Effects of triple therapy on disease burden in patients of GOLD groups C and D: results from the observational COPD cohort COSYCONET.

BACKGROUND: Randomized controlled trials described beneficial effects of inhaled triple therapy (LABA/LAMA/ICS) in patients with chronic obstructive pulmonary disease (COPD) and high risk of exacerbations. We studied whether such effects were also detectable under continuous treatment in a retrospective observational setting. METHODS: Data from baseline and 18-month follow-up of the COPD cohort COSYCONET were used, including patients categorized as GOLD groups C/D at both visits (n = 258). Therapy groups were defined as triple therapy at both visits (triple always, TA) versus its complement (triple not always, TNA). Comparisons were performed via multiple regression analysis, propensity score matching and inverse probability weighting to adjust for differences between groups. For this purpose, variables were divided into predictors of therapy and outcomes. RESULTS: In total, 258 patients were eligible (TA: n = 162, TNA: n = 96). Without adjustments, TA patients showed significant (p < 0.05) impairments regarding lung function, quality of life and symptom burden. After adjustments, most differences in outcomes were no more significant. Total direct health care costs were reduced but still elevated, with inpatient costs much reduced, while costs of total and respiratory medication only slightly changed. CONCLUSION: Without statistical adjustment, patients with triple therapy showed multiple impairments as well as elevated treatment costs. After adjusting for differences between treatment groups, differences were reduced. These findings are compatible with beneficial effects of triple therapy under continuous, long-term treatment, but also demonstrate the limitations encountered in the comparison of controlled intervention studies with observational studies in patients with severe COPD using different types of devices and compounds.

Rational use of inhaled corticosteroids for the treatment of COPD: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: Inhaled corticosteroids (ICS) are a type of medication delivered via an inhaler device that are commonly used in the treatment of asthma. ICS can also be used to treat chronic obstructive pulmonary disease (COPD), a progressive respiratory condition in which the lungs become worse over time. However, unlike in asthma, ICS are only effective in a small proportion of people with COPD. ICS can cause significant side effects in people with COPD, including pneumonia. Because of this, guidelines written by COPD experts recommend that ICS should largely be prescribed to people with COPD whose symptoms flare up frequently and become difficult to manage (episodes known as exacerbations). Despite this guidance, records collected from routine clinical practice suggest that many healthcare professionals prescribe ICS to people with COPD who do not have frequent exacerbations, putting them at unnecessary risk of side effects. The over-prescription of ICS in COPD may partly be due to the recent introduction of single-inhaler combination therapies, which combine ICS with other medicines (bronchodilators). This 'one inhaler for all' approach is a concerning trend as it goes against global COPD treatment guidelines, which recommend ICS use in only a small proportion of people. This is a plain language summary of a review article originally published in the journal NPJ Primary Care Respiratory Medicine. In this review, we investigate the benefits and risks of ICS use in COPD. Using data from both randomized controlled trials (RCTs) and observational studies, we explain which people benefit from ICS use, and why health regulatory bodies have concluded that ICS do not help people with COPD to live longer. Lastly, we provide practical guidance for doctors and people with COPD regarding when ICS should be prescribed and when they should be withdrawn.

Open and Closed Triple Inhaler Therapy in Patients with Uncontrolled Asthma.

Long-acting muscarinic antagonists (LAMAs) are a class of inhalers that has recently been included as add-on therapy in the GINA guidelines, either in a single inhaler device with inhaled corticosteroids plus long-acting ß2-agonists (ICS + LABA) (closed triple inhaler therapy) or in a separate one (open triple inhaler therapy). This review summarizes the existing evidence on the addition of LAMAs in patients with persistently uncontrolled asthma despite ICS + LABA treatment based on clinical efficacy in the reduction of asthma symptoms and exacerbations, the improvement in lung function, and its safety profile.

Pharmacokinetic considerations surrounding triple therapy for uncontrolled asthma.

INTRODUCTION: Solid pharmacological rationale and clinical evidence support the use of a combination of an inhaled corticosteroid (ICS), a long-acting ß2-agonist, and a long-acting muscarinic antagonist in severe asthma, which clinically results in increased lung function, improved symptoms, and decreased exacerbation rates. AREAS COVERED: We examined the pharmacokinetic issues associated with triple therapy for uncontrolled asthma. We considered the pharmacokinetic characteristics of the three drug classes, the role of inhalers in influencing their pharmacokinetic behavior, and the impact of severe asthma on the pharmacokinetics of inhaled drugs. EXPERT OPINION: The pharmacokinetics of ICSs and bronchodilators are not affected to a great extent by severe asthma, according to a detailed review of the currently accessible literature. Compared to healthy people, patients with severe asthma show only minor variations in a few pharmacokinetic characteristics, which are unlikely to have therapeutic significance and do not require particular attention. However, the difficulty of obtaining pharmacokinetic profiles of the three drugs included in a triple therapy suggests that the clinical response should be followed over time, which can be considered a good surrogate indicator of whether the drugs have reached sufficient concentrations in the lung to exert a valid pharmacological action.

Investigating the rationale for COPD maintenance therapy prescription across Europe, findings from a multi-country study.

This study aims to understand healthcare professionals' thoughts and motivations about optimal management and treatment of patients with chronic obstructive pulmonary disease (COPD). We conducted a DELPHI survey through an online questionnaire distributed to 220 panellists from six European countries and a discrete choice experiment to describe the relationship between selected clinical criteria and the initial COPD treatment of choice. One hundred twenty-seven panellists (general practitioners [GPs] and pulmonologists) completed the survey. Despite the familiarity and use (89.8%) of the GOLD classification for initial treatment selection, a frequent use of LAMA/LABA/ICS was noted. In fact, panellists agreed that inhaled corticosteroids (ICS) are over-prescribed in the primary care setting. Our study showed that GPs felt less confident than pulmonologists with ICS withdrawal. This mismatch observed between best practice and behaviour indicates the need to increase awareness and efforts to improve the adherence to guidelines in clinical practice.

Clinical and economic outcomes in patients with chronic obstructive pulmonary disease initiating maintenance therapy with tiotropium bromide/olodaterol or fluticasone furoate/umeclidinium/vilanterol.

BACKGROUND: Clinical practice guidelines recommend dual long-acting muscarinic antagonists (LAMAs)/long-acting ß2agonists (LABAs) as maintenance therapy in patients with chronic obstructive pulmonary disease (COPD) and dyspnea or exercise intolerance. Escalation to triple therapy (TT) (LAMA/LABA/inhaled corticosteroid) is conditionally recommended for patients with continued exacerbations on dual LAMA/LABA therapy. Despite this guidance, TT use is widespread across COPD severities, which could impact clinical and economic outcomes. OBJECTIVE: To compare COPD exacerbations, pneumonia events, and disease-related and all-cause health care resource utilization and costs (in 2020 US dollars) in patients initiating fixed-dose combinations of either LAMA/LABA (tiotropium/olodaterol [TIO + OLO]) or TT (fluticasone furoate/umeclidinium/vilanterol [FF + UMEC + VI]). METHODS: This retrospective observational study of administrative claims included patients with COPD aged 40 years or older initiating TIO + OLO or FF + UMEC + VI from June 2015 to November 2019. TIO + OLO and FF + UMEC + VI cohorts in the overall and maintenance-naive populations were 1:1 propensity score matched on baseline demographics, comorbidities, COPD medications, health care resource utilization, and costs. Multivariable regression compared clinical and economic outcomes up to 12 months in FF + UMEC + VI vs TIO + OLO postmatched cohorts. RESULTS: After matching, there were 5,658 and 3,025 pairs in the overall and maintenance-naive populations, respectively. In the overall population, the risk of any (moderate or severe) exacerbation was 7% lower in FF + UMEC + VI vs TIO + OLO initiators (adjusted hazard ratio [aHR] = 0.93; 95% CI = 0.86-1.0; P = 0.047). There was no difference in the adjusted risk of any exacerbation in the maintenance-naive population (aHR = 0.99; 95% CI = 0.88-1.10). Pneumonia risk was not statistically different between cohorts in the overall (aHR = 1.12; 95% CI = 0.98-1.27) and maintenance-naive (aHR = 1.13; 95% CI = 0.95-1.36) populations. COPD- and/or pneumonia-related adjusted total annualized costs (95% CI) were significantly greater for FF + UMEC + VI vs TIO + OLO in the overall ($17,633 [16,661-18,604] vs $14,558 [13,709-15,407]; P < 0.001; differences [% of relative increase] = $3,075 [21.1%]) and maintenancenaive ($19,032 [17,466-20,598] vs $15,004 [13,786-16,223]; P < 0.001; $4,028 [26.8%]) populations, with significantly higher pharmacy costs with FF + UMEC + VI (overall: $6,567 [6,503-6,632] vs $4,729 [4,676-4,783]; P < 0.001; $1,838 [38.9%]; maintenance-naive: $6,642 [6,560-6,724] vs $4,750 [4,676-4,825]; P < 0.001; $1,892 [39.8%]). CONCLUSIONS: A lower risk of exacerbation was observed with FF + UMEC + VI vs TIO + OLO in the overall population but not among the maintenance-naive population. Patients with COPD initiating TIO + OLO had lower annualized costs than FF + UMEC + VI initiators in the overall and maintenance-naive populations. Thus, in the maintenance-naive population, initiation with dual LAMA/LABA therapy per practice guidelines can improve real-world economic outcomes. Study registration number: ClinicalTrials.gov (identifier: NCT05127304). DISCLOSURES: The study was funded by Boehringer Ingelheim Pharmaceuticals, Inc (BIPI). To ensure independent interpretation of clinical study results and enable authors to fulfill their role and obligations under the ICMJE criteria, BIPI grants all external authors access to relevant clinical study data. In adherence with the BIPI Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data after publication of the primary manuscript in a peer-reviewed journal, regulatory activities are complete and other criteria are met. Dr Sethi has received honoraria/fees for consulting/speaking from Astra-Zeneca, BIPI, and GlaxoSmithKline. He has received consulting fees for serving on data safety monitoring boards from Nuvaira and Pulmotect. He has received consulting fees from Apellis and Aerogen. His institution has received research funds for his participation in clinical trials from Regeneron and AstraZeneca. Ms Palli was an employee of BIPI at the time the study was conducted. Drs Clark and Shaikh are employees of BIPI. Ms Buysman and Mr Sargent are employees and Dr Bengtson was an employee of Optum, which was contracted by BIPI to conduct this study. Dr Ferguson reports grants and personal fees from Boehringer Ingelheim during the conduct of the study; grants from Novartis, Altavant, and Knopp; grants and personal fees from AstraZeneca, Verona, Theravance, Teva, and GlaxoSmithKline; and personal fees from Galderma, Orpheris, Dev.Pro, Syneos, and Ionis outside the submitted work. He was a paid consultant for BIPI for this study. The authors received no direct compensation related to the development of the manuscript. BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.

Prevalence of Uncontrolled Asthma despite Treatment with Medium- or High-Dose ICS/LABA Using Patient-Reported Outcomes in Japan: The KOCU (KnOwing the Controlled statUs of Asthma in Japan) Study.

INTRODUCTION: Evidence on the prevalence of uncontrolled asthma upon the standard of care in Japan is scarce and inconsistent. We report the prevalence of uncontrolled asthma using the Japanese Guidelines for Asthma (JGL) 2018 and Global Initiative for Asthma (GINA) 2019 classifications in patients who are currently receiving standard-of-care treatment in a real-life setting. METHODS: In this prospective, 12-week, noninterventional study, patients with asthma aged 20-75 years and continuously treated with medium- or high-dose inhaled corticosteroid (ICS)/LABA, with or without other controller(s), were assessed for their asthma control status. The demographics, clinical characteristics, treatment patterns, health care resource utilization, patient-reported outcomes (PROs), and adherence to prescribed treatments were assessed for patients classified as either controlled or uncontrolled. RESULTS: Of 454 patients, 53.7% and 36.3% of the patients reported their asthma as uncontrolled based on the JGL and GINA criteria, respectively. Uncontrolled asthma was even higher (JGL, 75.0%; GINA, 63.5%) within the subpopulation of 52 patients receiving long-acting muscarinic antagonists (LAMAs; i.e., ICS/LABA/LAMA subpopulation). Sensitivity analysis by propensity matching identified significant odds ratios of controlled versus uncontrolled asthma for several demographics and clinical characteristics: male; sensitization to animals, fungi, or birch; comorbidities including food allergy or diabetes; and history of exacerbation were associated with the risk of uncontrolled asthma. No significant changes in PROs were observed. CONCLUSION: The frequency of uncontrolled asthma in the study population was high, as per JGL and GINA guidelines, despite good adherence to ICS/LABA treatment and other prescribed treatments over 12 weeks.

Effectiveness and tolerability of dual and triple combination inhaler therapies compared with each other and varying doses of inhaled corticosteroids in adolescents and adults with asthma: a systematic review and network meta-analysis.

BACKGROUND: Current guidelines recommend a higher-dose inhaled corticosteroids (ICS) or adding a long-acting muscarinic antagonist (LAMA) when asthma is not controlled with medium-dose (MD) ICS/long-acting beta2-agonist (LABA) combination therapy. OBJECTIVES: To assess the effectiveness and safety of dual (ICS/LABA) and triple therapies (ICS/LABA/LAMA) compared with each other and with varying doses of ICS in adolescents and adults with uncontrolled asthma. SEARCH METHODS: We searched multiple databases for pre-registered randomised controlled trials (RCTs) of at least 12 weeks of study duration from 2008 to 18 February 2022. SELECTION CRITERIA: We searched studies, including adolescents and adults with uncontrolled asthma who had been treated with, or were eligible for, MD-ICS/LABA, comparing dual and triple therapies. We excluded cluster- and cross-over RCTs. DATA COLLECTION AND ANALYSIS: We conducted a systematic review and network meta-analysis according to the previously published protocol. We used Cochrane's Screen4ME workflow to assess search results and Grading of Recommendations Assessment, Development and Evaluation (GRADE) to assess the certainty of evidence. The primary outcome was steroid-requiring asthma exacerbations and asthma-related hospitalisations (moderate to severe and severe exacerbations). MAIN RESULTS: We included 17,161 patients with uncontrolled asthma from 17 studies (median duration 26 weeks; mean age 49.1 years; male 40%; white 81%; mean forced expiratory volume in 1 second (MEF 1)1.9 litres and 61% predicted). The quality of included studies was generally good except for some outcomes in a few studies due to high attrition rates. Medium-dose (MD) and high-dose (HD) triple therapies reduce steroid-requiring asthma exacerbations (hazard ratio (HR) 0.84 [95% credible interval (CrI) 0.71 to 0.99] and 0.69 [0.58 to 0.82], respectively) (high-certainty evidence), but not asthma-related hospitalisations, compared to MD-ICS/LABA. High-dose triple therapy likely reduces steroid-requiring asthma exacerbations compared to MD triple therapy (HR 0.83 [95% CrI 0.69 to 0.996], [moderate certainty]). Subgroup analyses suggest the reduction in steroid-requiring exacerbations associated with triple therapies may be only for those with a history of asthma exacerbations in the previous year but not for those without. High-dose triple therapy, but not MD triple, results in a reduction in all-cause adverse events (AEs) and likely reduces dropouts due to AEs compared to MD-ICS/LABA (odds ratio (OR) 0.79 [95% CrI 0.69 to 0.90], [high certainty] and 0.50 [95% CrI 0.30 to 0.84], [moderate certainty], respectively). Triple therapy results in little to no difference in all-cause or asthma-related serious adverse events (SAEs) compared to dual therapy (high certainty). The evidence suggests triple therapy results in little or no clinically important difference in symptoms or quality of life compared to dual therapy considering the minimal clinically important differences (MCIDs) and HD-ICS/LABA is unlikely to result in any significant benefit or harm compared to MD-ICS/LABA. AUTHORS' CONCLUSIONS: Medium-dose and HD triple therapies reduce steroid-requiring asthma exacerbations, but not asthma-related hospitalisations, compared to MD-ICS/LABA especially in those with a history of asthma exacerbations in the previous year. High-dose triple therapy is likely superior to MD triple therapy in reducing steroid-requiring asthma exacerbations. Triple therapy is unlikely to result in clinically meaningful improvement in symptoms or quality of life compared to dual therapy considering the MCIDs. High-dose triple therapy, but not MD triple, results in a reduction in all-cause AEs and likely reduces dropouts due to AEs compared to MD-ICS/LABA. Triple therapy results in little to no difference in all-cause or asthma-related SAEs compared to dual therapy. HD-ICS/LABA is unlikely to result in any significant benefit or harm compared to MD-ICS/LABA, although long-term safety of higher rather than MD- ICS remains to be demonstrated given the median duration of included studies was six months. The above findings may assist deciding on a treatment option when asthma is not controlled with MD-ICS/LABA.

Economic impact of implementing prescription of single-inhaler triple therapies versus current multiple-inhaler triple therapies for COPD in the Apulia Region.

BACKGROUND: The most impacting direct costs associated to COPD for the National Health Systems (NHS) are those related to accesses to the emergency room and hospital admissions, due to the onset of one or more COPD exacerbations. At the same time, severe COPD treatment, that often require a combination of medicaments, represents a substantial economic burden for the National Health Systems (NHS). This study aimed to evaluate the potential saving deriving from the implementation in the prescription of the two currently available single-inhaler triple therapies (SITTs) versus the currently used multiple-inhaler triple therapies (MITTs) in an eligible COPD population residing in the Apulia Region. METHODS: A budget impact model was developed hypothesizing the progressive replacement of the different MITTs on the reference market (Scenario A) with the pre-established SITTs, assuming a degree of penetration of 30%, 50% and 100% (Scenario B). Drug costs were based on prices published on the Official Gazette and therapy durations were based on prescribing information over the year 2019 (IQVIA™ prescription dataset). RESULTS: Our analysis showed that the extemporaneous MITT with the highest prevalence on the reference market was the inhaled corticosteroids/long-acting ß2-agonists (ICS/LABA) combination plus a long-acting muscarinic antagonists (LAMA). This association of medicaments was paradoxically also the one associated to the highest expense value. The expanded use of a pre-established ICS/LAMA/LABA SITT was associated to a significant economic saving, ranging from a minimum of -€ 1,108,814 (SITT use: 30%) to a maximum of -€ 3,658,950 (SITT use: 100%). The cheapest pre-established SITT contained the fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) combination. CONCLUSION: A pre-fixed ICS/LAMA/LABA SITT is cost-saving, compared to the different currently used extemporaneous MITTs. Clinicians should consider the potential benefits of finding less expensive regimens while maintaining adequate efficacy in the prescriptive decision making process of COPD patients.

Prescription Pathways from Initial Medication Use to Triple Therapy in Older COPD Patients: A Real-World Population Study.

BACKGROUND AND OBJECTIVE: Triple therapy with an inhaled corticosteroid (ICS), a long-acting ß2-agonist bronchodilator (LABA) and a long-acting muscarinic antagonist (LAMA) is recommended as step-up therapy for chronic obstructive pulmonary disease (COPD) patients who continue to have persistent symptoms and increased risk of exacerbation despite treatment with dual therapy. We sought to evaluate different treatment pathways through which COPD patients were escalated to triple therapy. METHODS: We used population health databases from Ontario, Canada to identify individuals aged 66 or older with COPD who started triple therapy between 2014 and 2017. Median time from diagnosis to triple therapy was estimated using the Kaplan-Meier method. We classified treatment pathways based on treatments received prior to triple therapy and evaluated whether pathways differed by exacerbation history, blood eosinophil counts or time period. RESULTS: Among 4108 COPD patients initiating triple therapy, only 41.2% had a COPD exacerbation in the year prior. The three most common pathways were triple therapy as initial treatment (32.5%), LAMA to triple therapy (29.8%), and ICS + LABA to triple therapy (15.4%). Median time from diagnosis to triple therapy was 362 days (95% confidence interval:331-393 days) overall, but 14 days (95% CI 12-17 days) in the triple therapy as initial treatment pathway. This pathway was least likely to contain patients with frequent or severe exacerbations (22.0% vs. 31.5%, p < 0.001) or with blood eosinophil counts ≥300 cells/µL (18.9% vs. 22.0%, p < 0.001). CONCLUSION: Real-world prescription of triple therapy often does not follow COPD guidelines in terms of disease severity and prior treatments attempted.

Effectiveness of Treatment With Dual Bronchodilation (LABA/LAMA) Compared With Combination Therapy (LABA/ICS) for Patients With COPD: A Population-Based Study.

BACKGROUND: Initiation of treatment of COPD with a combination of a long-acting beta-agonist (LABA) and an inhaled corticosteroid (ICS) is frequent irrespective of the risk of exacerbations. METHOD: We performed a retrospective, population-based, observational study aimed at comparing the effectiveness of a LABA/long-acting antimuscarinic agent (LAMA) and LABA/ICS in patients with COPD over a one-year follow-up. Data were obtained from an administrative healthcare claims database. The primary outcome was the risk of first exacerbation. A sensitivity analysis was conducted in a propensity-score matched population. RESULTS: The population consisted of 14,046 COPD patients; 11,329 (80.6%) initiated LABA/ICS and 2717 (19.4%) LABA/LAMA. The matched population included 1650 patients in each arm. During follow-up, 69.6% patients in the LABA/ICS group and 64.4% in the LABA/LAMA group presented an exacerbation. The mean time to the first exacerbation was 6.03 months (95% confidence interval (CI): 5.94-6.12) for LABA/ICS and 6.4 months (95%CI: 6.21-6.59) for LABA/LAMA; p<0.001. The time to scalation to triple therapy was also significantly prolonged in LABA/LAMA. Similar results were obtained in the matched population. LABA/LAMA was associated with a significantly lower risk of exacerbations and escalation to triple therapy compared to LABA/ICS, except in patients with frequent exacerbations and high blood eosinophils in which no differences were observed in the time to first exacerbation. CONCLUSION: Initiation of treatment with LABA/LAMA was associated with a lower risk of exacerbation and escalation to triple therapy compared to LABA/ICS in the majority of patients with COPD in primary care.

Dual bronchodilation for the treatment of COPD: From bench to bedside.

Because there is a solid pharmacological rationale based on positive interactions between long-acting muscarinic receptor antagonists (LAMAs) and long-acting ß-agonists (LABAs) for their ability to relax human airway smooth muscle in vitro alongside several randomised controlled trials (RCTs) and real-world observational studies that support the use of LAMA/LABA fixed-dose combinations (FDCs) for the treatment of patients with chronic obstructive pulmonary disease (COPD), in this narrative review we discuss the preclinical and clinical proofs supporting the use of LAMA + LABA therapy in COPD and why this therapeutic approach optimises bronchodilation. Robust evidence indicates that all LAMA/LABA FDCs are consistently more effective than LAMA or LABA administered alone in improving lung function, dyspnoea, quality of life and exercise capacity in patients with COPD. However, the ability of dual bronchodilation with FDCs of LAMA/LABA to prevent or reduce the risk of COPD exacerbations remains unclear due to conflicting data from large RCTs, despite several mechanisms explaining why such combinations should be of value in decreasing the frequency of COPD exacerbations. Both LABAs and LAMAs mechanistically can affect the cardiovascular system, but from clinical studies to date, LAMA/LABA FDCs have an acceptable cardiovascular safety profile, at least in the COPD population enrolled in RCTs. Indirect evidence suggests that some FDCs may even exert a protective role against serious cardiovascular adverse events compared to monotherapies. Consequently, several LAMA/LABA FDCs have been developed and approved for clinical use as treatments for patients with COPD. However, to date, there are unfortunately very few head-to-head studies comparing the safety and efficacy of different LAMA/LABA FDCs, making it difficult to choose the most appropriate combination, although the use of meta-analyses has provided some information in this regard. Endurance time Exercise time until exhaustion measured by a standard endurance test. Inspiratory capacity The maximum volume of air that can be inspired after reaching the end of a normal, quiet expiration. It is the sum of the tidal volume and the inspiratory reserve volume. St George's Respiratory Questionnaire (SGRQ) A tool to measure health status in patients with respiratory disease. It has three domains: symptoms, activity and impacts. A total score is also calculated. A minimal important difference (range) of ∼4 (2.4-5.6) units in the SGRQ total score is supported by published studies. Surface under the cumulative ranking curve analysis (SUCRA) A numerical representation of the overall rating that displays a single value for each treatment. SUCRA levels vary from 0% to 100%. The higher the SUCRA value and the closer it is to 100%, the more likely therapy is in the top rank or one of the top rankings; the lower the SUCRA value and the closer it is to 0%, the more likely therapy is in the bottom rank or one of the bottom ranks. Transition dyspnoea index (TDI) Widely used in clinical studies of COPD to measure shortness of breath, indicating change in response to an intervention. The total score ranges from -9 to 9; the negative value indicates deterioration, whereas a positive value indicates improvement. There is sufficient evidence to suggest that the minimal important difference for the TDI score is 1 unit. Trough FEV1 The mean volume of air that can be forced out in 1 second approximately 12 (with a twice-daily agent) or 24 (with a once-daily agent) hours after the last administration of bronchodilator.

Discontinuation of Inhaled Corticosteroids from Triple Therapy in COPD: Effects on Major Outcomes in Real World Clinical Practice.

Recent reports provide evidence-based guidelines for the withdrawal of inhaled corticosteroids (ICS) in COPD, but data on patients treated with ICS-based triple therapy are sparse and contradictory. We assessed the effect of ICS discontinuation on the incidence of severe exacerbation and pneumonia in a real-world population of patients with COPD who initiated triple therapy. We identified a cohort of patients with COPD treated with LAMA-LABA-ICS triple therapy during 2002-2018, age 50 or older, from the UK's CPRD database. Subjects who discontinued ICS were matched 1:1 on time-conditional propensity scores to those continuing ICS and followed for one year. Hazard ratios (HR) of severe exacerbation and pneumonia were estimated using Cox regression. The cohort included 42,667 patients who discontinued ICS matched to 42,667 who continued ICS treatment. The hazard ratio of a severe exacerbation with ICS discontinuation relative to ICS continuation was 0.86 (95% CI: 0.78-0.95), while for severe pneumonia it was 0.96 (95% CI: 0.88-1.05). The incidence of severe exacerbation after ICS discontinuation was numerically higher than after continuation among patients with two or more exacerbations in the prior year (HR 1.09; 95% CI: 0.94-1.26) and among those with FEV1 <30% predicted (HR 1.29; 95% CI: 1.04-1.59). This large real-world study in the clinical setting of COPD treatment suggests that certain patients on triple therapy can be safely withdrawn from ICS and remain on bronchodilator therapy. As residual confounding cannot be ruled out, ICS discontinuation is not warranted for patients with multiple exacerbations and with very severe airway obstruction.

A Review of the Unique Drug Development Strategy of Indacaterol Acetate/Glycopyrronium Bromide/Mometasone Furoate: A First-in-Class, Once-Daily, Single-Inhaler, Fixed-Dose Combination Treatment for Asthma.

A novel, once-daily (o.d.), fixed-dose combination (FDC) of indacaterol acetate (IND), glycopyrronium bromide (GLY), and mometasone furoate (MF), delivered by the inhaler Breezhaler® device, is the first long-acting beta2-adrenergic agonist/long-acting muscarinic antagonist/inhaled corticosteroid (LABA/LAMA/ICS) therapy to be approved for maintenance treatment of asthma in adults inadequately controlled on LABA/ICS. The approval of IND/GLY/MF in the European Union (EU) also included an optional electronic sensor and smartphone (or other suitable device) application, making it the first "digital companion" that can be prescribed with an asthma medication. As a result, the European Medicines Agency included this approval as one of the "outstanding contributions to public health" (for Pneumology/Allergology) in their 2020 highlights report. Alongside IND/GLY/MF, an o.d. LABA/ICS FDC, IND/MF, was also developed and approved. This review outlines the unique strategy used in the accelerated development of IND/GLY/MF that combined various approaches: (1) selecting individual components with established efficacy/safety, (2) bridging doses to optimize efficacy/safety of IND/GLY/MF and IND/MF delivered via the Breezhaler® device, (3) developing IND/GLY/MF and IND/MF in parallel, and (4) submission for regulatory approval before formal completion of the pivotal phase III studies. IND/GLY/MF and IND/MF were combined in a single-development plan (PLATINUM program), which comprised four phase III studies: QUARTZ and PALLADIUM evaluated IND/MF while IRIDIUM and ARGON evaluated IND/GLY/MF. A unique feature was the inclusion of two LABA/ICS comparators in the pivotal IRIDIUM study-IND/MF as an internal comparator, and high-dose salmeterol xinafoate/fluticasone propionate (SAL/FLU) as a marketed comparator. In the ARGON study, IND/GLY/MF was compared against o.d. tiotropium (via Respimat®) plus twice-daily (b.i.d.) high-dose SAL/FLU (via Diskus®). As a result of this development strategy, the development and approval of IND/GLY/MF was accelerated by ca. 4 years as against what would be expected from a traditional approach, novel data were generated, and a unique optional digital companion was approved in the EU. A Video Abstract by Dr Dominic Brittain, Global Drug Development, Novartis. (MP4 228293 kb).

Usage of long-acting muscarinic antagonists and biologics as add-on therapy for patients in the United States with moderate-to-severe asthma.

Many asthma patients remain uncontrolled on inhaled corticosteroids (ICS) and long-acting beta agonists (LABAs), but guidance for selecting add-on therapies, including long-acting muscarinic antagonists (LAMAs) or biologics, is limited. We describe how prescribing practices for add-on LAMA and biologic therapy have changed with increased treatment options and revised treatment guidelines. We further identify differences in treatment initiation and discontinuation rates by patient characteristics, including concomitant COPD.This retrospective cohort study analyzed insurance claims in the IBM Marketscan database for adult US asthma patients treated with medium- or high-dose ICS/LABA between 2012 and 2019 (n = 277,373). We used negative binomial regression models to evaluate LAMA and biologic initiation rates and their association with patient characteristics, and survival analysis methods for assessing discontinuation rates.Between 2012 and 2019, LAMA and biologic uptake increased approximately 5-fold and 20-fold, respectively. LAMA initiation was significantly higher among patients with concomitant COPD, a group typically unstudied in clinical trials, versus those with asthma only (rate ratio of 5.90, 95% CI: 5.76-6.04). High-dose ICS/LABA treatment and the need for oral corticosteroid (OCS) bursts had stronger associations with biologic initiation. Probability of discontinuation (i.e. non-persistence) in the first year was 40.5% and 22.7% for those initiating LAMAs and biologics, respectively, with higher LAMA discontinuation rates among patients with asthma only versus those with concomitant COPD.Our results provide insights into how clinicians apply treatment guidelines for initiating add-on LAMA and biologic therapies in moderate-to-severe asthma patients and highlight patients who have an unmet treatment need after discontinuation.

Triple Inhaler versus Dual Bronchodilator Therapy in COPD: Real-World Effectiveness on Mortality.

Randomized trials of triple therapy including an inhaled corticosteroid (ICS) for chronic obstructive pulmonary disease (COPD) reported remarkable benefits on mortality compared with dual bronchodilators, likely resulting from ICS withdrawal at randomization. We compared triple therapy with dual bronchodilator combinations on major COPD outcomes in a real-world clinical practice setting. We identified a cohort of COPD patients, age 50 or older, treated during 2002-2018, from the United Kingdom's Clinical Practice Research Datalink. Patients initiating treatment with a long-acting muscarinic antagonist (LAMA), a long-acting beta2-agonist (LABA) and an ICS on the same day, were compared with patients initiating a LAMA and LABA, weighted by fine stratification of propensity scores. Subjects were followed-up one year for all-cause mortality, severe exacerbation and pneumonia. The cohort included 117,729 new-users of LAMA-LABA-ICS and 26,666 of LAMA-LABA. The adjusted hazard ratio (HR) of all-cause mortality with LAMA-LABA-ICS compared with LAMA-LABA was 1.17 (95% CI: 1.04-1.31) while for severe exacerbation and pneumonia it was 1.19 (1.08-1.32) and 1.29 (1.16-1.45) respectively. However, mortality was not elevated with triple therapy among patients with asthma diagnosis (HR 0.99; 95% CI: 0.74-1.34), with two or more prior exacerbations (HR 0.88; 95% CI: 0.70-1.11), and with FEV1 percent predicted >30%. In a real-world setting of COPD treatment, triple therapy initiation was not more effective than dual bronchodilators at preventing all-cause mortality and severe COPD exacerbations. Triple therapy may be unsafe among patients without prior exacerbations, in whom ICS are not recommended, with no asthma diagnosis and with very severe airflow obstruction.Supplemental data for this article is available online at https://doi.org/10.1080/15412555.2021.1977789 .

Triple versus LAMA/LABA combination therapy for Japanese patients with COPD: A systematic review and meta-analysis.

BACKGROUND: In symptomatic COPD patients with a history of exacerbations, additional treatment with inhaled corticosteroid (ICS) to long-acting muscarinic antagonist (LAMA) and long-acting beta-agonist (LABA) combination therapy is recommended based on the evidence of low incidence of exacerbations but with a caution for pneumonia. However, ethnic differences may affect the response to drugs. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of this treatment in the Japanese population (PROSPERO: CRD42020191978). METHODS: We searched relevant randomized control trials and analyzed the exacerbations, quality of life, lung function, and adverse events including pneumonia and mortality as the outcomes of interest. RESULTS: We identified a total of three RCTs (N = 632). Treatment with ICS/LAMA/LABA triple therapy significantly decreased the exacerbations (rate ratio, 0.56; 95% CI, 0.38 to 0.85) and improved the trough FEV1 (mean difference, 0.04; 95% CI, 0.01 to 0.07) compared to LAMA/LABA therapy. However, triple therapy showed a significantly higher incidence of pneumonia compared to LAMA/LABA (odds ratio, 3.38; 95% CI, 1.58 to 7.22). Concerning other adverse events including mortality, there were no significant difference between these therapies. CONCLUSIONS: In the current meta-analysis of the Japanese population, we confirmed that triple therapy causes a higher incidence of pneumonia than LAMA/LABA treatment but is a more preferable treatment since it showed a lower incidence of exacerbations and higher trough FEV1 in patients with symptomatic moderate to severe COPD. However, since the sample sizes were not statistically large enough, further trials involving Japanese patients are needed.

Manifesto on inhaled triple therapy in asthma: an Interasma (Global Asthma Association - GAA) document.

Objective: The optimal use of drug combinations for the management of asthma is providing significant results. This has prompted Interasma (Global Asthma Association) to take a position on inhaled triple therapy in asthma.Methods: We performed an extensive literature research to clinical trials, meta-analyses, randomized controlled trials and systematic reviews.Results: Starting from an extensive literature review, Interasma executive committee discussed and approved this Manifesto, developed by Interasma scientific network (INES) members.Conclusions: The manifesto describes the evidence gathered to date and states, advocates, and proposes issues on inhaled corticosteroid (ICS) plus long-acting beta 2 agonist (LABA) and long-acting muscarinic antagonists (LAMA) with the aim of challenging assumptions, fostering commitment, and bringing about change.

Characteristics of COPD patients treated with single­inhaler triple therapy in real-life clinical practice.

BACKGROUND: Inflammation associated with chronic obstructive pulmonary disease (COPD) causes narrowing of the airways and destruction of the lung parenchyma. The triple therapy (ICS+LABA+LAMA) may improve lung function, patient­reported outcomes, and exacerbation risk in a specified subset of GOLD group D patients. A better understanding of the factors leading to the single­inhaler triple therapy (SITT) prescription in real-life scenario is still an unmet need. METHODS: We assessed the characteristics of 838 GOLD group D patients treated with SITT and way of how those patients had been routinely managed before in their outpatient settings. The cross-sectional observational survey was based on an assessment of routine practice patterns and retrospective collection of anonymous medical data. RESULTS: Severe and very severe forms of airflow obstruction were experienced by 52 % and 34 % of patients, respectively. The mean number of exacerbations during the 12­month period antecedent to SITT prescription was 2.01. Before starting SITT, various combinations of COPD medications were prescribed: LABA (95 %), followed by ICS and LAMA. Compared to patients with 0-1 exacerbation, the patients with ≥2 exacerbations had higher levels of mMRC and CAT scores (2.47 vs 2.69 and 16.02 vs 19.31, respectively, both p <0.001), worse treatment adherence and higher need for rescue medication (4.7 vs 3.9 units, p=0.0011). The driver for switching the treatment to SITT was an expected improvement in lung function followed by reduction in dyspnoea and number of exacerbations. CONCLUSIONS: Despite current treatment, the burden of COPD remains significant in GOLD group D patients. The lung function, symptoms burden and exacerbation history are among the most important factors involved in the decision for stepping up to SITT with potential roles of both bronchodilator and anti-inflammatory components (Tab. 2, Fig. 9, Ref. 66).

Treatment efficacy of LAMA versus placebo for stable chronic obstructive pulmonary disease: A systematic review and meta-analysis.

BACKGROUND: Four long-acting muscarinic antagonists (LAMAs), tiotropium, glycopyrronium, aclidinium, and umeclidinium, are currently available for the treatment of stable chronic obstructive pulmonary disease (COPD). However, no integrated analysis has sought to determine the effectiveness of these LAMAs. Thus, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of LAMA versus placebo in patients with stable COPD. METHODS: A literature search of relevant randomized control trials that administered LAMA to stable COPD patients was conducted, and the exacerbations, quality of life (QoL), dyspnea score, lung function, and adverse event of patients were evaluated. RESULTS: A total of 33 studies were included in this meta-analysis. LAMA significantly decreased the frequency of exacerbations compared to the placebo (OR 0.75; 95% CI 0.66 to 0.85; P < 0.001). The mean changes in the St George's Respiratory Questionnaire score (mean difference, -3.61; 95% CI, -4.27 to -2.95; P < 0.00001), transitional dyspnea index score (mean difference 1.00; 95% CI 0.83 to 1.17; P < 0.00001), and trough FEV1 (mean difference 0.12; 95% CI 0.11 to 0.13; P < 0.0001) indicated significantly greater improvement in the LAMA group than the placebo group. The number of withdrawals due to adverse events in the LAMA group was significantly fewer than that in the placebo group (OR -0.02; 95% CI -0.03 to -0.01; P = 0.002). CONCLUSION: LAMA is superior to placebo due to lower frequency of exacerbations and adverse events, as well as higher trough FEV1, QoL, and dyspnea score for stable COPD.