2.6 per canister per month; 95 percent confidence interval, 1.7 to 3.9) and of death or near death from asthma, considered together (odds ratio, 1.9; 95 percent confidence interval, 1.6 to 2.4). For death from asthma, use of the beta-agonist fenoterol was associated with an odds ratio of 5.4 per canister, as compared with 2.4 for the beta-agonist albuterol. On a microgram-equivalent basis, the odds ratio for this outcome with fenoterol was 2.3, as compared with 2.4 with albuterol.
An increased risk of death or near death from asthma was associated with the regular use of inhaled beta 2-agonist bronchodilators, especially fenoterol. Regardless of whether beta-agonists are directly responsible for these adverse effects or are simply a marker for more severe asthma, heavy use of these agents should alert clinicians that it is necessary to reevaluate the patient's condition.
The association between the use of inhaled beta-agonists by metered-dose inhaler and the risk of fatal or near-fatal asthma has been demonstrated. It shows that asthmatics who use one canister of beta-agonist per month more than the number used by other similar asthmatics have twice the risk of fatal or near-fatal asthma. The present investigation assesses the magnitude of this excess risk when an asthmatic increases his/her own monthly use of inhaled beta-agonists over time. From a previous nested case-control study of 129 deaths and near-deaths from asthma (cases) and 655 controls from a cohort of 12,301 asthmatics, the subset using at least 12 inhalers during the 12 month study period was identified (97 cases and 258 controls). A profile score, ranging 0-11, was formed to quantify the patterns of beta-agonist use over time for each subject, covering the entire spectrum extending from decreasing to increasing use. The relative risk was 15.2 (95% confidence interval (CI) 2.4-96.2) per unit increase of the profile score in subjects with a pattern of increasing beta-agonist use (profile score of 6.5 or more), but this relative risk was only 1.5 (95% CI 0.8-2.6) per unit when the profile score was less than 6.5 (non-increasing use). This relative risk was independent of the risk associated with the total quantity of beta-agonist use in the 12 month period, which remained around 1.6 (95% CI 1.3-2.0) per inhaler per month. We conclude that above and beyond the quantity of beta-agonist used during a one year period, a pattern of increasing use of beta-agonist inhalers over that period is a major predictive factor of unfavourable outcomes in asthma. Any trend, over a six month span, of a doubling in the monthly use of beta-agonists, or, alternatively, of an increase by one canister in this monthly use, should be regarded as a serious warning sign of an impending life-threatening attack of asthma.
Airway epithelial cells play a central role in the inflammatory, apoptotic, and remodeling processes associated with asthma. Within this context, a key function is exerted by transforming growth factor-(TGF-), whose biological effects are mediated at least in part by mitogen-activated protein kinases (MAPKs). The aim of our study was to investigate, in primary cultures of human bronchial epithelial cells (HBEC), the effects of TGF-(10 ng/ml) on both MAPK activation and apoptosis, in the presence or absence of a pretreatment with budesonide (10 8 M). MAPK activation was detected by Western blotting, using anti– phospho-MAPK monoclonal antibodies, which specifically recognize the phosphorylated, active forms of these enzymes. Apoptosis was assayed by caspase-3 activation and fluorescence microscopy, using annexin-V (An-V) and propidium iodide (PI) as markers of cell death. Our results show that TGF-induced a marked (9-fold) increase in p38 MAPK phosphorylation, and also dramatically enhanced cell death, which was completely prevented by specific MAPK inhibitors. Both MAPK activation and apoptosis were effectively inhibited by budesonide (BUD), thereby suggesting that the powerful antiapoptotic action of inhaled glucocorticoids may be very important for their protective role against epithelial injury, which represents a key patho-genic event in asthma.
The assessment of asthma control is pivotal to the evaluation of treatment response in individuals and in clinical trials. Previously, asthma control, severity, and exacerbations were defined and assessed in many different ways.
The Task Force was established to provide recommendations about standardization of outcomes relating to asthma control, severity, and exacerbations in clinical trials and clinical practice, for adults and children aged 6 years or older.
A narrative literature review was conducted to evaluate the measurement properties and strengths/weaknesses of outcome measures relevant to asthma control and exacerbations. The review focused on diary variables, physiologic measurements, composite scores, biomarkers, quality of life questionnaires, and indirect measures.
The Task Force developed new definitions for asthma control, severity, and exacerbations, based on current treatment principles and clinical and research relevance. In view of current knowledge about the multiple domains of asthma and asthma control, no single outcome measure can adequately assess asthma control. Its assessment in clinical trials and in clinical practice should include components relevant to both of the goals of asthma treatment, namely achievement of best possible clinical control and reduction of future risk of adverse outcomes. Recommendations are provided for the assessment of asthma control in clinical trials and clinical practice, both at baseline and in the assessment of treatment response.
The Task Force recommendations provide a basis for a multicomponent assessment of asthma by clinicians, researchers, and other relevant groups in the design, conduct, and evaluation of clinical trials, and in clinical practice.
We studied patterns of inhaler usage in a sample of participants from two centers in the Lung Health Study clinical trial. The inhaler, containing either ipratropium bromide or a placebo, was prescribed to be taken as two inhalations three times daily. For 4 months we recorded adherence by both self-report (n = 95) and canister weight change (n = 70). We compared these results with data obtained from a microprocessor monitoring device, the Nebulizer Chronolog (NC), which records the date and time of each inhaler actuation. Seventy-three percent of the participants reported using the inhaler an average of three times daily; however, NC data showed that only 15% of the participants actually used the inhaler an average of 2.5 or more times per day. Canister weight overestimated adherence because only 62% of the NC sets contained the prescribed two actuations. Fourteen percent showed a pattern of actuation of their inhalers more than 100 times in a 3-h interval. We interpret this usage pattern to reflect deliberate emptying of inhalers to appear to be in good compliance with the prescribed program. We conclude that self-report and weighing of inhaler canisters overestimate adherence to the prescribed regimens. Furthermore, a substantial number of monitored inhaler users appear to deliberately dump their medication prior to follow-up visits.
The association between the use of inhaled beta-agonists by metered-dose inhaler and the risk of fatal or near-fatal asthma has been demonstrated. It shows that asthmatics who use one canister of beta-agonist per month more than the number used by other similar asthmatics have twice the risk of fatal or near-fatal asthma. The present investigation assesses the magnitude of this excess risk when an asthmatic increases his/her own monthly use of inhaled beta-agonists over time. From a previous nested case-control study of 129 deaths and near-deaths from asthma (cases) and 655 controls from a cohort of 12,301 asthmatics, the subset using at least 12 inhalers during the 12 month study period was identified (97 cases and 258 controls). A profile score, ranging 0-11, was formed to quantify the patterns of beta-agonist use over time for each subject, covering the entire spectrum extending from decreasing to increasing use. The relative risk was 15.2 (95% confidence interval (CI) 2.4-96.2) per unit increase of the profile score in subjects with a pattern of increasing beta-agonist use (profile score of 6.5 or more), but this relative risk was only 1.5 (95% CI 0.8-2.6) per unit when the profile score was less than 6.5 (non-increasing use). This relative risk was independent of the risk associated with the total quantity of beta-agonist use in the 12 month period, which remained around 1.6 (95% CI 1.3-2.0) per inhaler per month.(ABSTRACT TRUNCATED AT 250 WORDS)
Asthma control is improved by combining inhaled corticosteroids with long-acting beta2-agonists. However, fluctuating asthma control still occurs. We hypothesized that in patients receiving low maintenance dose budesonide/formoterol (bud/form), replacing short-acting beta2-agonist (SABA) reliever with as-needed bud/form would provide rapid symptom relief and simultaneous adjustment in antiinflammatory therapy, thereby reducing exacerbations. In this double-blind, randomized, parallel-group study, 2,760 patients with asthma aged 4-80 years (FEV1 60-100% predicted) received either terbutaline 0.4 mg as SABA with bud/form 80/4.5 microg twice a day (bud/form + SABA) or bud 320 microg twice a day (bud + SABA) or bud/form 80/4.5 microg twice a day with 80/4.5 microg as-needed (bud/form maintenance + relief). Children used a once-nocte maintenance dose. Bud/form maintenance + relief prolonged time to first severe exacerbation (p < 0.001; primary endpoint), resulting in a 45-47% lower exacerbation risk versus bud/form + SABA (hazard ratio, 0.55; 95% confidence interval, 0.44, 0.67) or bud + SABA (hazard ratio, 0.53; 95% confidence interval 0.43, 0.65). Bud/form maintenance + relief also prolonged the time to the first, second, and third exacerbation requiring medical intervention (p < 0.001), reduced severe exacerbation rate, and improved symptoms, awakenings, and lung function compared with both fixed dosing regimens.
This study compared the efficacy and safety of budesonide/formoterol (Symbicort) Turbuhaler)) with salbutamol pressurized metered-dose inhaler (pMDI) with spacer for relief of acute bronchoconstriction in patients with asthma. In this randomized, double-blind, parallel-group study, patients (n = 104 allocated to treatment; n = 103 received treatment; mean age 45 years) seeking medical attention for acute asthma (mean FEV(1) 43% of predicted) received two doses repeated at t = -5 and 0 min of either budesonide/formoterol (320/9 microg, two inhalations) or salbutamol (100 microg x eight inhalations); total doses 1280/36 microg and 1600 microg, respectively. All patients received prednisolone 60 mg at 90 min and FEV(1) was assessed over 3h. FEV(1) 90 min after dosing (primary variable) increased compared with pre-dose FEV(1) by an average of 30% and 32% for budesonide/formoterol and salbutamol, respectively (P = 0.66), with similar increases at all timepoints from 3 to 180 min for both groups. Mean pulse rate over 3h was significantly higher in the salbutamol group versus the budesonide/formoterol group (92 vs. 88 bpm; P < 0.01). No treatment differences were seen for other vital signs, including ECG. High-dose budesonide/formoterol was effective and well tolerated for the treatment of acute asthma, with rapid onset of efficacy and a safety profile over 3h similar to high-dose salbutamol.
The aim of this study was to compare the efficacy and safety of formoterol versus salbutamol as reliever medication in patients presenting at an emergency dept with acute asthma. A randomised, double-blind, double-dummy, parallel group study was performed in four Australian emergency treatment centres. The study included a total of 78 adult patients (mean baseline forced expiratory volume in one second (FEV1) 1.83 L; 59% predicted) with acute asthma. Based on the expected dose equivalence of formoterol Turbuhaler 4.5 microg (delivered dose) and salbutamol pressurised metered-dose inhaler 200 microg (metered dose), patients received a total of formoterol Turbuhaler 36 microg (delivered) or salbutamol pressurised metered-dose inhaler with spacer 1,600 microg (metered), divided into two equal doses at 0 and 30 min. FEV1, peak expiratory flow and systemic beta2-agonist effects were monitored for 4 h. The primary variable was FEV1% pred at 45 min. At 45 min, mean increases in FEV1 expressed in % pred were 6.6% and 9.3%, respectively, with a small adjusted mean difference in favour of salbutamol (3.0%, 95% confidence interval -2.0-8.0). Transient increases in systemic beta2-agonist effects occurred predominantly with salbutamol, although no significant treatment differences were observed. Eight patients discontinued due to adverse events. In this study of patients presenting at emergency depts with acute asthma, formoterol Turbuhaler 36 microg was well tolerated and, as rescue therapy, had an efficacy that was not different from that of salbutamol pressurised metered-dose inhaler with spacer 1,600 microg in the number of patients studied.
Randomised controlled trials (RCTs) must be internally valid (i.e., design and conduct must eliminate the possibility of bias), but to be clinically useful, the result must also be relevant to a definable group of patients in a particular clinical setting (i.e., they must be externally valid). Lack of external validity is the most frequent criticism by clinicians of RCTs, systematic reviews, and guidelines, and is one explanation for the widespread underuse in routine practice of many treatments that have been shown to be beneficial in trials and are recommended in guidelines [1]. Yet medical journals, funding agencies, ethics committees, the pharmaceutical industry, and governmental regulators seem to give external validity a low priority. Admittedly, whereas the determinants of internal validity are intuitive and can generally be worked out from first principles, understanding of the determinants of the external validity of an RCT requires clinical rather than statistical expertise, and often depends on a detailed understanding of the particular clinical condition under study and its management in routine clinical practice. However, reliable judgments about the external validity of RCTs are essential if treatments are to be used correctly in as many patients as possible in routine clinical practice.
The results of RCTs or systematic reviews will never be relevant to all patients and all settings, but they should be designed and reported in a way that allows clinicians to judge to whom the results can reasonably be applied. Table 1 lists some of the important potential determinants of external validity, each of which is reviewed briefly below. Many of the considerations will only be relevant in certain types of trials, for certain interventions, or in certain clinical settings, but they can each sometimes undermine external validity. Moreover, the list is not exhaustive and requires more detailed annotation and explanation than is possible in this short review.
Table 1
Main Issues That Can Affect External Validity and Should Be Addressed in Reports of the Results of Randomised Controlled Trials or Systematic Reviews and Considered by Clinicians
Some of the issues that determine external validity are relevant to the distinction between pragmatic trials and explanatory trials [2], but it would be wrong to assume that pragmatic trials necessarily have greater external validity than explanatory trials. For example, broad eligibility criteria, limited collection of baseline data, and inclusion of centres with a range of expertise and differing patient populations have many advantages, but they can also make it very difficult to generalise the overall average effect of treatment to a particular clinical setting.
Clinical trials have recently demonstrated that using a budesonide/formoterol combination inhaler as regular maintenance treatment twice daily but also as a rescue therapy for breakthrough symptoms can provide more effective control of asthma, particularly in reducing exacerbations, than using a short-acting beta2-agonist or formoterol as rescue therapy. This suggests that the corticosteroid component of the combination therapy plays an important role in rescue therapy. Formoterol as a rescue therapy is effective in relieving symptoms by relaxing airway smooth muscle but is also likely to have important inhibitory effects on mast cells, plasma exudation and neutrophilic inflammation. Inhaled corticosteroids have much more rapid suppressing effects on airway inflammation than previously recognised and the increased dose used as rescue therapy may prevent the increase in airway inflammation that occurs during the evolution of an exacerbation, thus preventing its development. It is likely that the molecular interactions between beta2-agonists and corticosteroids also enhance the effect of the combination therapy as rescue therapy. There is now a strong scientific rationale for single inhaler therapy in asthma, but more research is now needed to better understand the mechanisms involved.
Budesonide/formoterol is an effective treatment for both asthma and chronic obstructive pulmonary disease. This study compared the efficacy and safety of a novel hydrofluoroalkane (HFA) pressurised metered-dose inhaler (pMDI) formulation of budesonide/formoterol with that of budesonide pMDI and budesonide/formoterol dry-powder inhaler (DPI; Turbuhaler).
This was a 12-week, multinational, randomised, double-blind, double-dummy study involving patients aged > or = 12 years with asthma. All patients had a forced expiratory volume in 1 s of 50-90% predicted normal and were inadequately controlled on inhaled corticosteroids (500-1600 microg/day) alone. Following a 2-week run-in, during which they received their usual medication, patients were randomised (two inhalations twice daily) to budesonide pMDI 200 microg, budesonide/formoterol DPI 160/4.5 microg or budesonide/formoterol pMDI 160/4.5 microg. The primary efficacy end-point was change from baseline in morning peak expiratory flow (PEF).
In total, 680 patients were randomised, of whom 668 were included in the primary analysis. Therapeutically equivalent increases in morning PEF were observed with budesonide/formoterol pMDI (29.3 l/min) and budesonide/formoterol DPI (32.0 l/min) (95% confidence interval: -10.4 to 4.9; p = 0.48). The increase in morning PEF with budesonide/formoterol pMDI was significantly higher than with budesonide pMDI (+28.7 l/min; p < 0.001). Similar improvements with budesonide/formoterol pMDI vs. budesonide pMDI were seen for all secondary efficacy end-points. Both combination treatments were similarly well tolerated.
Budesonide/formoterol, administered via the HFA pMDI or DPI, is an effective and well-tolerated treatment for adult and adolescent patients with asthma, with both devices being therapeutically equivalent.
Poor adherence with inhaled corticosteroids is an important problem in asthma management. Previous approaches to improving adherence have had limited success.
To determine whether treatment with a single inhaler containing a long-acting beta(2)-agonist and a corticosteroid for maintenance treatment and symptom relief can overcome the problem of poor adherence with inhaled corticosteroids.
Randomised, parallel group, open-label trial.
Forty-four general practices in Nottinghamshire.
Participants who used less than 70% of their prescribed dose of inhaled corticosteroid and had poorly controlled asthma were randomised to budesonide 200 microg one puff twice daily plus their own short-acting beta(2)-agonist as required (control group), or budesonide/formoterol 200/6 microg one puff once daily and as required (active group) for 6 months. The primary outcome was inhaled corticosteroid dose.
Seventy-one participants (35 control, 36 active group) were randomised. Adherence with budesonide in the control group was approximately 60% of the prescribed dose. Participants in the active group used approximately 80% more budesonide than participants in the control group (448 versus 252 microg/day, mean difference 196 mug, 95% confidence interval 113 to 279; P<0.001) and were less likely to withdraw from the study (3 versus 13; P<0.01). No safety issues were identified.
Using a single inhaler for both maintenance treatment and symptom relief approximately doubled the dose of inhaled corticosteroid taken, suggesting this could be a useful strategy to overcome the problems related to poor adherence with inhaled corticosteroids.
Poor adherence to medication regimens is a well-documented phenomenon in clinical practice and an ever-present concern in clinical trials. Little is known about adherence to inhaled medication regimens over extended periods. The present paper describes the 2-yr results of the Lung Health Study (LHS) program, which was developed to maintain long-term adherence to an inhaled medication regimen in 3,923 special intervention participants (as measured by self-report and medication canister weight). The LHS is a double-blind, multicenter, randomized controlled clinical trial of smoking intervention and bronchodilator therapy (ipratropium bromide or placebo) for early intervention in chronic obstructive pulmonary disease (COPD). At the first 4-mo follow-up visit, nearly 70% of participants reported satisfactory or better adherence. Over the next 18 mo, self-reported satisfactory or better adherence declined to about 60%. Canister weight classified adherence as satisfactory or better in 72% of participants returning all canisters at 1 yr, and in 70% of the participants returning all canisters at the 2-yr follow-up. Self-reporting confirmed by canister weight classified 48% of participants at 1 yr as showing satisfactory or better adherence. Overusers were 50% more likely than others to misrepresent their true smoking status, suggesting that canister weights indicating overuse may be deceptive. Results of multiple logistic regression analysis indicate that the best compliance was found in participants who were married, older, white, had more severe airways obstruction, less shortness of breath, and fewer hospitalizations, and who had not been confined to bed for respiratory illnesses. In summary, a structured program for promoting adherence to an inhaled medication regimen was successful in achieving initial satisfactory adherence in the majority of participants; however, adherence declined notably from the conclusion of this program to the first-year follow-up, and more gradually over the second year.
Electronic monitoring of inhaled asthma medications is one method to measure medication adherence and patterns of use. Information on the performance of monitors in a randomized controlled trial allows researchers and clinicians to understand their utility and limitations. The Smartinhaler Tracker is an electronic monitor for metered-dose inhalers (MDIs) that records the date, time, and number of actuations.
To determine the performance of the Smartinhaler monitors used in a 24-week randomized controlled trial of 303 patients with asthma in a real-world setting.
Prestudy use checks involved 2 actuations of the MDI, with a further 2 performed 2 hours later. Within-study monitor checks, performed before dispensing at clinic visits 2 to 4, included a computerized check of monitor clock function, actuation accuracy, and battery life. Within-study data checks involved computerized checks of monitor clock function before data upload.
Two thousand six hundred seventy-eight of 2728 monitors (98.2%) passed prestudy use checks. Seventy-six of 2642 monitors (2.9%) dispensed to participants failed within-study monitor checks. Fifty-one of 2642 monitors (1.9%) malfunctioned before data upload, mostly as a result of fluid immersion. Ninety-three of 2642 monitors (3.5%) were lost or thrown away by participants. Complete data was available from 2498 of 2642 dispensed monitors (94.5%) and 2498 of 2549 returned monitors (98.0%).
The Smartinhaler Tracker is a reliable monitor for measuring MDI use in a real-world setting. Use of extensive monitor and data-checking protocols reduces data loss. In a research or clinical setting, the use of a validated and reliable electronic monitor represents the reference standard for assessing patterns of medication use.
As a general phenomenon, corticosteroids may suppress the activity in the hypothalamic-pituitary-adrenal (HPA) axis. The adrenal stimulation test is a commonly used method to assess the relative risk of exogenous corticosteroids to induce systemic side effects.
This clinical trial was performed to assess the effects of budesonide on the HPA axis (at 800, 1600, or 3200 microg/day, given as a twice daily regimen, administered by means of the Turbuhaler) in adult patients with mild, non-steroid-dependent asthma.
Sixty-four asthmatic patients received budesonide or placebo by inhalation or 10 mg/day oral prednisone once daily as a positive control in a double-blind, double-dummy, randomized, placebo-controlled, parallel-group, multicenter study. Plasma cortisol concentration was measured to assess the effect on the HPA axis before and during a 6-hour infusion of synthetic adrenocorticotropic hormone (ACTH), cosyntropin.
After 6 weeks of treatment, plasma cortisol concentrations after adrenal stimulation by cosyntropin infusion had fallen by 4% in the placebo group; by 13%, 11%, and 27% in the budesonide groups (800, 1600, and 3200 microg/day, respectively); and by 35% in the prednisone group. The decrease was significant only in the 3200 microg/day budesonide (p = 0.03) and prednisone (p = 0.005) groups. Over the same time period, decreases in basal plasma cortisol concentrations were 1% in the placebo group; 19%, 19%, and 34% in the three budesonide groups; and 37% in the prednisone group. Only in the prednisone group was the decrease significant (p = 0.03 vs placebo).
In this study budesonide inhaled by means of the Turbuhaler, at doses recommended for clinical use (800 or 1600 microg/day), did not produce any statistically significant suppression of the HPA axis compared with placebo.
The inhaled corticosteroid (ICS)/long-acting beta-agonist (LABA) combination inhaler has the potential to improve adherence with ICS therapy in asthma.
To determine whether ICS/LABA combination inhaler therapy improves adherence compared with separate inhaler use.
In a 24-week randomized controlled parallel group study, 111 subjects were prescribed 125 microg fluticasone dipropionate (FP) and 25 microg salmeterol, 2 actuations twice daily through either a combination inhaler or separate inhalers concurrently. Medication use was recorded by covert electronic monitors. The primary outcome variable was adherence during the final 6-week period, defined as the number of doses taken as a percentage of those prescribed.
Complete adherence data from the final 6-week period were available for 49 and 54 subjects in the separate and combination groups, respectively. The mean (SD) adherence was 73.7% (36.0) for FP, 76.7% (30.5) for salmeterol, and 82.4% (24.5) for FP/salmeterol. There were no significant differences in adherence between FP/salmeterol and FP (-8.7%; 95% CI, -10.6 to 3.3) and salmeterol (-5.6%; 95% CI, -16.4 to 5.1). There was no significant difference in overuse among the FP, salmeterol, or FP/salmeterol groups. In 2 (4%) of 49 subjects, salmeterol was effectively taken as monotherapy during a 6-week period.
In the setting of a randomized controlled trial, use of a combination ICS/LABA inhaler does not markedly increase adherence above that observed with separate inhaler use. LABA monotherapy was observed in a small proportion of patients prescribed ICS and LABA therapy via separate inhalers.
Monitoring indicators of subacute lack of asthma control (SALAC) may help to reduce asthma morbidity.
To determine whether SALAC, independent of current asthma exacerbations, is associated with subsequent acute asthma exacerbations.
Administrative claims data from PharMetrics/IMS Health were used to identify patients 12 years or older continuously enrolled in a participating U.S. health plan from 2001 to 2004 with >or=1 asthma claim (International Classification of Diseases, Ninth Revision, Clinical Modification code 493.x), no chronic obstructive pulmonary disease or cystic fibrosis claims, and >or=1 prescription for an asthma medication during 2001-2004. SALAC was defined as more than 4 asthma-related physician visits (or >or=2/quarter) or more than 5 short-acting beta((2))-adrenergic agonist prescriptions during 2001. Effect of asthma control category (Exacerbation Only [EO], SALAC Only [SO], Both Exacerbation and SALAC [Both], Neither Exacerbation nor SALAC [Neither]) in 2001 on acute asthma exacerbations (hospitalization, emergency department visit, or short-term oral corticosteroid use) during 2002-2004 was assessed using logistic regression, adjusting for gender, age, health plan type, and region.
Of 11,779 patients, 8% were assigned to the EO group, 26% to SO, 12% to Both, and 54% to Neither in 2001. The incidence of exacerbations in 2002-2004 was higher for Both (61.8%) versus EO (55.0%) and for SO (37.3%) versus Neither (31.9%). The risk of exacerbation in 2002-2004 was increased significantly (p < .0001) for Both (3.394; 95% confidence interval [CI] = 3.009, 3.827), EO (2.503; 95% CI = 2.176, 2.879), and SO (1.277; 95% CI = 1.166, 1.399) versus Neither.
In this study, the risk of subsequent exacerbation was greatest in patients with both SALAC and acute asthma exacerbations, followed by those with exacerbations only and those with SALAC only. SO identified an additional 26% of asthma patients at increased risk for subsequent exacerbation. The results from this study demonstrate that SALAC indicators and a history of acute asthma exacerbations are independent predictors of future acute asthma exacerbations and highlight the important role of subacute asthma worsening in predicting and preventing future asthma exacerbations.
The safety of long-acting beta(2)-agonists (LABAs) in asthma is debated. This study examined the safety of the inhaled corticosteroid (ICS)/LABA combination budesonide/formoterol dry powder inhaler used as maintenance and reliever therapy versus combination treatments based on guideline recommendations.
Safety data from six double-blind, randomised clinical trials (RCTs) in asthma where budesonide/formoterol was used as maintenance and reliever therapy for at least 6 months were reviewed (N=14 346). All-cause mortality and asthma-related serious adverse events (SAEs) (co-primary endpoints), overall and cardiac SAEs, and discontinuations due to adverse events (DAEs) were assessed. Estimated Mantel-Haenszel (MH) relative risks (RR) with this regimen versus comparators were calculated.
There was no increase in all-cause mortality with budesonide/formoterol maintenance and reliever therapy (four deaths [0.07%] versus nine [0.10%]; pooled MH RR 0.70, 95% confidence interval [CI] 0.21-2.30). Asthma-related SAEs were reduced with budesonide/formoterol maintenance and reliever therapy: 41 (0.73%) versus 121 (1.38%); pooled MH RR 0.59, 95% CI 0.42-0.85. All-cause and asthma-related DAEs were also reduced with budesonide/formoterol maintenance and reliever therapy: pooled MH RR 0.60 (95% CI 0.46-0.79) and 0.43 (0.28-0.68), respectively. Overall and cardiac-related SAEs were comparable between treatment groups: pooled MH RR 0.96 (95% CI 0.82-1.14) and 1.26 (0.72-2.22), respectively.
Budesonide/formoterol dry powder inhaler maintenance and reliever therapy was well tolerated in RCTs versus fixed-dose alternatives and not associated with increased risk of death or cardiac-related SAEs and DAEs, and asthma-related SAEs and DAEs were significantly reduced. Given the limitations of RCTs, particularly exclusion of patients with co-morbidities, ongoing surveillance is appropriate.
Formoterol has a fast onset of action and can therefore be used to relieve symptoms of asthma. A combination inhaler can deliver formoterol with different doses of inhaled corticosteroid; when used as a reliever both drugs will be delivered more frequently when asthma symptoms increase. This has the potential to treat both bronchoconstriction and inflammation in the early stages of exacerbations.
To assess the efficacy and safety of combined inhalers containing both formoterol and an inhaled corticosteroid when used for reliever therapy in adults and children with chronic asthma.
We last searched the Cochrane Airways Group trials register in April 2008.
Randomised trials in adults and children with chronic asthma, where a combination inhaler containing formoterol and inhaled corticosteroid is compared with fast-acting beta2-agonist alone for the relief of asthma symptoms. This should be the only planned difference between the trial arms.
Two review authors independently extracted the characteristics and results of each study. Authors or manufacturers were asked to supply unpublished data in relation to primary outcomes.
Three trials involving 5905 participants were included. In patients with mild asthma who do not need maintenance treatment, no clinically important advantages of budesonide/formoterol as reliever were found in comparison to formoterol as reliever.Two studies enrolled patients with more severe asthma who were not controlled on high doses of inhaled corticosteroids (around 700 mcg/day in adults), and had suffered a clinically important asthma exacerbation in the past year. Hospitalisations related to asthma in the two studies comparing budesonide/formoterol for maintenance and relief with the same dose of budesonide/formoterol for maintenance with terbutaline for relief yielded an odds ratio of 0.68 (95% CI 0.40 to 1.16), which was not a statistically significant reduction. One adult study found a reduction in exacerbations requiring oral corticosteroids compared to terbutaline, odds ratio 0.56 (95% CI 0.42 to 0.74) and the study in children found less serious adverse events with budesonide/formoterol used for maintenance and relief. There was no significant difference in annual growth in children using budesonide/formoterol reliever in comparison to terbutaline.
In mild asthma it is not yet known whether patients who use a budesonide/formoterol inhaler for relief of asthma symptoms derive any clinically important benefits. In more severe asthma, one study that enrolled patients who were not controlled on quite high doses of inhaled corticosteroids, and had suffered an exacerbation in the previous year, demonstrated a reduction in the risk of exacerbations that require oral corticosteroids with budesonide/formoterol for maintenance and relief in comparison with budesonide/formoterol for maintenance and terbutaline or formoterol for relief. The incidence of serious adverse events in children was also less using budesonide/formoterol for maintenance and relief in one study, which similarly enrolled children who were not controlled on medium to high doses of inhaled corticosteroids, and compared to terbutaline relief with an explorative maintenance dose of budesonide/formoterol that is not approved for treatment.
Alternative hypotheses explaining a worldwide epidemic of asthma deaths during the 1960s are reviewed and their comparative strengths are evaluated, not only according to how they fit the experimental, clinical, and pharmacologic evidence available, but also according to how consistently they explain both the international variations and the secular changes that were observed. Using data from six countries during 1962 through 1974, a multivariate regression analysis is applied to test hypotheses about the average relation of sales of aerosols containing sympathomimetics to the mortality attributed to asthma. Results point to an association between mortality and the per capita sales of a particularly strong dose preparation of isoproterenol aerosol in conjunction with misuse of the drug by patients in the period when the aerosols were first introduced.
A case-control study has previously been reported of asthma deaths in people aged 5-45 years who had a hospital admission for asthma (the index admission) in New Zealand during 1981-1987. The study has been re-analysed to examine the association between markers of asthma severity and risk of asthma death or hospital admission; patients prescribed fenoterol were excluded from this re-analysis because of the previously reported interaction between fenoterol, asthma severity, and asthma deaths. The re-analysis included 39 patients who died of asthma during the 12 months after their index admission, 226 patients who had a readmission for asthma during the 12 months after their index admission, and 263 controls chosen from all index admissions. An admission in the previous 12 months was the strongest marker of subsequent risk of death (odds ratio (OR) = 3.5, 95% confidence interval (CI): 1.8-6.9, P less than 0.01), and was also a strong marker of subsequent risk of readmission (OR = 3.0, 95% CI: 2.1-4.2, P less than 0.01); the risk increased with the number of previous admissions. Three or more categories of prescribed asthma drugs was also associated with subsequent death (OR = 1.7, 95% CI: 0.9-3.3, P = 0.13) or readmission (OR = 1.9, 95% CI: 1.3-2.7, P less than 0.01); prescribed oral corticosteroids was only weakly associated with subsequent death (OR = 1.3, 95% CI: 0.6-2.8, P = 0.59), but was more strongly associated with subsequent readmission (OR = 1.9, 95% CI: 1.2-2.8, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Interviews were conducted with 101 consecutive adult patients admitted to Wellington Hospital with a diagnosis of asthma to assess the extent to which beta agonist drugs are self-administered by asthmatic patients during severe asthma. The 99 patients prescribed an inhaled beta agonist were subdivided into two groups: group A comprising 79 patients prescribed a beta agonist for inhalation via an inhaler (metered dose aerosol or dry powder device) alone; group B comprising 20 patients prescribed beta agonist for inhalation via both an inhaler and nebuliser. In group A, the attacks of asthma lasted greater than 24 hours in 64/79 patients, and 22% of these patients reported taking more than 60 doses of their inhaler, and 52% more than 30 doses during the 24 hr period prior to admission. In group B, the attacks of asthma lasted greater than 24 h in 17/20 patients, and 35% of these patients self-administered their nebuliser more than six times, and 76% more than four times during the 24 h period prior to admission. In addition to their nebuliser use, these patients also took a median 23 doses of their inhaler during this 24 h period. This use of inhaled beta agonist contrasts with the recommended practice in both the USA and Europe, where most physicians recommend no more than 15 doses of a beta agonist as the maximal dose per day. We conclude that asthmatic patients in New Zealand self-administer high doses of inhaled beta 2 agonist drugs during severe exacerbations of asthma.
A case-control study was conducted to examine the hypothesis that fenoterol by metered dose inhaler (MDI) increases the risk of death in patients with asthma. The case group comprised 117 patients aged 5-45 who died of asthma between August, 1981, and July, 1983. For each case, 4 controls, matched for age and ethnic group, were selected from asthma admissions to hospitals to which the cases themselves would have been admitted, had they survived. The relative risk of asthma death in patients prescribed fenoterol by MDI was 1.55 (95% CI 1.04-2.33, p = 0.03). The possibility of confounding or effect modification by severity was assessed by consideration of subgroups defined by markers of asthma severity. The fenoterol MDI relative risk was 2.21 (95% CI 1.26-3.88, p = 0.01) in patients prescribed three or more categories of asthma drugs, 2.16 (95% CI 1.14-4.11, p = 0.02) in patients with a hospital admission for asthma during the previous 12 months, and 6.45 (95% CI 2.72-15.3, p less than 0.01) in patients prescribed oral corticosteroids at time of death or admission. In the group of patients with the most severe asthma (defined by a hospital admission during the previous year and prescription of oral corticosteroids) the fenoterol MDI relative risk was 13.29 (95% CI 3.45-51.2, p less than 0.01). After adjustment for severity, no other asthma treatment commonly used in New Zealand seemed to be associated with an increased risk of asthma death. Not all sources of bias can be definitely excluded; however, when considered together with other epidemiological and experimental evidence, these findings are consistent with the hypothesis that use of fenoterol by MDI increases the risk of death in severe asthma.
The circumstances preceding death from asthma were investigated in 52 young persons aged 5 to 34 years dying in Greater London and the South-East Lancashire conurbation between February 1968 and January 1969. Information was gathered at interviews with general practitioners, hospital staff, and relatives or witnesses of the last hours of life. The findings at necropsy were obtained from coroners or hospital pathologists.All the patients were severely affected; most had required regular medication to control their asthma, many had been in hospital for an acute attack and many were deteriorating before death. Despite this, death was regarded as ‘sudden and unexpected’ in at least 79% of patients and it seems probable that the severity of their condition was often not recognized by patients, relatives, and doctors.Several publications have suggested that sudden death has been associated with overdosage by pressure-packed aerosols containing sympathomimetic bronchodilators, and specific enquiries were made about their use. In 11 of 30 cases (37%) in which sufficient information was available the evidence suggested that excessive inhalation of bronchodilators might have contributed to death. Ten of these patients had used a pressure-packed aerosol containing a sympathomimetic bronchodilator and one other patient had inhaled disodium cromoglycate with added isoprenaline. Throughout the period of the investigation the mortality from asthma showed a sharp and continuing decline and it is estimated that less than half the deaths studied (46%) would have been caused by the epidemic factor.Apart from an occasional report of compulsive use, the principal reason for overdosage appears to have been failure to appreciate the lack of a normal response is an indication for a different type of treatment and management and not an indication to increase the dose. No other factor was discovered which might have caused the observed increase in mortality.
International guidelines on asthma management indicate that the primary goal of treatment should be optimum asthma control. The aim of this study was to develop and validate the Asthma Control Questionnaire (ACQ). The authors generated a list of all symptoms used to assess control and sent it to 100 asthma clinicians who were members of guidelines committees (18 countries). They scored each symptom for its importance in evaluating asthma control. From the 91 responses, the five highest scoring symptoms were selected for the ACQ. In addition, there is one question on beta2-agonist use and another on airway calibre (total questions=7). The ACQ was tested in a 9-week observational study of 50 adults with symptomatic asthma. The ACQ and other measures of asthma health status were assessed at baseline, 1, 5 and 9 weeks. In patients whose asthma was stable between clinic visits, reliability of the ACQ was high (intraclass correlation coefficient (ICC)=0.90). The questionnaire was very responsive to change in asthma control (p<0.0001). Cross-sectional and longitudinal validity were supported by correlations between the ACQ and other measures of asthma health status being close to a priori predictions. In conclusion, the Asthma Control Questionnaire has strong evaluative and discriminative properties and can be used with confidence to measure asthma control.
There is controversy about the role of beta-agonists in asthma mortality, and the impact of asthma management plans remains unclear. We compared blood beta-agonist levels in patients dying from asthma with those in controls, and estimated the risks associated with specific classes of medication and patterns of management. We identified 89 asthma deaths and recruited 322 patients presenting to hospitals with acute asthma. A questionnaire was administered to the next of kin in 51 cases, and to 202 controls. Blood drawn from 35 cases and 229 controls was assayed for salbutamol. Smoking, drinking, and family problems were significantly more likely among the cases of asthma death than among the controls. The two groups were reasonably well matched with regard to markers of chronic asthma severity. Cases of asthma death were significantly less likely than controls to use a peak flow meter. Written action plans were associated with a 70% reduction in the risk of death. Use of nebulized bronchodilators or oral steroids was significantly more likely in cases of asthma death. Mean blood salbutamol concentrations were 2.5 times higher in cases of asthma. The use of oral steroids for an attack of asthma reduced the risk of death by 90%. More widespread adoption of written asthma management plans, with less reliance on beta-agonists and closer medical supervision, should reduce asthma mortality.
Although inhaled corticosteroid (ICS) use is associated with a decreased risk of hospitalization for asthma, the impact of ICS on the risk of life-threatening asthma exacerbation is less clear. The effect of ICS and inhaled beta agonist (IBA) dispensing on the risk of intensive care unit admission for asthma, a surrogate for life-threatening exacerbation, is evaluated.
Using computerized International classification of diseases (ICD)-9 discharge diagnoses, a cohort of all 2,344 adult Northern California members of a health maintenance organization hospitalized for asthma over a 2-yr period were identified. Computerized pharmacy data was used to ascertain asthma medications dispensed during the 3-, 6-, and 12-month intervals preceding index hospitalization for asthma.
During the 3-months preceding hospitalization, a minority of subjects had no IBA units dispensed (34%), with 14% receiving low level (1 unit), 20% medium level (2–3 units), and 32% high level (≥4 units) therapy. A substantial proportion received no ICS units (55%), whereas 13% had low, 16% medium, and 15% high level therapy. In multiple logistic regression analysis, high level IBA use was associated with a greater risk of intensive care unit (ICU) admission for asthma after controlling for asthma severity. There was no relationship, however, between low or medium level IBA use and ICU admission. Conversely, medium level and high level ICS use were associated with a reduced risk of ICU admission. Analysing 6- and 12-month medication dispensing data, similar risk patterns were observed.
Inhaled corticosteroid dispensing was associated with reduced risk of intensive care unit admission among adults hospitalized for asthma, whereas the opposite applied for high dose beta agonist usage. This suggests that ICS prescription to adults with moderate-to-severe asthma could reduce the risk of life-threatening exacerbation.
A double-blind, randomized crossover study in 28 asthmatic patients assessed the relative therapeutic index for inhaled formoterol and salbutamol. Pre-drug administration FEV1 (mean 2.08 l) was 49-93% of predicted and reversibility 16-82% after inhalation of salbutamol. Patients inhaled single doses of formoterol (Oxis) (4.5,18 and 54 microg, delivered doses) via Turbuhaler, salbutamol (Ventolin) (200 and 1800 microg) via pressurized metered dose inhaler (pMDI) and placebo at intervals of 48 h or more. Individual maximum FEV1 and minimum S-K+ were calculated. Relative local (maximum FEV1) and systemic (minimum S-K+) dose potencies, and their ratio, the relative therapeutic index, were estimated using a non-linear mixed effect model. The drug effects were well tolerated and dose dependent. A log-linear approximation was used to describe the bronchodilatory effect, whereas a sigmoid approximation was more apt to describe the decrease in serum potassium concentration. A bivariate dose-response model based on these principles was fitted simultaneously to all data. The mean relative therapeutic index between formoterol 4.5-54 microg given via Turbuhaler and salbutamol 200-1800 microg given via pMDI was estimated to be 2.5 in favour of formoterol; this trend was not statistically significant.
The aim of the study was to compare the safety and effectiveness of as-needed formoterol with salbutamol in a large international real-life asthma study. Children and adults (n=18,124) were randomised to 6 months as-needed treatment with open-label formoterol 4.5 microg Turbuhaler or salbutamol 200 microg pressurised metered dose inhaler or equivalent. Primary safety variables were asthma-related and nonasthma-related serious adverse events (SAE)s and adverse events (AE)s resulting in discontinuation (DAE)s. The primary efficacy variable was time to first asthma exacerbation. The incidences of AEs, SAEs and DAEs arising from SAEs were not significantly different between treatments. DAEs for nonserious AEs were higher with formoterol. Asthma-related AEs decreased with formoterol (1,098 (12.3%) versus 1,206 (13.5%)), asthma-related SAEs were similar (108 (1.2%) versus 121 (1.4%)) but more asthma-related DAEs occurred in the formoterol group (89 (1.0%) versus 48 (0.5%)). Time to first exacerbation was prolonged (hazard ratio 0.86) and less as-needed and maintenance medication was used with formoterol. Reductions of exacerbations with as-needed formoterol versus salbutamol increased with increasing age and asthma medication level. This real-life study demonstrates that formoterol as-needed has a similar safety profile to salbutamol, and its use as a reliever therapy is associated with fewer asthma symptoms and exacerbations.
In making treatment decisions, doctors and patients must take into account relevant randomised controlled trials (RCTs) and systematic reviews. Relevance depends on external validity (or generalisability)--ie, whether the results can be reasonably applied to a definable group of patients in a particular clinical setting in routine practice. There is concern among clinicians that external validity is often poor, particularly for some pharmaceutical industry trials, a perception that has led to underuse of treatments that are effective. Yet researchers, funding agencies, ethics committees, the pharmaceutical industry, medical journals, and governmental regulators alike all neglect external validity, leaving clinicians to make judgments. However, reporting of the determinants of external validity in trial publications and systematic reviews is usually inadequate. This review discusses those determinants, presents a checklist for clinicians, and makes recommendations for greater consideration of external validity in the design and reporting of RCTs.
Patients with severe persistent asthma who are inadequately controlled despite treatment according to current asthma management guidelines have a significant unmet medical need. Such patients are at high risk of serious exacerbations and asthma-related mortality.
Here, we pooled data from seven studies to determine the effect of omalizumab, an anti-immunoglobulin E (IgE) monoclonal antibody, on asthma exacerbations in patients with severe persistent asthma. Omalizumab was added to current asthma therapy and compared with placebo (in five double-blind studies) or with current asthma therapy alone (in two open-label studies). The studies included 4308 patients (2511 treated with omalizumab), 93% of whom had severe persistent asthma according to the Global Initiative for Asthma (GINA) 2002 classification. Using the Poisson regression model, results were calculated as the ratio of treatment effect (omalizumab : control) on the standardized exacerbation rate per year.
Omalizumab significantly reduced the rate of asthma exacerbations by 38% (P < 0.0001 vs control) and the rate of total emergency visits by 47% (P < 0.0001 vs control). Analysis of demographic subgroups showed that the efficacy of omalizumab on asthma exacerbations was unaffected by patient age, gender, baseline serum IgE (split by median) or by 2- or 4-weekly dosing schedule, although benefit in absolute terms appeared to be greatest in patients with more severe asthma, defined by a lower value of percentage predicted forced expiratory volume in 1 s (FEV(1)) at baseline.
These results suggest that omalizumab may fulfil an important need in patients with severe persistent asthma, many of whom are not adequately controlled on current therapy.
Monitoring devices attached to pressurised metered dose inhalers provide an important objective measurement of patient adherence with asthma medications in clinical and research settings. The Smart-inhaler is a relatively new device that has not been previously validated. This study examines the accuracy of the Smart-inhaler in a bench-top experiment and compares it with a previously validated device, the Doser. Ten Smart-inhalers and five Dosers were actuated twice on two occasions per day for 30 days (120 doses). Six Smart-inhalers were also actuated 30 times in rapid succession to examine the ability of the Smart-inhaler to detect "dumping". Five Smart-inhalers failed to detect the first one or two doses. However, when the aerosol canister was placed more firmly in the device, actuating the device in the process, the following two doses were recorded accurately in all ten devices. Otherwise all ten Smart-inhalers and five Dosers recorded all actuations faithfully and there were no spurious recordings. The six Smart-inhalers recorded all 30 doses delivered in rapid succession. The Smart-inhaler and Doser are both highly accurate at measuring actuated doses and no spurious doses were recorded in an in vitro setting.
The development of self-management plans arose as clinicians tried to design better methods by which they could deliver asthma care and reduce the significant mortality and morbidity associated with this disease. The basic principles that resulted have been widely endorsed, and self-management plans are now recommended in the long-term management of adult asthma. Self-management plans essentially focus on the early recognition of unstable or deteriorating asthma, by monitoring peak flow or symptoms. Through the use of written guidelines, patients are then able to determine when it is necessary to adjust therapy or obtain medical assistance. There is now convincing evidence that the use of self-management plans by patients with asthma leads to a marked reduction in morbidity and a reduced requirement for acute medical treatment including hospital admissions. Recent research has also clarified many of the different issues concerning their structure and implementation. In some respects the skill in the use of the asthma self-management plan system of care is the ability to modify the standard plans to meet the particular needs of the individual asthmatic patient, including their preferences.
The contributions of as-needed inhaled corticosteroids and long-acting beta2 agonists (LABA) to asthma control have not been fully established. We compared the efficacy and safety of three reliever strategies: a traditional short-acting beta2 agonist; a rapid-onset LABA (formoterol); and a combination of LABA and an inhaled corticosteroid (budesonide-formoterol) in symptomatic patients receiving budesonide-formoterol maintenance therapy.
We did a 12-month, double-blind, parallel-group study in 3394 patients (aged 12 years or older), in 289 centres in 20 countries, who were using inhaled corticosteroids at study entry and symptomatic on budesonide-formoterol (160 microg and 4.5 microg, respectively), one inhalation twice daily, during a 2-week run-in. After run-in, patients were randomly assigned budesonide-formoterol maintenance therapy plus one of three alternative as-needed medications-terbutaline (0.4 mg), formoterol (4.5 microg), or budesonide-formoterol (160 microg and 4.5 microg). The primary outcome was time to first severe exacerbation, defined as an event resulting in hospitalisation, emergency room treatment, or both, or the need for oral steroids for 3 days or more.
Time to first severe exacerbation was longer with as-needed budesonide-formoterol versus formoterol (p=0.0048; log-rank test) and with as-needed formoterol versus terbutaline (p=0.0051). The rate of severe exacerbations was 37, 29, and 19 per 100 patients per year with as-needed terbutaline, formoterol, and budesonide-formoterol, respectively (rate ratios budesonide-formoterol versus formoterol 0.67 [95% CI 0.56-0.80; p<0.0001]; budesonide-formoterol versus terbutaline 0.52 [0.44-0.62; p<0.0001]; formoterol versus terbutaline 0.78 [0.67-0.91; p=0.0012]). Asthma control days increased to a similar extent in all treatment groups. As-needed formoterol did not significantly improve symptoms compared with as-needed terbutaline. All treatments were well tolerated.
Both monocomponents of budesonide-formoterol given as needed contribute to enhanced protection from severe exacerbations in patients receiving combination therapy for maintenance.
Current reviews on the use of inhaled corticosteroids (ICS) for acute asthma underestimated their early (minutes) clinical impact and produced conclusions of questionable validity.
The analysis of the best evidence available on the early (1 to 4 h) clinical impact of ICS for patients with acute asthma in the emergency department (ED) setting.
Published (from 1966 to 2006) randomized controlled trials were retrieved using different databases (MEDLINE, EMBASE, Cochrane Controlled Trials Register), bibliographic reviews of primary research, review articles, and citations from texts. Primary outcome measures were admission and ED discharge rates.
Seventeen studies met criteria for inclusion in the review (470 adults and 663 children and adolescents). After 2 to 4 h of protocol, a greater reduction in admission rate was observed with trials that used multiple doses of ICS (odds ratio [OR], 0.30; 95% confidence interval [CI], 0.16 to 0.55), especially when they were compared with placebo. Patients treated with ICS also displayed a faster clinical improvement compared with placebo or systemic corticosteroids (SCS), increasing the probability of an early ED discharge (OR, 4.70; 95% CI, 2.97 to 7.42; p = 0.0001). The advantage of the use of ICS was also demonstrated in spirometric and clinical measures as early as 60 min. These benefits were obtained only when patients received multiple doses of ICS along with beta-agonists compared with placebo or SCS.
Data suggests that ICS present early beneficial effects (1 to 2 h) when they were used in multiple doses administered in time intervals < or = 30 min over 90 to 120 min. The nongenomic effect is a possible candidate by covering the link between molecular pathways and the clinical effects of corticosteroids.
Budesonide/formoterol in one inhaler is an established therapy for asthma and chronic obstructive pulmonary disease. The long-term safety and efficacy profile of a novel hydrofluoroalkane (HFA) pressurized metered-dose inhaler (pMDI) formulation of budesonide/formoterol was compared with that of budesonide/formoterol in a dry powder inhaler (DPI; Turbuhaler). This multinational, 52-week, randomized, open, parallel-group study included patients aged > or = 12 years with asthma who had a forced expiratory volume in 1s (FEV1)> or = 50% of predicted normal; all patients used inhaled corticosteroids (400-1200 microg/day) and needed additional short-acting beta 2-agonist therapy. Patients were randomized to receive budesonide/formoterol pMDI or DPI 160/4.5 microg, two inhalations twice daily. Safety endpoints included assessment of adverse events and laboratory parameters. Efficacy endpoints included change from baseline in FEV1 and time to first severe asthma exacerbation. Overall, 673 patients (446pMDI, 227DPI) were included. There were no clinically significant differences between treatment groups in the nature, incidence or severity of adverse events or laboratory parameters. The number of patients experiencing adverse events was comparable in the pMDI (332/446 [74%]) and DPI (175/227 [77%]) groups; the most commonly reported adverse event was upper respiratory tract infection. The proportion of patients discontinuing as a result of adverse events was low in both groups (pMDI 12/446 [3%], DPI 2/227 [1%]). Lung function was improved to a similar extent in both groups and there was no detectable difference in time to first severe asthma exacerbation. The novel HFA pMDI formulation of budesonide/formoterol is an equally well tolerated and effective treatment for adults and adolescents with asthma as the budesonide/formoterol DPI.
Two identically designed, randomized, multicenter, single-dose, crossover studies were conducted in patients aged > or = 18 years with mild to moderate asthma previously treated with inhaled corticosteroids. After 2 weeks on twice-daily budesonide pressurized metered-dose inhaler (pMDI) 160 microg, patients received a randomized sequence of budesonide/formoterol pMDI 80/4.5 microg x 2 inhalations (160/9 microg), fluticasone/salmeterol dry powder inhaler (DPI) 250/50 microg x 1 inhalation, albuterol pMDI 90 microg x 2 inhalations (180 microg), and placebo pMDI (3-to 14-day washout periods). Improvements in forced expiratory volume in 1 second (FEV(1)) at 3 minutes were significantly (p < 0.001) greater after treatment with budesonide/formoterol pMDI compared with fluticasone/salmeterol DPI and similar to that of albuterol pMDI. In addition, significantly (p < 0.001) more patients treated with budesonide/formoterol pMDI achieved a 15% improvement in FEV(1) within 15 minutes compared with patients treated with fluticasone/salmeterol DPI and placebo. Thus, the early bronchodilatory effects of budesonide/formoterol pMDI were greater than with fluticasone/salmeterol DPI.
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