Introduction
Escalation to triple therapy with an inhaled corticosteroid (ICS), a long-acting muscarinic antagonist (LAMA), and a long-acting β
2-agonist (LABA) is recommended for patients with chronic obstructive pulmonary disease (COPD) who continue to experience exacerbations despite dual therapy with LAMA/LABA [
1]. Traditionally, triple therapy has required the use of two or three separate inhalers (multiple-inhaler triple therapy; MITT); however, more recently, single-inhaler triple therapies (SITTs) have been developed. SITTs can help facilitate greater treatment persistence and adherence by reducing the burden of the mode of administration. MITT has been shown to be associated with an increased risk of treatment discontinuation and reduced adherence compared with single-inhaler use [
2‐
4].
Once-daily SITT with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) was approved for the long-term maintenance of moderate-to-severe COPD in adult patients who are not adequately treated by a combination of ICS/LABA or LABA/LAMA in Europe in November 2017 [
5]. Previous clinical trials have demonstrated that patients with COPD initiated on FF/UMEC/VI experience reduced rates of exacerbations (moderate or severe) and lower rates of COPD-related hospitalizations compared with patients receiving dual therapy with ICS/LABA or LABA/LAMA [
6].
Although previous studies have demonstrated that prompt vs. delayed initiation of MITT following an exacerbation of COPD reduces subsequent exacerbations and medical costs [
7,
8], there is limited real-world evidence of the consequences of delaying initiation of SITT when indicated. A recent retrospective study in the US reported that prompt initiation (within 30 days of an exacerbation) of SITT with FF/UMEC/VI following a moderate or severe COPD exacerbation was associated with significantly fewer subsequent exacerbations and lower healthcare costs compared with delayed initiation of FF/UMEC/VI (within 31–180 days of an exacerbation) [
9]. However, these findings may be specific to this healthcare system, and the effects of delayed initiation have not been assessed for patients in England.
The aim of this study was to assess the outcomes of prompt (0–30 days following an exacerbation) vs. delayed (31–180 days following an exacerbation) initiation of SITT with FF/UMEC/VI among a general practice cohort of patients with COPD in England.
Discussion
This study aimed to assess the outcomes of prompt vs. delayed initiation of SITT with FF/UMEC/VI among a cohort of patients with COPD in England. Initiation of FF/UMEC/VI within 0–30 days of an exacerbation was associated with numerically lower subsequent exacerbations compared with delayed initiation, though statistical significance was not reached. Low sample size, the ratio of prompt to delayed patients (1:3), or unknown/unmeasured variables not included in the model may have led to the study being underpowered, or otherwise impaired the ability to detect significant differences between the cohorts. When ≤ 14 days was used as the cut-off to define prompt initiation, prompt initiators had a significantly lower rate of subsequent exacerbations compared with delayed initiators. This implies that very prompt initiation may have a clinical benefit and that treatment should be started within 14 days of an exacerbation where possible. Of note, patients were not followed-up for the primary outcome until they initiated FF/UMEC/VI, preventing any time bias. In the main analysis, subsequent exacerbations were only assessed from the point of FF/UMEC/VI initiation (i.e., exacerbations occurring prior to initiation of FF/UMEC/VI were permitted but were not included in the outcome). The result of the additional analyses, censoring patients at initiation of FF/UMEC/VI, suggests that the benefit of prompt initiation is due to both efficacy of FF/UMEC/VI vs. prior therapy as well as benefit of prompt initiation of new therapy following an exacerbation.
Prompt initiation of FF/UMEC/VI following the index exacerbation was also associated with fewer all-cause and COPD-related hospital readmissions at all time points assessed, as well as lower COPD-related prescription costs compared with delayed initiation. A significant association was observed between time-to-treatment initiation (as a continuous variable) and rate of subsequent exacerbations. This indicates that timing of treatment has a bearing on clinical outcome and prognosis, suggesting that the rate of subsequent exacerbations may increase for each day of delayed initiation of FF/UMEC/VI following an exacerbation. This study included patients following the first exacerbation during the observation period (i.e., the first exacerbation in the previous 12 months). The findings suggest that physicians should consider a change of therapy after a single breakthrough exacerbation on prior maintenance therapy, rather than delaying change of therapy until after a patient has had several exacerbation events. The proportion of patients receiving each class of maintenance therapy immediately prior to index was similar among the prompt and the delayed cohorts for most regimens; however, there were more patients in the prompt cohort receiving LABA/LAMA immediately prior to index compared with the delayed cohort. Of note, around half of the included patients were using MITT immediately prior to their index exacerbation. Therefore, some patients receiving MITT remain uncontrolled and may benefit from an earlier switch to SITT.
The findings of this analysis are similar to previous studies. A retrospective study of over 10,000 patients with COPD in the US assessed the effects of prompt (≤ 30 days following index) vs. delayed (31–180 days following index) initiation of MITT following an exacerbation [
7]. Total and severe exacerbation rates were 28.2% and 64.7% higher, respectively, in the delayed cohort compared with the prompt cohort (p < 0.0001). Total, medical, and prescription all-cause costs were 18.7%, 22.8%, and 8.8% higher, respectively, in the delayed cohort compared with the prompt cohort. Another retrospective study (using a similar design to the current study) of over 1000 patients with COPD in the US assessing the effect of prompt (≤ 30 days following index) vs. delayed (31–180 days following index) initiation of FF/UMEC/VI following an exacerbation reported that prompt patients had significantly lower rates of moderate/severe (RR [95% CI]: 0.79 [0.65–0.94], p = 0.004), moderate (RR [95% CI]: 0.84 [0.69–0.99], p = 0.038), and severe (RR [95% CI]: 0.57 [0.37–0.79], p = 0.002) exacerbations [
9]. Mean all-cause and COPD-related total costs were also significantly lower among prompt initiators compared with delayed initiators.
Once-daily SITT with FF/UMEC/VI has previously been shown to be associated with a lower rate of moderate/severe exacerbations vs. dual therapy (FF/VI or UMEC/VI) [
6] and significant improvements in lung function and health status vs. MITT [
19]. FF/UMEC/VI has also been found to be a cost-effective treatment option compared with dual therapies and MITT [
20‐
23]. The evidence from the current study may be useful in informing clinical guidance on the optimum management strategy for patients with COPD, particularly those hospitalized due to a severe exacerbation. It also highlights the lost potential for improved outcomes for the majority of patients in the study (75%) who were delayed initiators. Future studies may wish to prospectively investigate the effectiveness of prompt initiation of SITT upon discharge on reduction of future exacerbations and re-hospitalization. The data suggest that earlier initiation of FF/UMEC/VI could lessen the overall costs of intervention from healthcare professionals and pharmacological therapies used to manage the condition.
Although it is possible that similar findings may be observed for other SITTs, it should be noted that these data relate to FF/UMEC/VI only and may not be generalizable due to differences in constituent molecules, inhaler devices, and/or dosing frequency; therefore, caution should be taken when interpreting these findings in the context of other SITTs.
This study has a few potential limitations, which should be considered. Linkage to HES limits the sample to patients registered at a GP practice in England only; however, patient care/management is expected to be similar across the rest of the UK. Patients who died within 12 months of the index exacerbation have been excluded from the analysis, introducing the possibility of survivorship bias. Also, only medications prescribed in the primary care setting will have been captured; medications initiated in hospital and continued by the GP may have led to the incorrect classification of “delayed initiators” for some patients. However, this would be expected to result in a conservative estimate, thus reducing the observed effect of prompt initiation and biasing towards the null hypothesis.
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