Characteristics of Users and New Initiators of Single- and Multiple-Inhaler Triple Therapy for Chronic Obstructive Pulmonary Disease in Germany.

Purpose: To assess patient characteristics of users and new initiators of triple therapy for chronic obstructive pulmonary disease (COPD) in Germany. Patients and Methods: Retrospective cohort study of patients with COPD and ≥1 prescription for single-inhaler triple therapy (SITT; fluticasone furoate/umeclidinium/vilanterol [FF/UMEC/VI] or beclomethasone dipropionate/glycopyrronium bromide/formoterol [BDP/GLY/FOR]) or multiple-inhaler triple therapy (MITT), using data from the AOK PLUS German sickness fund (1 January 2015-31 December 2019). The index date was the first date of prescription for FF/UMEC/VI or BDP/GLY/FOR (SITT users), or the first date of overlap of inhaled corticosteroid, long-acting ß2-agonist, and long-acting muscarinic antagonist (MITT users). Two cohorts were defined: the prevalent cohort included all identified triple therapy users; the incident cohort included patients newly initiating triple therapy for the first time (no prior use of MITT or SITT in the last 2 years). Patient characteristics and treatment patterns were assessed on the index date and during the 24-month pre-index period. Results: In total, 18,630 patients were identified as prevalent triple therapy users (MITT: 17,945; FF/UMEC/VI: 700; BDP/GLY/FOR: 908; non-mutually exclusive) and 2932 patients were identified as incident triple therapy initiators (MITT: 2246; FF/UMEC/VI: 311; BDP/GLY/FOR: 395; non-mutually exclusive). For both the prevalent and incident cohorts, more than two-thirds of patients experienced ≥1 moderate/severe exacerbation in the preceding 24 months; in both cohorts more BDP/GLY/FOR users experienced ≥1 moderate/severe exacerbation, compared with FF/UMEC/VI and MITT users. Overall, 97.9% of prevalent triple therapy users and 86.4% of incident triple therapy initiators received maintenance treatment in the 24-month pre-index period. Conclusion: In a real-world setting in Germany, triple therapy was most frequently used after maintenance therapy in patients with recent exacerbations, in line with current treatment recommendations.

Triple therapy (a combination of three different respiratory inhaled medications) is recommended for patients with chronic obstructive pulmonary disease (COPD) who experience repeated short-term symptom flare-ups when taking dual therapy (a combination of two different respiratory medications). Previously, patients had to take triple therapy using two or three separate inhalers. More recently, single-inhaler triple therapies have been developed, meaning patients can take all three different medications at the same time via one single inhaler. This study assessed the characteristics of patients who were already receiving triple therapy, or who started triple therapy (either via multiple inhalers or a single inhaler), in Germany between January 2015 and December 2019. In total, 18,630 patients who were already receiving triple therapy during the study period, and 2932 patients who newly started using triple therapy were included. The study reported that more than two-thirds of included patients had experienced at least one flare-up of COPD symptoms in the 2 years before starting triple therapy. Most patients had also received another therapy for COPD before starting triple therapy. A small proportion of patients started taking triple therapy after receiving no other therapy for COPD in the previous 2 years. The results of the study suggest that triple therapy for COPD in Germany is most often used in accordance with recommendations (patients already receiving therapy and experiencing repeated symptom flare-ups).

Development and validation of a claims-based algorithm to identify moderate exacerbations in patients with asthma treated in the US.

INTRODUCTION: Definitions of moderate asthma exacerbation have been inconsistent, making their economic burden difficult to assess. An algorithm to accurately identify moderate exacerbations from claims data is needed. METHODS: A retrospective cohort study of Reliant Medical Group patients aged ≥18 years, with ≥1 prescription claim for inhaled corticosteroid/long-acting ß2-agonist, and ≥1 medical claim with a diagnosis code for asthma was conducted. The objective was to refine current algorithms to identify moderate exacerbations in claims data and assess the refined algorithm's performance. Positive and negative predictive values (PPV and NPV) were assessed via chart review of 150 moderate exacerbations events and 50 patients without exacerbations. Sensitivity analyses assessed alternative algorithms and compared healthcare resource utilization (HRU) between algorithm-identified patients (claims group) and those confirmed by chart review (confirmed group) to have experienced a moderate exacerbation. RESULTS: Algorithm-identified moderate exacerbations were: visit of ≤1 day with an asthma exacerbation diagnosis OR visit of ≤1 day with selected asthma diagnoses AND ≥1 respiratory pharmacy claim, excluding systemic corticosteroids, within 14 days after the first claim. The algorithm's PPV was 42%; the NPV was 78%. HRU was similar for both groups. CONCLUSION: This algorithm identified potential moderate exacerbations from claims data; however, the modest PPV underscores its limitations in identifying moderate exacerbations, although performance was partially due to identification of previously unidentified severe exacerbations. Application of this algorithm in future claims-based studies may help quantify the economic burden of moderate and severe exacerbations in asthma when an algorithm identifying severe exacerbations is applied first.

Frequency and economic burden of exacerbations in inhaled corticosteroid/long-acting beta-agonist-treated patients with asthma: A retrospective US claims study.

INTRODUCTION: Despite adherence to inhaled corticosteroid/long-acting ß2-agonist (ICS/LABA) therapy, many patients with asthma experience moderate exacerbations. Data on the impact of moderate exacerbations on the healthcare system are limited. This study assessed the frequency and economic burden of moderate exacerbations in patients receiving ICS/LABA. METHODS: Retrospective, longitudinal study analyzed data from Optum's de-identified Clinformatics® Data Mart Database recorded between October 1, 2015, and December 31, 2019. Eligibility criteria included patients ≥18 years of age with ≥1 ICS/LABA claim and ≥1 medical claim for asthma in the 12 months pre-index (first ICS/LABA claim). Primary objectives included describing moderate exacerbation frequency, and associated healthcare resource utilization (HRU) and costs. A secondary objective was assessing the relationship between moderate exacerbations and subsequent risk of severe exacerbations. Patients were stratified by moderate exacerbation frequency in the 12 months post index. Moderate exacerbations were identified using a newly developed algorithm. RESULTS: In the first 12 months post index 61.6% of patients experienced ≥1 moderate exacerbation. Mean number of asthma-related visits was 4.1 per person/year and median total asthma-related costs was $3544. HRU and costs increased with increasing exacerbation frequency. Outpatient and inpatient visits accounted for a similar proportion of these costs. Moderate exacerbations were associated with an increased rate and risk of future severe exacerbations (incidence rate ratio, 1.56; hazard ratio, 1.51 [both p < 0.001]). CONCLUSIONS: This study highlighted that a high proportion of patients continue to experience moderate exacerbations despite ICS/LABA therapy and subsequently experience increased economic burden and risk of future severe exacerbations.

Characteristics, treatment patterns and burden of illness in US patients with asthma newly initiating multiple-inhaler triple therapy.

INTRODUCTION: For patients with asthma who remain symptomatic on medium-dose inhaled corticosteroid/long-acting ß2-agonist, add-on long-acting muscarinic antagonist is a treatment option, which can be administered as multiple-inhaler triple therapy (MITT). A high proportion of patients (61.5%-88.2%) discontinue MITT use within 1 year postinitiation; however, which patients discontinue and their treatment patterns at initiation are unknown. This study aimed to understand the demographic, clinical and treatment-related characteristics of patients with asthma who newly initiated MITT, by discontinuation status. METHODS: This retrospective cohort study used administrative data from IBM Truven MarketScan Commercial Claims and Encounters Database with Medicare supplement between 1 January 2016 and 31 December 2019. Adult patients with asthma who initiated MITT between 1 January 2017 and 31 March 2019 were included and were classified based on their discontinuation status. 'Continuous users' had continuous use of MITT and 'discontinuers' discontinued treatment within the 6-month period postinitiation. Demographics and clinical characteristics, asthma treatment use prior to MITT initiation (12-month baseline period), mode of MITT initiation and complexity of regimen were described. RESULTS: Of 4132 patients (mean age: 49.0 years, 67.9% female), 78.0% (n=3224) were discontinuers; 22.0% (n=908) were continuous users. Demographic and other clinical and treatment-related characteristics during baseline were broadly similar between cohorts. A significantly higher proportion of continuous users versus discontinuers had ≥6 dispensed claims for short-acting ß2-agonist canisters (16.0% vs 12.5%; p=0.006) during baseline and initiated a once-daily MITT regimen (35.2% vs 26.2%; p<0.001). Fewer continuous MITT users used a mix of once-daily and twice-daily regimens than those who discontinued MITT (64.3% vs 72.3%; p<0.001). CONCLUSIONS: Most patients with asthma discontinued MITT within 6 months. Results indicate that patients with a history of uncontrolled, symptomatic asthma and those using less complex triple therapy regimens at initiation are less likely to discontinue MITT than patients with controlled asthma and those using a complex MITT regimen.

Treatment pathways, economic burden and clinical outcomes in new users of inhaled corticosteroid/long-acting B2-agonist dual therapy with chronic obstructive pulmonary disease in a primary care setting in England: a retrospective cohort study.

OBJECTIVE: Management of chronic obstructive pulmonary disease (COPD) with inhaled corticosteroid/long-acting ß2-agonist (ICS/LABA) improves lung function and health status and reduces COPD exacerbation risk versus monotherapy. This study described treatment use, healthcare resource utilisation (HCRU), healthcare costs and outcomes following initiation of single-device ICS/LABA as initial maintenance therapy (IMT). DESIGN: Retrospective cohort study. SETTING: Primary care, England. DATA SOURCES: Linked data from the Clinical Practice Research Datalink Aurum and Hospital Episode Statistics datasets. PARTICIPANTS: Patients with COPD and ≥1 single-device ICS/LABA prescription between July 2015 and December 2018 were included. PRIMARY AND SECONDARY OUTCOME MEASURES: Treatment pathways, COPD-related HCRU and healthcare costs, COPD exacerbations, time to triple therapy, medication adherence (proportion of days covered ≥80%) and indexed treatment time to discontinuation. Data for patients without prior maintenance therapy history (IMT users) and non-triple users were assessed over a 12-month follow-up period. RESULTS: Of 13 451 new ICS/LABA users, 5162 were IMT users (budesonide/formoterol, n=1056; beclomethasone dipropionate/formoterol, n=2427; other ICS/LABA, n=1679), for whom at 3 and 12 months post-index, 45.6% and 39.4% were still receiving any ICS/LABA. At >6 to ≤12 months, the proportion of IMT users with ≥1 outpatient visit (10.1%) and proportion with ≥1 inpatient stay (12.6%) had increased from those at 3 months (9.0% and 7.4%, respectively). Inpatient stays contributed most to total COPD-related healthcare costs. For non-triple IMT users, at 3 and 12 months post-index, 4.5% and 13.7% had ≥1 moderate-to-severe COPD exacerbation. Time to triple therapy initiation and time to discontinuation of index medication ranged from 45.9 to 50.2 months and 2.3 to 2.8 months between treatments. Adherence was low across all time points (21.5-27.6%). Results were similar across indexed therapies. CONCLUSIONS: In the year following treatment initiation, ICS/LABA adherence was poor and many patients discontinued or switched therapies, suggesting that more consideration and optimisation of treatment is required in England for patients initiating single-device ICS/LABA therapy.

Benefit of Prompt Vs Delayed Initiation of Triple Therapy Following an Exacerbation in Patients with COPD in Japan: A Retrospective Cohort Study.

Purpose: There is currently limited evidence for the optimal timing of triple therapy initiation in Japan, which is crucial for optimizing strategies for the effective treatment of chronic obstructive pulmonary disease (COPD). This study assessed the impact of prompt vs delayed initiation of triple therapy following a COPD exacerbation on clinical and economic outcomes in patients in Japan. Patients and Methods: Retrospective cohort study of patients in the Medical Data Vision Co., Ltd. database initiating triple therapy as single-inhaler triple therapy (fluticasone furoate/umeclidinium/vilanterol or budesonide/glycopyrronium/formoterol) or multiple-inhaler triple therapy within 180 days of a moderate-to-severe exacerbation (index). For the main analysis, patients were categorized as prompt or delayed initiators, initiating triple therapy within 0-30 days or 31-180 days of index, respectively. Inverse probability of treatment weighting based on propensity scores was used to adjust for measured confounders between prompt and delayed cohorts. Results: For the main analysis, 610 (60.3%) and 402 (39.7%) patients were prompt and delayed initiators, respectively. The rate of subsequent moderate-to-severe exacerbations following index exacerbation was numerically lower in prompt vs delayed initiators (weighted rate ratio 0.95, 95% confidence interval [CI]: 0.74-1.21; P = 0.6603). Time-to-first subsequent moderate-to-severe exacerbation increased significantly in prompt vs delayed initiators (weighted hazard ratio 0.77, 95% CI: 0.64-0.93; P = 0.0053). In patients indexed on a severe exacerbation, delayed initiation resulted in significantly higher 90-day all-cause readmissions vs prompt initiation (42.1% vs 30.6%; P = 0.0329 [weighted estimates]). Weighted healthcare resource utilization rates were numerically lower in prompt vs delayed initiators, and weighted direct costs (all cause and COPD-related) were significantly lower in prompt initiators. Conclusion: This real-world study demonstrated that earlier initiation of triple therapy resulted in several benefits in clinical outcomes for COPD and may also reduce the economic burden of COPD management in Japan.

Benefit of prompt initiation of single-inhaler fluticasone furoate, umeclidinium, and vilanterol (FF/UMEC/VI) in patients with COPD in England following an exacerbation: a retrospective cohort study.

BACKGROUND: Triple therapy is recommended for patients with chronic obstructive pulmonary disease (COPD) who remain symptomatic despite dual therapy. The optimal timing of triple therapy following an exacerbation of COPD is unknown. The outcomes of prompt (≤ 30 days) vs. delayed (31-180 days) initiation of single-inhaler triple therapy with fluticasone furoate, umeclidinium, and vilanterol (FF/UMEC/VI) following an exacerbation of COPD were examined. METHODS: This was a retrospective cohort study of linked English primary (Clinical Practice Research Datalink) and secondary (Hospital Episode Statistics) care data. Patients aged ≥ 35 years with COPD were indexed on the first and/or earliest date of exacerbation between November 15, 2017 and March 31, 2019 with subsequent FF/UMEC/VI initiation within 180 days. Patients were required to be continuously registered with a general practitioner for ≥ 12 months prior to and following index. Subsequent exacerbations, direct medical costs, and hospital readmissions were compared between prompt and delayed initiators. Inverse probability of treatment weighting was used to adjust for measured confounders between cohorts. RESULTS: Overall, 1599 patients were included (prompt: 393, delayed: 1206). After weighting, prompt initiators had numerically lower moderate/severe exacerbations compared with delayed initiators (rate ratio: 0.87, 95% confidence interval [CI]: 0.76-1.01, p = 0.0587). Both all-cause and COPD-related 30-day hospital readmissions were significantly lower among patients with prompt initiation compared with delayed initiators (all-cause: 23.6% vs. 34.6%, odds ratio [95% CI]: 0.58 [0.36-0.95], p = 0.0293; COPD-related: 20.3% vs. 30.6%, odds ratio [95% CI]: 0.58 [0.35-0.96], p = 0.0347). Prompt initiators also had numerically lower all-cause total costs and significantly lower COPD-related costs per-person-per year compared with delayed initiators (COPD-related: £742 vs. £801, p = 0.0016). CONCLUSION: Prompt initiation of FF/UMEC/VI following a moderate/severe exacerbation was associated with fewer subsequent exacerbations, fewer hospital readmissions, and lower COPD-related medical costs compared with delayed initiation.

Triple therapy with an inhaled corticosteroid (ICS), a long-acting muscarinic antagonist (LAMA), and a long-acting ß2-agonist (LABA) is recommended for patients with chronic obstructive pulmonary disease (COPD) who still experience symptoms while taking dual therapy (LABA/LAMA or ICS/LABA). Triple therapy can be taken using single or multiple inhalers. The best time to start triple therapy for patients who may benefit from it following a short-term worsening (flare-up) of their COPD symptoms is unknown. This study assesses the effect of starting treatment with triple therapy sooner compared with later in patients with COPD.Patients who experienced a flare-up of their COPD symptoms were split into two groups ­ those who started taking triple therapy (via a single inhaler) within 30 days of their symptom flare-up and those who started taking triple therapy 31­180 days following their symptom flare-up. Over the 12 months following the initial flare-up, patients who started triple therapy earlier (within 30 days) had fewer subsequent symptom flare-ups, fewer hospital admissions, and lower healthcare costs compared with patients who started triple therapy later (31­180 days). These findings suggest that doctors should consider prescribing triple therapy (via a single inhaler) to their patients with COPD straight away if they experience a flare-up of their symptoms.

Comparative Effectiveness of Umeclidinium/Vilanterol versus Indacaterol/Glycopyrronium on Moderate-to-Severe Exacerbations in Patients with Chronic Obstructive Pulmonary Disease in Clinical Practice in England.

Purpose: Chronic obstructive pulmonary disease (COPD) exacerbations are associated with significant morbidity and mortality and increased economic healthcare burden for patients with COPD. Long-acting muscarinic antagonist (LAMA)/long-acting ß2-agonist (LABA) dual therapy is recommended for patients receiving mono-bronchodilator therapy who experience exacerbations or ongoing breathlessness. This study compared two single-inhaler LAMA/LABA dual therapies, umeclidinium/vilanterol (UMEC/VI) and indacaterol/glycopyrronium (IND/GLY), on moderate-to-severe exacerbation rates in patients with COPD in England. Patients and Methods: This retrospective cohort study used linked primary care electronic health record data (Clinical Practice Research Datalink-Aurum) and secondary care data (Hospital Episode Statistics) to assess outcomes for patients with COPD who had a first prescription for single-inhaler UMEC/VI or IND/GLY (index date) between 1 January 2015 and 30 September 2019 (indexing period). Analyses compared UMEC/VI and IND/GLY on moderate-to-severe, moderate, and severe exacerbations, healthcare resource utilization (HCRU), and direct costs at 6, 12, 18, and 24 months, and time-to-first on-treatment exacerbation up to 24 months post-index date. Following inverse probability of treatment weighting (IPTW), non-inferiority and superiority of UMEC/VI versus IND/GLY were assessed. Results: In total, 12,031 patients were included, of whom 8753 (72.8%) were prescribed UMEC/VI and 3278 (27.2%) IND/GLY. After IPTW, for moderate-to-severe exacerbations, weighted rate ratios were <1 at 6, 12, and 18 months and equal to 1 at 24 months for UMEC/VI; around the null value for moderate exacerbations and <1 at all timepoints for severe exacerbations. UMEC/VI showed lower HCRU incidence rates than IND/GLY for all-cause Accident and Emergency visits and COPD-related inpatient stays and associated all-cause costs at 6 months post-indexing. Time-to-triple therapy was similar for both treatments. Conclusion: UMEC/VI demonstrated non-inferiority to IND/GLY in moderate-to-severe exacerbation reduction at 6, 12 and 18 months. These results support previous findings demonstrating similarity between UMEC/VI and IND/GLY on reduction of moderate-to-severe exacerbations.

Comparison of Rescue Medication Prescriptions in Patients with Chronic Obstructive Pulmonary Disease Receiving Umeclidinium/Vilanterol versus Tiotropium Bromide/Olodaterol in Routine Clinical Practice in England.

Purpose: Routinely collected healthcare data on the comparative effectiveness of the long-acting muscarinic antagonist/long-acting ß2-agonist combination umeclidinium/vilanterol (UMEC/VI) versus tiotropium bromide/olodaterol (TIO/OLO) for chronic obstructive pulmonary disease (COPD) is limited. This study compared rescue medication prescriptions in patients with COPD in England receiving UMEC/VI versus TIO/OLO. Patients and Methods: This retrospective cohort study used primary care data from the Clinical Practice Research Datalink Aurum database linked with secondary care administrative data from Hospital Episode Statistics. Patients with a COPD diagnosis at age ≥35 years were included (indexed) following initiation of single-inhaler UMEC/VI or TIO/OLO between July 1, 2015, and September 30, 2019. Outcomes included the number of rescue medication prescriptions at 12-months (primary), and at 6-, 18- and 24-months (secondary), adherence at 6-, 12-, 18- and 24-months post-index, defined as proportion of days covered ≥80% (secondary), and time-to-initiation of triple therapy (exploratory). Inverse probability of treatment weighting (IPTW) was used to balance potential confounding baseline characteristics. Superiority of UMEC/VI versus TIO/OLO for the primary outcome of rescue medication prescriptions was assessed using an intention-to-treat analysis with a p-value < 0.05. Results: In total, 8603 patients were eligible (UMEC/VI: n = 6536; TIO/OLO: n = 2067). Following IPTW, covariates were well balanced across groups. Patients initiating UMEC/VI had statistically significantly fewer (mean [standard deviation]; p-value) rescue medication prescriptions versus TIO/OLO in both the unweighted (4.84 [4.78] vs 5.68 [5.00]; p < 0.001) and weighted comparison (4.91 [4.81] vs 5.48 [5.02]; p = 0.0032) at 12 months; consistent results were seen at all timepoints. Adherence was numerically higher for TIO/OLO versus UMEC/VI at all timepoints. Time-to-triple therapy was similar between treatment groups. Conclusion: UMEC/VI was superior to TIO/OLO in reducing rescue medication prescriptions at 12 months after treatment initiation in a primary care cohort in England, potentially suggesting improvements in symptom control with UMEC/VI compared with TIO/OLO.

Burden of Disease in Patients with Mild or Mild-to-Moderate Chronic Obstructive Pulmonary Disease (Global Initiative for Chronic Obstructive Lung Disease Group A or B): A Systematic Literature Review.

Background: Patients with mild or mild-to-moderate chronic obstructive pulmonary disease (COPD), defined as Global Initiative for Chronic Obstructive Lung Disease (GOLD) group A/B, are regarded as having a lower risk of experiencing multiple or severe exacerbations compared with patients classified as GOLD group C/D. Current guidelines suggest that patients in GOLD A/B should commence treatment with a bronchodilator; however, some patients within this population who have a higher disease burden may benefit from earlier introduction of dual bronchodilator or inhaled corticosteroid-containing therapies. This study aimed to provide research-based insights into the burden of disease experienced by patients classified as GOLD A/B, and to identify characteristics associated with poorer outcomes. Methods: A systematic literature review (SLR) was conducted to identify evidence (burden of disease and prevalence data) relating to the population of interest (patients with COPD classified as GOLD A/B). Results: A total of 79 full-text publications and four conference abstracts were included. In general, the rates of moderate and severe exacerbations were higher among patients in GOLD group B than among those in group A. Among patients classified as GOLD A/B, the risk of exacerbation was higher in those with more symptoms (modified Medical Research Council or COPD Assessment Test scales) and more severe airflow limitation (forced expiratory volume in 1 second % predicted). Conclusion: Data from this SLR provide clear evidence of a heavier burden of disease for patients in GOLD B, compared with those in GOLD A, and highlight factors associated with worse outcomes for patients in GOLD A/B.

Comparative Effectiveness of Umeclidinium/Vilanterol versus Inhaled Corticosteroid/Long-Acting ß2-Agonist in Patients with Chronic Obstructive Pulmonary Disease in a Primary Care Setting in England.

Purpose: To compare adherence to once-daily umeclidinium/vilanterol (UMEC/VI), a long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA), and twice-daily inhaled corticosteroids (ICS)/LABA single-inhaler dual therapy in patients with chronic obstructive pulmonary disease (COPD) in a primary care cohort in England. Patients and Methods: Active comparator, new-user, retrospective cohort study using CPRD-Aurum primary care data and linked Hospital Episode Statistics secondary care administrative data. Patients without exacerbations in the previous year were indexed on first/earliest prescription date of once-daily UMEC/VI or twice-daily ICS/LABA as initial maintenance therapy between July 2014-September 2019. Primary outcome: medication adherence at 12 months post-index, defined as proportion of days covered (PDC) ≥80%. PDC represented proportion of time over the treatment duration that the patient was theoretically in possession of the medication. Secondary outcomes: adherence at 6, 18, and 24 months post-index, time-to-triple therapy, time-to-first on-treatment COPD exacerbation, COPD-related and all-cause healthcare resource utilization (HCRU), and direct health-care costs. A propensity score was generated and inverse probability of treatment weighting (IPTW) was used to balance potential confounders. Superiority was defined as >0% difference between treatment groups. Results: In total, 6815 eligible patients were included (UMEC/VI:1623; ICS/LABA:5192). At 12 months post-index, weighted odds of a patient being adherent were significantly greater with UMEC/VI versus ICS/LABA (odds ratio [95% CI]: 1.71 [1.09, 2.66]; p=0.0185), demonstrating superiority of UMEC/VI. Patients taking UMEC/VI were statistically significantly more adherent than those taking ICS/LABA at 6, 18, and 24 months post-index (p<0.05). Differences in time-to-triple therapy, time-to-moderate COPD exacerbations, HCRU, and direct medical costs were not statistically significant between treatments after IPTW was applied. Conclusion: At 12 months post-treatment initiation, once-daily UMEC/VI was superior to twice-daily ICS/LABA in medication adherence among patients with COPD without exacerbations in the previous year, newly initiating dual maintenance therapy in England. The finding was consistent at 6, 18, and 24 months.

Treatment Patterns, Healthcare Utilization and Clinical Outcomes of Patients with Chronic Obstructive Pulmonary Disease Initiating Single-Inhaler Long-Acting ß2-Agonist/Long-Acting Muscarinic Antagonist Dual Therapy in Primary Care in England.

Purpose: Selection of treatments for patients with chronic obstructive pulmonary disease (COPD) may impact clinical outcomes, healthcare resource use (HCRU) and direct healthcare costs. We aimed to characterize these outcomes along with treatment patterns, for patients with COPD following initiation of single-inhaler long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA) dual therapy in the primary care setting in England. Patients and Methods: This retrospective cohort study used linked primary care electronic medical record data (Clinical Practice Research Datalink-Aurum) and secondary care administrative data (Hospital Episode Statistics) in England to assess outcomes for patients with COPD who had a prescription for one of four single-inhaler LAMA/LABA dual therapies between 1st June 2015-31st December 2018 (indexing period). Outcomes were assessed during a 12-month follow-up period from the index date (date of earliest prescription of a single-inhaler LAMA/LABA within the indexing period). Incident users were those without previous LAMA/LABA dual therapy prescriptions prior to index; this manuscript focuses on a subset of incident users: non-triple therapy users (patients without concomitant inhaled corticosteroid use at index). Results: Of 10,991 incident users included, 9888 (90.0%) were non-triple therapy users, indexed on umeclidinium/vilanterol (n=4805), aclidinium/formoterol (n=2109), indacaterol/glycopyrronium (n=1785) and tiotropium/olodaterol (n=1189). At 3 months post-index, 63.3% of non-triple therapy users remained on a single-inhaler LAMA/LABA, and 22.1% had discontinued inhaled therapy. Most patients (86.9%) required general practitioner consultations in the first 3 months post-index. Inpatient stays were the biggest contributor to healthcare costs. Acute exacerbations of COPD (AECOPDs), adherence, time-to-triple therapy, time-to-first on-treatment moderate-to-severe AECOPD, time-to-index treatment discontinuation, HCRU and healthcare costs were similar across indexed therapies. Conclusion: Patients initiating treatment with single-inhaler LAMA/LABA in primary care in England were unlikely to switch treatments in the first three months following initiation, but some may discontinue respiratory medication. Outcomes were similar across indexed treatments.

Comparative Adherence and Persistence of Single- and Multiple-Inhaler Triple Therapies Among Patients with Chronic Obstructive Pulmonary Disease in an English Real-World Primary Care Setting.

Purpose: Triple therapy comprising a long-acting muscarinic antagonist, long-acting ß2-agonist and inhaled corticosteroid is recommended for patients with chronic obstructive pulmonary disease (COPD) who continue to experience frequent exacerbations or symptoms whilst receiving dual therapy. Adherence and persistence to multiple-inhaler triple therapy (MITT) is known to be poor. This study assessed comparative adherence to single-inhaler triple therapy (SITT) versus MITT in a real-world setting in England. Patients and Methods: This was a retrospective cohort study using linked primary care (Clinical Practice Research Datalink Aurum) and secondary care (Hospital Episode Statistics [HES] Admitted Patient Care) data to identify patients with COPD who were newly initiated on SITT or MITT between November 2017 and June 2019. Eligible patients were aged ≥35 years and had a forced expiratory volume in 1 second/forced vital capacity <0.7, linkage to HES and continuous registration with a general practitioner for 12 months pre- and 6 months post-initiation. Inverse probability of treatment weighting was used to balance baseline characteristics between cohorts. Adherence was measured using the proportion of days covered by days' supply of SITT or MITT prescriptions. Persistence was measured with a gap of >30 days between the end of a prescription and the following refill used to determine non-persistence. Results: Overall, 4080 SITT and 6579 MITT users comprised the study cohort. After weighting, the baseline characteristics between the cohorts were comparable (absolute standardized mean difference <10%). SITT users had significantly higher adherence than MITT users at 6, 12, and 18 months post-initiation (p<0.001 for all comparisons). Median persistence was higher among SITT users than MITT users (5.09 months vs 0.99 months). Conclusion: Patients with COPD in England initiating SITT had significantly better adherence and persistence compared with MITT initiators. These improvements continued at least 18 months following treatment initiation.

Characterisation of patients with chronic obstructive pulmonary disease initiating single-device inhaled corticosteroids/long-acting ß2-agonist dual therapy in a primary care setting in England.

INTRODUCTION: Treatment pathways of patients with chronic obstructive pulmonary disease (COPD) receiving single-device dual therapies in England remain unclear. This study describes the characteristics of patients with COPD before initiating treatment with a single-device inhaled corticosteroid/long-acting ß2-agonist (ICS/LABA) in primary care in England. METHODS: This is a retrospective, descriptive study of linked primary and secondary healthcare data (Clinical Practice Research Datalink Aurum, Hospital Episode Statistics). Patients with COPD were indexed on first prescription of fixed-dose, single-device ICS/LABA (June 2015-December 2018). Demographics, clinical characteristics, prescribed treatments, healthcare resource use (HCRU) and direct healthcare costs were assessed over 12 months pre-index. Incident users (indexed on first ever prescription) could be non-triple users (no concomitant long-acting muscarinic antagonist at index); a subset were initial maintenance therapy (IMT) users (no history of pre-index maintenance therapy). RESULTS: Overall, 13 451 incident users (non-triple users: 7448, 55.4%; IMT users: 5162, 38.4%) were indexed on beclomethasone dipropionate/formoterol (6122, 45.5%), budesonide/formoterol (2703, 20.1%) or Other ICS/LABA combinations (4626, 34.4%). Overall, 20.8% of incident users had comorbid asthma and 42.6% had ≥1 moderate-to-severe acute exacerbation of COPD pre-index. Baseline characteristics were similar across indexed therapies. At 3 months pre-index, 45.3% and 35.4% of non-triple and IMT users were receiving maintenance treatment. HCRU and direct healthcare costs were similar across indexed treatments. Prescribing patterns varied regionally. CONCLUSION: Patient characteristics, prior treatments, prior COPD-related HCRU and direct healthcare costs were similar across single-device ICS/LABAs in primary care in England. A high proportion of patients were not receiving any respiratory medication pre-index, indicating that prescribing in primary care in England is more closely aligned with national guidelines than global treatment strategies. Comorbid asthma may have influenced prescribing decisions. Less than half of users had preindex exacerbations, suggesting that ICS/LABA is not being prescribed principally based on exacerbation history.

Characterization of Patients with Chronic Obstructive Pulmonary Disease Initiating Single-Inhaler Long-Acting Muscarinic Antagonist/Long-Acting ß2-Agonist Dual Therapy in a Primary Care Setting in England.

Purpose: Treatment pathways of patients with chronic obstructive pulmonary disease (COPD) receiving single-inhaler dual therapies remain unclear. We aimed to describe characteristics, prescribed treatments, healthcare resource use (HCRU) and costs of patients with COPD who initiated single-inhaler long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA) dual therapy in primary care in England. Patients and Methods: Retrospective study using linked data from Clinical Practice Research Datalink Aurum and Hospital Episode Statistics datasets. Patients with COPD with ≥1 single-inhaler LAMA/LABA prescription between June 2015 and December 2018 (index) were included. Demographic and clinical characteristics, prescribed treatments, HCRU and costs were evaluated in the 12 months pre-index. Data are presented for patients not receiving concomitant inhaled corticosteroids at index (non-triple users). Results: Of 10,991 patients initiating LAMA/LABA, 9888 were non-triple users, of whom 21.3% (n=2109) received aclidinium bromide/formoterol, 18.1% (n=1785) received indacaterol/glycopyrronium, 12.0% (n=1189) received tiotropium bromide/olodaterol and 48.6% (n=4805) received umeclidinium/vilanterol. Demographic and clinical characteristics were similar across indexed therapies. LAMA monotherapy was the most frequently prescribed respiratory therapy at 12 (18.4-25.8% of patients) and 3 months (23.9-33.7% of patients) pre-index across indexed therapies; 42.5-59.0% of patients were prescribed no respiratory therapy at these time points. COPD-related HCRU during the 12 months pre-index was similar across indexed therapies (general practitioner consultations: 62.0-68.6% patients; inpatient stays: 19.3-26.1% patients). Pre-index COPD-related costs were similar across indexed therapies, with inpatient stays representing the highest contribution. Mean total direct annual COPD-related costs ranged from £805-£1187. Conclusion: Characteristics of patients newly initiating single-inhaler LAMA/LABA dual therapy were highly consistent across indexed therapies. As half of non-triple users were not receiving respiratory therapy one year prior to LAMA/LABA initiation, there may be an opportunity for early optimization of treatment to relieve clinical burden versus current prescribing patterns in primary care in England.

Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) Triple Therapy Compared with Other Therapies for the Treatment of COPD: A Network Meta-Analysis.

INTRODUCTION: Randomized controlled trials (RCTs) comparing triple therapies (inhaled corticosteroid [ICS], long-acting ß2-agonist [LABA], and long-acting muscarinic antagonist [LAMA]) for the treatment of chronic obstructive pulmonary disease (COPD) are limited. This network meta-analysis (NMA) investigated the comparative efficacy of single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus any triple (ICS/LABA/LAMA) combinations and dual therapies in patients with COPD. METHODS: This NMA was conducted on the basis of a systematic literature review (SLR), which identified RCTs in adults aged at least 40 years with COPD. The RCTs compared different ICS/LABA/LAMA combinations or an ICS/LABA/LAMA combination with any dual therapy (ICS/LABA or LAMA/LABA). Outcomes of interest included forced expiratory volume in 1 s (FEV1), annualized rate of combined moderate and severe exacerbations, St George's Respiratory Questionnaire (SGRQ) total score and SGRQ responders, transition dyspnea index focal score, and rescue medication use (RMU). Analyses were conducted at 24 weeks (primary endpoint), and 12 and 52 weeks (if feasible). RESULTS: The NMA was informed by five trials reporting FEV1 at 24 weeks. FF/UMEC/VI was statistically significantly more effective at increasing trough FEV1 (based on change from baseline) than all triple comparators in the network apart from UMEC + FF/VI. The NMA was informed by 17 trials reporting moderate or severe exacerbation endpoints. FF/UMEC/VI demonstrated statistically significant improvements in annualized rate of combined moderate or severe exacerbations versus single-inhaler budesonide/glycopyrronium bromide/formoterol fumarate (BUD/GLY/FOR). At 24 weeks, the NMA was informed by five trials. FF/UMEC/VI showed statistically significant improvements in annualized rate of combined moderate or severe exacerbations versus UMEC + FF/VI and BUD/GLY/FOR. FF/UMEC/VI also demonstrated improvements in mean SGRQ score versus other triple therapy comparators at 24 weeks, and a significant reduction in RMU compared with BUD/GLY/FOR (160/18/9.6). CONCLUSION: The findings of this NMA suggest favorable efficacy with single-inhaler triple therapy comprising FF/UMEC/VI. Further analysis is required as additional evidence becomes available.

Comparative Efficacy of Umeclidinium/Vilanterol Versus Other Bronchodilators for the Treatment of Chronic Obstructive Pulmonary Disease: A Network Meta-Analysis.

INTRODUCTION: Few randomised controlled trials (RCTs) have directly compared long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA) dual maintenance therapies for patients with chronic obstructive pulmonary disease (COPD). This systematic literature review and network meta-analysis (NMA) compared the efficacy of umeclidinium/vilanterol (UMEC/VI) versus other dual and mono-bronchodilator therapies in symptomatic patients with COPD. METHODS: A systematic literature review (October 2015-November 2020) was performed to identify RCTs ≥ 8 weeks long in adult patients with COPD that compared LAMA/LABA combinations against any long-acting bronchodilator-containing dual therapy or monotherapy. Data extracted on changes from baseline in trough forced expiratory volume in 1 s (FEV1), St George's Respiratory Questionnaire (SGRQ) total score, Transitional Dyspnoea Index (TDI) focal score, rescue medication use and moderate/severe exacerbation rate were analysed using an NMA in a frequentist framework. The primary comparison was at 24 weeks. Fixed effects model results are presented. RESULTS: The NMA included 69 full-length publications (including 10 GSK clinical study reports) reporting 49 studies. At 24 weeks, UMEC/VI provided statistically significant greater improvements in FEV1 versus all dual therapy and monotherapy comparators. UMEC/VI provided similar improvements in SGRQ total score compared with all other LAMA/LABAs, and significantly greater improvements versus UMEC 125 µg, glycopyrronium 50 µg, glycopyrronium 18 µg, tiotropium 18 µg and salmeterol 50 µg. UMEC/VI also provided significantly better outcomes versus some comparators for TDI focal score, rescue medication use, annualised moderate/severe exacerbation rate, and time to first moderate/severe exacerbation. CONCLUSION: UMEC/VI provided generally better outcomes compared with LAMA or LABA monotherapies, and consistent improvements in lung function (measured by change from baseline in trough FEV1 at 24 weeks) versus dual therapies. Treatment with UMEC/VI may improve outcomes for symptomatic patients with COPD compared with alternative maintenance treatments.

Bronchodilators are medicines that open the airways, allowing patients with chronic obstructive pulmonary disease (COPD) to breathe more easily. There are two different types of bronchodilators, namely long-acting muscarinic antagonists (LAMAs) and long-acting ß₂-agonists (LABAs), which can be used on their own or combined (LAMA/LABAs). Only a few clinical trials have compared different LAMA/LABA combinations with each other, so it is unclear which LAMA/LABA combination provides the greatest benefits for patients.In this study, we used network meta-analysis to compare a LAMA/LABA combination medicine called umeclidinium and vilanterol (UMEC/VI) with other LAMAs and LABAs used alone or in combination to treat patients with COPD. Network meta-analysis is a way of comparing two or more medicines by analysing data from many studies. We systematically searched for evidence from clinical trials in adult patients with COPD that were at least 8 weeks long and that compared LAMA/LABA combinations with a LAMA, a LABA, or another LAMA/LABA combination. We analysed data from 49 clinical trials that met these criteria.We found that patients treated with UMEC/VI had better lung function than patients treated with alternative LAMA/LABA combinations or bronchodilators used on their own. Patients treated with UMEC/VI had better quality of life than those receiving some other treatments, but not all. All the medicines we compared had similar side effects.Our results suggest that treating patients with COPD with UMEC/VI might improve their lung function and quality of life more than alternative bronchodilators.

A systematic literature review of burden of illness in adults with uncontrolled moderate/severe asthma.

BACKGROUND: There are limited published data on the burden of moderate/severe uncontrolled asthma. METHODS: We conducted a systematic literature review to better understand the impact of moderate-to-severe asthma in the US, the UK, Germany, France, Italy, Spain, Canada, Japan, and Australia in terms of prevalence, clinical measures, health-related quality of life (HRQoL) and economic burden, for patients whose asthma is uncontrolled despite inhaled corticosteroid/long-acting ß2-agonist (ICS/LABA) therapy. RESULTS: The prevalence of uncontrolled asthma among patients with moderate/severe disease varied but was as high as 100% in some subgroups. Patients with uncontrolled asthma generally had poor lung function (mean/median pre-bronchodilator forced expiratory volume in 1 second [FEV1]: 1.69-2.45 L; mean/median pre-bronchodilator percent predicted FEV1: 57.2-79.7). There was also a substantial but variable exacerbation burden associated with uncontrolled asthma, with the annualised rate of exacerbations ranging from 1.30 to 7.30 when considering various patient subgroups. Furthermore, the annualised rate of severe exacerbations ranged from 1.66 to 3.60. The HRQoL burden measured using disease-specific and generic instruments consistently demonstrated substantial impairment of HRQoL for those with uncontrolled asthma; Asthma Quality of Life Questionnaire scores ranged from 3.00 to 5.20, whilst EurQol-5 Dimensions index scores ranged from 0.53 to 0.59. Direct, indirect and total costs together with consumption of other healthcare resources associated with managing uncontrolled asthma were also substantial in the population studied; no caregiver burden was identified. CONCLUSIONS: Our findings suggest that significant unmet needs exist for patients with uncontrolled asthma despite the availability of ICS/LABA therapy. Novel treatments are needed to help reduce the burden to patients, healthcare systems and society.