Background
Non-cystic fibrosis (CF) bronchiectasis is an under-researched condition with no licensed treatment therapies [
1]. Approximately 20% of the bronchiectasis population are infected with
Pseudomonas aeruginosa[
2], which is known to be associated with a more rapid decline in lung function [
3] and poorer health-related quality of life (HRQoL) [
4]. In line with published guidelines, inhaled antibiotics along with other inhaled and oral medications are commonly prescribed ‘off-label’ for these patients, with the aim of reducing pulmonary exacerbations, maintaining lung function and improving HRQoL [
5]. Airway clearance is also routinely prescribed for these patients leading to a complex and burdensome treatment regimen.
Adherence to similar medications is consistently reported to be low in asthma, chronic obstructive pulmonary disease (COPD) and CF, with approximately 50% of patients reported to be non-adherent [
6‐
8]. Adherence to airway clearance is even lower than for medications, with up to 70% of patients with CF non-adherent to this treatment [
9]. In bronchiectasis, a study exploring patients’ perspectives on self-management reported that patients altered their adherence to treatments [
10]. A single study measured adherence in 22 patients with bronchiectasis prescribed colistin delivered via I-neb
® adaptive aerosol delivery (Praxis Pharmaceuticals) or Pari LC
® Plus and reported high levels of adherence, with 73% of participants categorised as adherent [
11]. However, this study had a small sample size, was retrospective, measured adherence to Pari LC
® Plus via self-report and did not determine if adherence was associated with health outcomes.
Studies in asthma, COPD and CF demonstrate that low adherence to treatment can negatively impact on key health outcomes including pulmonary exacerbations [
8,
12], HRQoL [
6,
13] as well as healthcare costs [
14,
15]. The first randomised controlled trial investigating the effectiveness of colistin (Promixin
®) in bronchiectasis has shown that it is effective in delaying time to first pulmonary exacerbation and improving HRQoL when patients are adherent i.e. inhale between 81–92.1% of prescribed medication [
16]. Thus, rates of adherence to treatment may affect important health outcomes such as pulmonary exacerbations, lung function and HRQoL in bronchiectasis. Rates of treatment adherence and the effect of treatment adherence on these health outcomes in bronchiectasis are not known. With large-scale studies of new and potentially expensive therapies that have been tailored for use in patients with bronchiectasis infected with
P. aeruginosa underway [
16,
17], it is important to determine treatment adherence in this population to ensure that adherence is maximised prior to the prescription of these new therapies.
Thus, the primary aim of this one-year study was to determine rates of treatment adherence (inhaled antibiotics, other respiratory medicines and airway clearance) in patients with bronchiectasis infected with P. aeruginosa over the year-long study. The secondary aim was to determine the association between adherence to treatment and health outcomes (pulmonary exacerbations, lung function and Quality of Life Questionnaire-Bronchiectasis [QOL-B]) in this population after 12 months. It was hypothesised that adherence would be low and patients who were adherent to inhaled antibiotics would have fewer pulmonary exacerbations.
Discussion
In this one-year study, treatment adherence was low in patients with bronchiectasis prescribed inhaled antibiotics for
P. aeruginosa infection
. The reported MPR adherence rates of 53% for inhaled antibiotics and other respiratory medicines and 41% for airway clearance (based on self-report) are comparable to studies in asthma, COPD and CF [
6‐
8] but lower than previously reported in bronchiectasis [
11,
16]. MPR is a more reliable method of adherence measurement than self-report in observational studies conducted in a ‘real-life’ setting [
13]; however, it still has the potential to over-estimate adherence [
8], making these findings even more clinically concerning. At present, treatment adherence is not routinely assessed in bronchiectasis. We have demonstrated that it is possible to collect these data within a ‘real-life’ setting and are aware that some centres already have access to pharmacy claims data; therefore, potential methods of objectively monitoring adherence in clinical practice are on the horizon. With the prescription of new and potentially expensive therapies for bronchiectasis, particularly for those infected with
P. aeruginosa[
16,
17], monitoring of adherence is likely to become an increasingly important aspect of bronchiectasis management.
We studied adherence to three different treatments and found that these treatments had different effects on the health outcomes studied. Similar to findings of other longitudinal adherence studies in CF and COPD [
8,
12], participants who were adherent to inhaled antibiotics had fewer pulmonary exacerbations, with nearly twice as many exacerbations in the non-adherent group. This is a significant finding given that exacerbations are thought to be associated with disease progression in this population [
1]. Whilst the current study did not aim to determine the efficacy of inhaled antibiotics, it did indicate that inhaled antibiotics may be effective in reducing pulmonary exacerbations in bronchiectasis when ≥80% of prescribed medication is consumed. These findings, taken together with the recently reported colistin findings, have important implications for future inhaled antibiotics studies and for the monitoring of adherence to inhaled antibiotics in clinical practice [
16]. We cannot discern the direction of the relationship between adherence and pulmonary exacerbations from our data and further research to better understand this relationship is needed. Approximately half of our participants were non-adherent to inhaled antibiotics. Therefore, irrespective of the direction of this relationship, interventions to improve adherence are likely to reduce the frequency of these critical pulmonary events and their associated costs.
The lack of association between adherence and FEV
1 % predicted is not surprising in this population, given the growing evidence that FEV
1 is not a sensitive measurement of lung function in bronchiectasis [
1,
30]. Furthermore, the effectiveness of the treatments included in this study on maintaining or reducing FEV
1 decline is not known.
Our mean QOL-B domain scores were all lower than those reported in the recent QOL-B paper, particularly for Physical and Role Functioning and Treatment Burden [
28]. Inhaler preparations of antibiotics delivered via inhaler rather than nebuliser (e.g. ciprofloxacin dry powder inhaler [
17]) may offer a potential method of reducing treatment burden in these patients with bronchiectasis. Inhaler delivery of antibiotics may improve adherence for those in whom time and effort are barriers to treatment. However, it is well recognised that adherence to inhalers in COPD and asthma is approximately 50% in most studies [
6,
7]. For others, such as those worried about long term use of antibiotics, an inhaler preparation of antibiotics will not be sufficient to overcome these barriers to adherence.
Our results demonstrated that adherence to airway clearance was associated with a higher burden of treatment and worse respiratory symptoms as measured by QOL-B. These findings may appear counter-intuitive when compared to findings in CF [
9]; however, the Treatment Burden domain asks patients about the amount of time they commit to their treatments on a daily basis; therefore, those who adherent are likely to spend longer on treatment and may report a higher treatment burden. The relationship between perceived symptoms and adherence is not clear-cut and there are many papers reporting conflicting results [
6,
8,
12,
15]. We have recently reported that a lack of belief about necessity for treatment can influence adherence decision-making for airway clearance, particularly when patients do not experience troublesome symptoms [
31]. Thus, it could be that this relationship reflects this finding, in that those with more symptoms may be more likely to adhere.
We did not find any association between adherence to inhaled antibiotics or other respiratory medicines and the QOL-B domains studied. This is similar to results from studies exploring associations between adherence to treatment and HRQoL in other chronic respiratory disease populations which have reported conflicting results [
6,
8,
12,
15]. The inconsistent effects of medications on HRQoL of patients with bronchiectasis may go some way to explaining this finding. Some medications such as colistin and azithromycin are associated with better HRQoL [
16,
32] whilst no significant improvement in HRQoL was reported for erythromycin [
33]. In addition, the composite nature of the MPR value for ‘other respiratory medicines’ may also have masked any relationships between individual medications (e.g. azithromycin) and QOL-B.
We have recently reported that adherence decision-making in bronchiectasis involves patients weighing up the pros and cons of adhering to treatment [
31]. The prescription of medications ‘off-label’ and without proven efficacy may be influencing this decision-making process, as patients may not perceive there to be any benefits of the prescribed treatments [
31]. This may be particularly true for inhaled corticosteroids, which are generally not recommended for prescription for bronchiectasis [
5] but which were prescribed for 87% of the participants in this study. Thus, there is an urgent need for efficacy studies in this population so that as we begin to focus on improving adherence, we do so for efficacious treatments.
This study was based in a ‘real life’ setting and the cost and lack of availability of electronic monitoring in clinical practice plus its potential behaviour altering effect precluded its inclusion in this study. Therefore, MPRs offered an accurate and feasible method of measuring medication adherence [
13]. It is accepted that MPR may overestimate medication adherence as it does not confirm ingestion or inhalation [
8]. Carryover and leftover were not included in our MPR calculations; however, the duration of the follow-up period of our study may have reduced the effect of any carryover/left-over as this is likely to average out over time [
22]. We collected MPR data on a 6 monthly basis; however, we only calculated MPR over the year of the study rather than 6 monthly to reduce the effect that seasonal variation in symptoms might have on adherence and health outcomes. A cut-off of 80% to denote adherence and non-adherence is commonly used in the adherence literature and in landmark bronchiectasis clinical trials [
17,
20]. Furthermore, the 80% cut-off has been shown to offer the optimal balance between specificity and sensitivity for self-reported and prescription refill adherence measures [
19].
The primary limitation of this study was its sample size. We did not reach the target of 100 participants within the study sites and timeframe. However, the study was not underpowered to detect a difference in pulmonary exacerbations and the sample size is similar to recently reported studies in bronchiectasis [
32,
33]. The study analysed the associations between adherence data collected over one year with health outcome data collected at one data collection point (12 months). This did not allow us to explore the variability within adherence during the study or to analyse the effect of adherence on outcomes at other time points e.g. 6 months after baseline. In most cases, participants used a regular community pharmacy to dispense all of their medications for bronchiectasis; however, it is possible that some data may have been missing if a participant or carer used a different pharmacy to those contacted. We minimised this by asking participants to provide an up-to-date list at each visit of all of the pharmacies they used and the researcher contacted all of these pharmacies. This study only included patients infected with
P. aeruginosa, who constitute approximately 20% of the bronchiectasis population [
2]. These patients tend to be sicker than other patients with bronchiectasis [
3,
4]. However, the mean age of 64 years, predominance of women, and the moderate impairment in lung function suggested that our sample was representative of the bronchiectasis population [
2].
Acknowledgements
The authors would like to thank Dr Ian Bradbury from Centre for Health and Rehabilitation Technologies, Institute of Nursing and Health Research, University of Ulster and Frontier Science Scotland for his assistance with statistical analysis. We would also like to thank staff at the Northern Ireland Clinical Research Network (Respiratory Health) and the bronchiectasis teams in the Belfast, South Eastern, Western, and Southern Health and Social Care Trusts for their assistance with recruitment to the study, in particular, Rosemary Hanna, Oonagh Hewitt, Diane Todd, Sharon Mills, and Dr Terence McManus.
Competing interests
AMcC, MT, JB and CH have no conflicts of interest. AQ has received investigator-initiated grants from Novartis and Gilead Sciences, consulting for Bayer-Schering and Abbott and serves on the North American Scientific Advisory Group to analyse data from ESCF supported by Genentech. SE has received consultancy fees paid to Queen’s University Belfast by Gilead Sciences, Novartis and Forest.
Authors’ contributions
AMcC, MT, SE, JB and CH contributed to the conception, design, data collection, analysis and interpretation. AMcC, MT, AQ, SE, JB and CH contributed to the drafting and revision of the manuscript and approval of the final manuscript. All authors read and approved the final manuscript.