Randomized controlled trial of adherence with single or combination inhaled corticosteroid/long-acting β-agonist inhaler therapy in asthma

doi:10.1016/j.jaci.2010.06.033

Journal of Allergy and Clinical Immunology

Volume 126, Issue 3, September 2010, Pages 505-510

https://doi.org/10.1016/j.jaci.2010.06.033 Get rights and content

Background

The inhaled corticosteroid (ICS)/long-acting β-agonist (LABA) combination inhaler has the potential to improve adherence with ICS therapy in asthma.

Objective

To determine whether ICS/LABA combination inhaler therapy improves adherence compared with separate inhaler use.

Methods

In a 24-week randomized controlled parallel group study, 111 subjects were prescribed 125 μg fluticasone dipropionate (FP) and 25 μg 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.

Results

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.

Conclusion

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.

Section snippets

Subjects

Adults in the Wellington region age 16 to 65 years with a diagnosis of asthma were enrolled (Fig 1). Subjects were recruited from existing research volunteer databases, newspaper advertisements, and letters via family doctors. To be included, subjects had to have a diagnosis of asthma and to be currently taking ICS at a stable dose with or without a separate LABA inhaler. Exclusion criteria were a diagnosis of chronic obstructive pulmonary disease, current use of a combination ICS/LABA inhaler,

Results

There were 111 subjects (50 male) enrolled in the study, 54 to the separate inhaler group and 57 in the combination inhaler group. The 2 groups were well matched with regard to age, sex, baseline lung function, and asthma control (Table I). After allowing for withdrawals, complete adherence data from the final 6-week study period were available for 49 and 54 subjects in the separate and combination groups, respectively (Fig 1). Eligible participants were recruited and studied between February

Discussion

This is the first randomized controlled trial in which the effect of a combination ICS/LABA inhaler on adherence with ICS therapy has been directly measured by covert electronic monitors. It has demonstrated that although the point estimates were consistent with greater adherence with FP/salmeterol, there was no significant difference compared with FP and salmeterol prescribed in separate inhalers. Furthermore, there was no evidence of a significant difference in preferential overuse of

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Cited by (30)

Therapeutic adherence among asthma patients: Variations according to age groups. How can it be improved? The potential contributions of new technologies
2022, Revue des Maladies Respiratoires
À l’occasion de rencontres entre pneumo-pédiatres et pneumologues d’adultes, nous avons revu la littérature concernant l’évolution de l’observance médicamenteuse dans l’asthme selon la classe d’âge des patients. Cette observance – acceptable chez les nourrissons – décroit avec l’âge, notamment à partir de l’adolescence. Certaines études montrent que les adultes sont également très inobservants. Les médicaments inhalés sont les moins bien pris. Plusieurs éléments expliquent la mauvaise observance : complexité des traitements, difficultés à utiliser les systèmes d’inhalation, mauvaise compréhension ou perception de leurs bénéfices, crainte des effets secondaires, image de pathologie chronique… Pourtant une mauvaise observance est associée à des risques d’escalade thérapeutique inutile et d’aggravation de l’asthme, avec d’avantage d’exacerbations, augmentation de l’absentéisme scolaire, dégradation de la qualité de vie, voire excès de mortalité. Le traitement de l’inobservance repose sur une bonne relation entre soignants et asthmatiques, une meilleure formation des soignants, une meilleure information des patients. Il doit être personnalisé. L’évolution des technologies, notamment informatiques, ouvre de nouvelles possibilités d’informations sur la maladie (réseaux, applications dédiées) qui peuvent aider à limiter les oublis (inhalateurs connecté) et contribuer à la recherche clinique. L’analyse de la littérature est compliquée par des définitions et des moyens de mesure de l’observance différents.
While asthma patients’ treatment adherence (TA) generally leaves to be desired, few data exist on TA evolution from age group to another. During the meeting of a working group of pneumo-pediatricians and adult pulmonologists, we reviewed the literature on adherence according to age group, examined explanations for poor adherence, and explored ways of improving adherence via new technologies. Asthma is a chronic disease for which TA is particularly low, especially during adolescence, but also among adults. Inhaled medications are the least effectively taken. Several explanations have been put forward: cost and complexity of treatments, difficulties using inhalation devices, poor understanding of their benefits, erroneous beliefs and underestimation of the severity of a fluctuating disease, fear of side effects, neglect, and denial (especially among teenagers). Poor TA is associated with risks of needless treatment escalation, aggravated asthma with frequent exacerbations, increased school absenteeism, degraded quality of life, and excessive mortality. Better compliance is based on satisfactory relationships between caregivers and asthmatics, improved caregiver training, and more efficient transmission to patients of relevant information. The recent evolution of innovative digital technologies opens the way for enhanced communication, via networks and dedicated applications, and thanks to connected inhalation devices, forgetfulness can be limited. Clinical research will also help to ameliorate TA. Lastly, it bears mentioning that analysis of the existing literature is hampered by differences in terms of working definitions and means of TA measurement.
Long-Acting β-Agonist in Combination or Separate Inhaler as Step-Up Therapy for Children with Uncontrolled Asthma Receiving Inhaled Corticosteroids
2017, Journal of Allergy and Clinical Immunology: In Practice
Citation Excerpt :
Further, it is possible that although separate ICS and LABA inhalers are issued with equal frequency, adherence with ICS is higher compared with separate LABA inhalers. Clearly more research is needed in this area, but the limited data from children presented here and from adults elsewhere38 suggest that FDC is associated with superior outcomes. Potentially, this may be explained by different taking behavior, for example, taking more separate inhalers when symptomatic.
Adding a long-acting β₂-agonist (LABA) to inhaled corticosteroids (ICS) using a fixed-dose combination (FDC) inhaler is the UK guideline recommendation for children aged more than 4 years with uncontrolled asthma. The evidence of benefit of adding an FDC inhaler over a separate LABA inhaler is limited.
The objective of this study was to compare the effectiveness of a LABA added as an FDC inhaler, and as a separate inhaler, in children with uncontrolled asthma.
Two UK primary care databases were used to create a matched cohort study with a 2-year follow-up period. We included children prescribed their first step-up from ICS monotherapy. Two cohorts were formed for children receiving an add-on LABA as an FDC inhaler, or a separate LABA inhaler. Matching variables and confounders were identified by comparing characteristics during a baseline year of follow-up. Outcomes were examined during the subsequent year. The primary outcome was an adjusted odds ratio for overall asthma control (defined as follows: no asthma-related hospital admission or emergency room visit, prescription for oral corticosteroids or antibiotic with evidence of respiratory consultation, and ≤2 puffs of short-acting β-agonist daily).
The final study consisted of 1330 children in each cohort (mean age 9 years; 59% male). In the separate ICS+LABA cohort, the odds of achieving overall asthma control were lower (adjusted odds ratio, 0.77 [95% confidence interval, 0.66-0.91]; P = .001) compared with the FDC cohort.
The study demonstrates a small but significant benefit in achieving asthma control from an add-on LABA as an FDC, compared with a separate inhaler and this supports current guideline recommendations.
Irregular and Ineffective: A Quantitative Observational Study of the Time and Technique of Inhaler Use
2016, Journal of Allergy and Clinical Immunology: In Practice
Cross-sectional observational studies suggest that between 50% and 60% of patients misuse a dry powder inhaler, whereas studies with electronic monitors indicate that patients sometimes overuse/underuse their inhalers. It is not known what impact errors and erratic use have on inhaler adherence.
The purpose of this study was to longitudinally quantify when and how patients adhered to a twice-daily preventer treatment by using a novel acoustic recording device attached to an inhaler (INhaler Compliance Assessment).
Patients with a history of asthma or chronic obstructive pulmonary disease (n = 123) from primary care and community pharmacies were given an INhaler Compliance Assessment-adapted inhaler for 1 month. Analysis of the audio files provided quantitative information on time and technique of inhaler use.
Data were available for 103 patients. Twenty-one patients (20%) used their inhaler in the correct manner at the correct interval. There were 5045 audio files with attempted inhalations, of which 1204 had technique errors (24%). Errors included inadequate flow (27%), drug priming without inhalation (19%), exhalation into the inhaler (18%), and multiple inhalations (25%). On average, participants made errors 20% of the time. Of 60 doses expected to be taken in a month per person, on average 49 doses (82%) were attempted and when errors were accounted for, the average number of actual doses taken was 34 doses (57%; P < .01) comparing attempted to actual doses.
These data highlight that ineffective and irregular inhaler use is common and when combined in a single calculation indicate that only 20% of participants used their inhaler correctly and on time.
Treatment adherence in asthmatic patients: The last frontier?
2014, Journal of Allergy and Clinical Immunology
Efficacy and safety of maintenance and reliever combination budesonide-formoterol inhaler in patients with asthma at risk of severe exacerbations: A randomised controlled trial
2013, The Lancet Respiratory Medicine
Citation Excerpt :
In the standard group, 32 (21%) of 152 patients used budesonide at less than 400 μg/day throughout the study, with 40 (26%) of 152 using more than 800 μg/day (figure 3B). These findings complement the previous finding that patients prescribed a different combination of corticosteroid plus long-acting β-agonist inhaler (fluticasone–salmeterol) as fixed-dose maintenance may vary their use of treatment according to perceived need.37 For the primary outcome, 56% of patients in the SMART group and 45% in the standard group had at least one high-use episode of β agonist (table 2).
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.
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.
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).
The SMART regimen has a favourable risk-to-benefit profile and can be recommended for use in adults at risk of severe asthma exacerbations.
Health Research Council of New Zealand.
Use of metered-dose inhaler electronic monitoring in a real-world asthma randomized controlled trial
2013, Journal of Allergy and Clinical Immunology: In Practice
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.

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: Supported by a research grant from GlaxoSmithKline (GSK study no. SAM106689).

: The trial was registered with the Australian New Zealand Clinical Trials Registry, ACTRN12606000508572.

: In this article, the term adherence has been used rather than compliance because of the willing partnership between the clinician and patient in the setting of the research study.

: Disclosure of potential conflict of interest: R. Beasley has received a consulting fee and research support from GlaxoSmithKline. The rest of the authors have declared that they have no conflict of interest.

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Asthma and lower airway diseaseRandomized controlled trial of adherence with single or combination inhaled corticosteroid/long-acting β-agonist inhaler therapy in asthma

Background

Objective

Methods

Results

Conclusion

Section snippets

Subjects

Results

Discussion

J Allergy Clin Immunol

Respir Med

J Allergy Clin Immunol

J Allergy Clin Immunol

Respir Med

J Allergy Clin Immunol

Chest

J Allergy Clin Immunol

Am J Med

J Allergy Clin Immunol

J Allergy Clin Immunol

Chest

J Allergy Clin Immunol

J Allergy Clin Immunol

Respir Med

Low-dose inhaled corticosteroids and the prevention of death from asthma

N Engl J Med

Asthma and lower airway disease
Randomized controlled trial of adherence with single or combination inhaled corticosteroid/long-acting β-agonist inhaler therapy in asthma