Digitally monitored inhaled therapy: a 'smart' way to manage severe asthma?

INTRODUCTION: One of the fundamental challenges of managing patients with severe asthma is treatment adherence, particularly with inhaled corticosteroids. Adherence is difficult to measure objectively and poor adherence is associated with worse outcomes. In this study, assess the ability of a 'smart' inhaler to record adherence in severe asthma patients and measure the impact of this on asthma control. METHODS: Consecutive consenting patients meeting criteria for biologics had their existing high-dose ICS/LABA//LAMA combination inhaler/s switched to mometasone/indacaterol/glycopyrronium (114/46/136). Routine clinical data, including blood eosinophils, FeNO, and ACQ-6 scores were collected at baseline and at 4 wk. Adherence was then checked on the Propeller Health app, and good adherence was defined as >80% of prescribed usage. Participants were then followed-up at 12 months to record the proportion of patients who were initiated on biologics. RESULTS: 77 patients (mean [SD] age = 50.4 [15.7] years, 67.5% female [n = 52]) participated. 71 participants were able to use the device and 65% (n = 46) of these attained good asthma control and were not initiated on biologics at 12-month follow-up. Both groups demonstrated a significant reduction in ACQ6 score at follow-up (2.81 vs. 1.92, p < 0.001 and 3.05 vs. 2.60, p < 0.001, respectively), but there was no statistically significant difference in improvement between groups. Patients with optimal adherence also demonstrated a significant reduction in median FeNO at follow-up (47 ppb vs. 40 ppb, p = 0.003). CONCLUSIONS: In severe asthma patients, 'smart' inhalers may represent an effective management tool to improve adherence and asthma control, therefore avoiding the need for patients to commence biological therapies.

Cardiovascular Events According to Inhaler Therapy and Comorbidities in Chronic Obstructive Pulmonary Disease.

Background: COPD coexists with many concurrent comorbidities. Cardiovascular complications are deemed to be major causes of death in COPD. Although inhaler therapy is the main therapeutic intervention in COPD, cardiovascular events accompanying inhaler therapy require further investigation. Therefore, this study aimed to investigate new development of cardiovascular events according to each inhaler therapy and comorbidities. Methods: This study analyzed COPD patients (age ≥ 40 years, N = 199,772) from the Health Insurance Review and Assessment Service (HIRA) database in Korea. The development of cardiovascular events, from the index date to December 31, 2020, was investigated. The cohort was eventually divided into three arms: the LAMA/LABA group (N = 28,322), the ICS/LABA group (N = 11,812), and the triple group (LAMA/ICS/LABA therapy, N = 6174). Results: Multivariable Cox analyses demonstrated that, compared to ICS/LABA therapy, triple therapy was independently associated with the development of ischemic heart disease (HR: 1.22, 95% CI: 1.04-1.43), heart failure (HR: 1.45, 95% CI: 1.14-1.84), arrhythmia (HR: 1.72, 95% CI: 1.41-2.09), and atrial fibrillation/flutter (HR: 2.31, 95% CI: 1.64-3.25), whereas the LAMA/LABA therapy did not show a significant association. Furthermore, emergency room visit during covariate assessment window was independently associated with the development of ischemic heart disease, heart failure, arrhythmia, and atrial fibrillation/flutter (p < 0.05). Conclusion: Our data suggest that cardiovascular risk should be considered in COPD patients receiving triple therapy, despite the confounding bias resulting from disparities in each group.

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.

Efficacy and safety of once-daily single-inhaler triple therapy for mild-to-moderate chronic obstructive pulmonary disease: a study protocol for a randomised and interventional study.

INTRODUCTION: Bronchodilators, including long-acting muscarinic antagonists (LAMA) and long-acting beta 2 agonists (LABA), are the main treatments for chronic obstructive pulmonary disease (COPD). The efficacy of triple therapy (inhaled corticosteroids/LAMA/LABA) has also been reported. However, the effect of triple therapy on patients with mild-to-moderate COPD has not yet been clarified. This study aims to investigate the safety and efficacy of triple therapy, compared with LAMA/LABA combination therapy, for lung function and health-related quality of life in patients with mild-to-moderate COPD and identify baseline characteristics and biomarkers to predict responders and non-responders to triple therapy. METHODS AND ANALYSIS: This is a multicentre, prospective, open-label, randomised, parallel-group study. Mild-to-moderate patients with COPD will be randomised to receive fluticasone furoate/umeclidinium/vilanterol or umeclidinium/vilanterol for 24 weeks. A total of 668 patients will be enrolled from March 2022 to September 2023 from 38 sites in Japan. The primary endpoint is the change in the trough forced expiration volume in 1 s after 12 weeks of treatment. Secondary endpoints are responder rates based on the COPD assessment test score and the St. George's Respiratory Questionnaire total score after 24 weeks of treatment. The safety endpoint is the occurrence of any adverse events. We will also investigate safety in terms of changes in microbial colonisation in sputum and antimycobacterium avium complex antibodies. ETHICS AND DISSEMINATION: The study protocol and informed consent documents were approved by the Saga University Clinical Research Review Board (approval number: CRB7180010). Written informed consent will be obtained from all patients. Recruitment of the patients began in March 2022. The results will be disseminated through scientific peer-reviewed publications and domestic and international medical conferences. TRIAL REGISTRATION NUMBERS: UMIN000046812 and jRCTs031190008.

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.

Open-inhaler versus single-inhaler triple therapy (long-acting muscarinic antagonist, inhaled corticosteroid, and long-acting ß2-agonist) in asthma patients: a narrative review.

OBJECTIVE: To review the evidence for the use of open-inhaler (inhaled corticosteroid [ICS] plus long-acting ß2-agonist [LABA] with separate add-on long-acting muscarinic antagonist [LAMA]) versus single-inhaler triple therapy (ICS/LABA/LAMA combination) and the merits of add-on LAMA to ICS/LABA in patients with uncontrolled asthma. DATA SOURCES: Original research articles were identified from PubMed using the search term "triple therapy asthma." Information was also retrieved from the ClinicalTrials.gov website. STUDY SELECTIONS: Articles detailing the use of add-on LAMA to ICS plus LABA (open-inhaler triple therapy), and closed triple therapy compared with ICS plus LABA dual therapy, addressing patient symptoms, exacerbations, and health-related quality of life. RESULTS: Open-inhaler triple therapy was associated with a significantly reduced incidence of hospitalizations and emergency department visits and a decrease in ICS dose, oral corticosteroids use, and antibiotics use. Exacerbations and acute respiratory events were also reduced. Single-inhaler triple therapy showed a greater improvement in lung function, asthma control, and health status and was noninferior to open-inhaler triple therapy for Asthma Quality of Life Questionnaire scores. Single-inhaler triple therapy may also lead to improved therapy adherence. CONCLUSION: Add-on LAMA to ICS plus LABA (open- or single-inhaler triple therapy) improves the response in patients who remain symptomatic and provides a reasonable alternative to ICS dose escalation in treatment-refractory patients.

Effect of inhaler and topical lavender oil on pain management of arteriovenous fistula cannulation.

BACKGROUND: The recurrent arteriovenous fistula (AVF) intervention in the treatment of hemodialysis induces pain in patients. Lavender oil has analgesic, antimicrobial, and calming effects. This oil is widely used in patients to reduce anxiety and stress associated with pain caused by analgesics. METHOD: The present study is a randomized controlled and experimental clinical trial in which patients (n = 90) who underwent hemodialysis with AVFs were randomly divided into three groups. The intensity of pain was measured in all patients at three different stages during the insertion of arterial needles for hemodialysis: (1) The topical application of 100% lavender essential oil, (2) the inhaler application of 100% lavender essential oil, and (3) no intervention. The placebo (water) was applied to groups 1 and 2. RESULTS: Our findings revealed that the mean pre-application pain scores in hemodialysis patients were 57.58 ± 20.28 in the working group, 48.53 ± 20.23 in the control group, 19.49 ± 15.66 in the post-application group, and 45.33 ± 25.52 in the control group (p < 0.005). The average pain scores after the application of lavender oil were 22.66 ± 15.35 in the inhaler lavender group, 16.33 ± 15.97 in the topical lavender group, and 45.33 ± 25.52 in the control group. CONCLUSIONS: After inhaler and topical application of lavender oil, a significant decrease in the severity of pain was recorded for patients at the time of arterial insertion of needles.

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.

Treatment patterns and cost of exacerbations in patients with chronic obstructive pulmonary disease using multiple inhaler triple therapy in South Korea.

BACKGROUND: Multiple inhaler triple therapy (MITT), comprising inhaled corticosteroids (ICS), long-acting beta-agonists (LABA), and long-acting muscarinic antagonists (LAMA), has been used as an escalation treatment for patients with chronic obstructive pulmonary disease (COPD). However, real-world use of MITT has not been investigated in Asia, including South Korea. This study reports baseline characteristics of patients with COPD initiated on MITT in South Korea, and their treatment patterns. Healthcare resource utilization (HRU) and costs associated with COPD exacerbations following MITT initiation were also assessed. METHODS: This was a retrospective cohort study using the South Korea National Health Insurance database (2014-2018). Included patients were ≥ 40 years, had a COPD diagnosis, were newly initiated on MITT and had ≥ 12 months' data both before (baseline) and after index date (the first day with overlapping supply of all MITT components). Treatment immediately before initiation and immediately following discontinuation of MITT were identified, and proportion of days covered (PDC) by MITT was calculated. HRU and costs (per person per year [PPPY]) associated with exacerbations were identified following MITT initiation; costs were calculated using the average 2020 exchange rate (0.0008 USD/KRW). RESULTS: Among 37,400 patients, the mean age was 69 (SD 10) years and 73% were males; 56% had ≥ 1 COPD exacerbation during the baseline period, with a mean of 2 (SD 5) events/year. ICS/LABA was the most frequent regimen prescribed immediately before initiation (37%) and immediately following discontinuation (41% of 34,264 patients) of MITT. At 3, 6, and 12 months from treatment initiation, mean PDC was 81%, 63% and 49%, respectively; median treatment duration was 102 days. The mean (95% confidence interval [CI]) number of total visits for severe COPD exacerbations was 0.77 PPPY (0.75-0.78); mean PPPY total healthcare costs were 2093 USD. CONCLUSIONS: Patients with COPD in South Korea experienced frequent exacerbations prior to MITT, and PDC by MITT was low. Patients may benefit from early optimization of COPD therapy, and greater emphasis on adherence to inhaled COPD therapy. Severe exacerbations were found to incur substantial costs; treatment alternatives that can reduce the rate of severe exacerbations are likely to minimize healthcare costs.

The effects of breathing exercises and inhaler training in patients with COPD on the severity of dyspnea and life quality: a randomized controlled trial.

BACKGROUND: Severe dyspnea and poor quality of life are common in chronic obstructive pulmonary disease (COPD). The most important reason for this is wrong applications in inhaler treatment. In addition, inhaler treatments that support non-pharmacological methods increase the effectiveness of the drug. The aim of this study was to determine the effects of breathing exercises and inhaler training for chronic obstructive pulmonary disease patients on the severity of dyspnea and life quality. METHODS: The research was a randomized controlled trial. A total of 67 patients with COPD were included. The patients were randomized into two groups. Intervention group 1 were given pursed lip breathing exercise and inhaler training and Intervention group 2 were given only inhaler training. A follow-up after 4 weeks was carried out in both groups. Patient outcomes in both groups were assessed by a COPD assessment test (CAT), the Modified Medical Research Council (mMRC) scale, and the St. George's Respiratory Questionnaire scale (SGRQ). This study followed the CONSORT checklist for randomized controlled trials. In the data analysis, independent t, Mann-Whitney U, ANOVA, Wilcoxon analysis, and Pearson chi-square tests were used. RESULTS: The pursed lips exercise and inhaler drug use skills of patients in both groups increased (p<0.001). The median value of the CAT and mMRC scores were statistically significant for both groups (p<0.005). The mean of life quality scores of patients in both groups decreased, and this result was found to be statistically significant in all sub-dimensions and in the total scale score for both groups (p<0.001). Although the increase in the quality of life and the decrease in the severity of dyspnea of the patients in both groups were significant, neither group was superior to the other (p>0.05). CONCLUSIONS: As a result of the study, it was found that the skill of using the inhaler and the life quality of the patients increased, and the severity of dyspnea decreased. Supporting inhaler treatments with non-pharmacological methods can increase drug efficacy and quality of life. TRIAL REGISTRATION: ClinicalTrials.gov NCT04739488. Registered on 21 Feb 2021.

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.

Clinical Characteristics, Treatment Persistence, and Outcomes Among Patients With COPD Treated With Single- or Multiple-Inhaler Triple Therapy: A Retrospective Analysis in Spain.

BACKGROUND: COPD is a leading cause of death and disability. COPD therapy goals include reducing exacerbations and improving symptom control. Single-inhaler triple therapy (SITT) or multiple-inhaler triple therapy (MITT) is indicated for patients with frequent exacerbations despite bronchodilator therapy. No available evidence compares SITT vs MITT in Spain in terms of treatment persistence, exacerbations, and other outcomes. RESEARCH QUESTION: Do COPD patients in Spain initiating SITT vs MITT have improved persistence, exacerbations, and health care resource utilization? STUDY DESIGN AND METHODS: This real-world, observational, retrospective cohort study analyzed electronic health records in the Spanish National Healthcare System BIG-PAC database to identify COPD patients aged ≥ 40 years initiating SITT or MITT (using two or three inhalers) between June 1, 2018 and December 31, 2019. Comparative data on persistence (allowing up to 60 days without prescription refill), exacerbation rates, and health care resource utilization and costs during 12-month follow-up were analyzed. Multivariate adjusted analyses were performed. RESULTS: Eligible patients (N = 4,625) initiating SITT (n = 1,011) or MITT (n = 3,614) had a mean age of 70.9 years; most were male (73.9%) with mainly moderate (62.0%) or severe (26.5%) airflow limitation. Between-cohort baseline characteristics were similar. At 12-month follow-up, SITT patients had higher persistence (hazard ratio [HR] = 1.37; 95% CI = 1.22-1.53; P < .001), reduced risk of exacerbations (HR = 0.68; 95% CI = 0.61-0.77; P = .001), and lower all-cause mortality risk (HR = 0.67; 95% CI = 0.63-0.71, P = .027), compared with MITT patients. SITT was associated with significantly reduced health care resource use (mean annual cost savings: €403 vs MITT). For both SITT and MITT, persistence was associated with improved exacerbation rates vs nonpersistence, and substantial adjusted mean annual cost savings (€2,115 and €2,700, respectively). INTERPRETATION: Patients initiating SITT had a clinically relevant improvement in persistence leading to reductions in mortality, incidence of exacerbations, and health care resource use with consequent mean cost savings.

A randomized clinical trial to assess the effect of zinc and vitamin D supplementation in addition to hypertonic saline on treatment of acute bronchiolitis.

BACKGROUND: Bronchiolitis, the most common cause of hospitalization in infancy has not yet a definitive treatment. This study was conducted to assess the effect of Zinc and vitamin D on treatment of infants with bronchiolitis. METHODS: In this double blind, randomized clinical trial, 94 infants aged 2 to 23 months, admitted in Mousavi Hospital in Zanjan, Iran, with the diagnosis of acute bronchiolitis were randomly assigned into 3 groups. The control group was only treated with hypertonic saline. The two case groups received either 100 unit/kg/day of Vitamin D or 20 mg/day of zinc in addition to hypertonic saline. Wheezing, duration of hospital stay, cough, cyanosis, respiratory distress and the respiratory rate in the first, third and seventh day of hospitalization were evaluated. RESULTS: There was no significant difference between groups in terms of age, sex, weight, passive smoking, wheezing, oxygen saturation, cyanosis and type of delivery. On the third day of hospitalization, the respiratory rate/min in the control group, the groups receiving vitamin D and zinc were 45.2 ± 10.7, 37.8 ± 3.9 and 41.1 ± 9.1 respectively and the result of repeated measure analysis didn't show any significant difference between the 3 groups (P = 0.562). Duration of hospitalization in the group receiving Vitamin D or zinc and in controls were 4.2 ± 2.6, 4.4 ± 2.2 and 5.1 ± 2.4 days respectively and this difference was not significant. Zinc receiving patients did not differ from the control group regarding to respiratory rate, cyanosis and wheezing. CONCLUSION: Vitamin D or zinc administration was not effective in reducing respiratory rate in children with bronchiolitis. Trial registration This project was approved by the Institutional Ethics Committee (IR, ZUMS.REC.1396.50), and registered on IRCT (IRCT20131217015835N7).

Characteristics of New Users of Single- and Multiple-Inhaler Triple Therapy for COPD in Primary Care in England.

Purpose: Inhaled triple therapy is recommended for patients with chronic obstructive pulmonary disease (COPD) who have poorly controlled symptoms and to reduce the risk of exacerbations. This study assessed the clinical characteristics of new users of single- and multiple-inhaler triple therapy (SITT and MITT) treated in a primary care setting in England. Patients and Methods: This cross-sectional, observational study used data from an electronic health record database (CPRD Aurum) of COPD patients registered with a primary care practice in England, with linkage to a secondary care database. Patients were required to have initiated a new triple therapy (index) between November 2017 and November 2018 and have ≥12 months of available medical history prior to the index date. Results: In total, 3536 patients initiated fluticasone furoate, umeclidinium, and vilanterol (FF/UMEC/VI) SITT for the first time: 65% had a Medical Research Council (MRC) dyspnea score ≥3, 45% had forced expiratory volume in 1 second (FEV1)% predicted <50%, and 64% had a moderate or severe exacerbation in the previous 12 months. The majority (83%) of new FF/UMEC/VI users had a history of MITT use. Immediately prior to FF/UMEC/VI initiation, 46% received MITT, 25% received an inhaled corticosteroid (ICS)/long-acting ß2-agonist (LABA), 12% received long-acting muscarinic antagonist (LAMA)/LABA, and 14% stepped up directly from LAMA monotherapy. A second cohort of 6540 patients initiated triple therapy (SITT or MITT) for the first time. COPD severity (airflow limitation, exacerbation history) was worse among patients initiating SITT versus MITT. In the 12 months before triple-therapy initiation, ICS/LABA was the most common treatment; a step up from LAMA/LABA was more common among patients initiating FF/UMEC/VI (34%) or beclomethasone/formoterol/glycopyrronium bromide SITT (25%) than MITT (14%). Conclusion: First-time triple therapy was frequently initiated in patients with COPD inadequately controlled on maintenance therapy. General practitioners in England generally identify appropriate patients who require initiation of triple therapy.

A single inhaler triple therapy fluticasone furoate/umeclidinium/vilanterol for the treatment of COPD.

INTRODUCTION: Single inhaler triple therapy (SITT) with an inhaled corticosteroid, a long-acting ß2-agonist, and a long-acting muscarinic antagonist is an effective and attractive therapeutic option codified in the recommendations of guidelines and treatment strategies for the management of COPD. AREAS COVERED: The preclinical and clinical development in COPD of fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) SITT and its use in the real world. EXPERT OPINION: Findings from phase III/IV trials and the use of FF/UMEC/VI in the real-world setting support the view that it may be a useful, safe, and cost-effective option for the maintenance treatment of COPD, especially when dealing with patients who are not adequately controlled with dual ICS/LABA or LAMA/LABA therapy. Only direct head-to-head comparisons will be able to establish whether FF/UMEC/VI may be preferable to the other SITTs approved for COPD due to its pharmacokinetic and pharmacodynamic characteristics and especially the fact that it is the only one that can be taken once-daily. In addition, there is a need for further studies, especially in the real world, to optimize the positioning of FF/UMEC/VI in the treatment of COPD, also considering the availability of FF/VI and UMEC/VI and the need for better differentiation between the three treatments.

Adherence and persistence to once-daily single-inhaler versus multiple-inhaler triple therapy among patients with chronic obstructive pulmonary disease in the USA: A real-world study.

BACKGROUND: Triple therapy comprising an inhaled corticosteroid, long-acting muscarinic antagonist, and long-acting ß2 agonist (ICS/LAMA/LABA) is recommended for chronic obstructive pulmonary disease (COPD) patients at risk of exacerbation. Multiple-inhaler triple therapy (MITT) is associated with poor adherence and persistence; however, these outcomes have not been evaluated for single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI). METHODS: This retrospective analysis of the IQVIA PharMetrics Plus claims database identified patients with COPD initiating triple therapy between 18 September 2017 and 30 June 2019. The first date of single-inhaler FF/UMEC/VI dispensing, or first day of overlapping ICS, LAMA, and LABA medications for MITT users, defined the index date. Patients were ≥40 years, had ≥12 months of continuous insurance coverage pre-index (baseline) and ≥6 months' coverage post-index; those with MITT during baseline were excluded. Inverse probability weighting was used to balance baseline characteristics. Adherence was assessed using proportion of days covered (PDC) and was evaluated using linear and log-binomial models. Persistence (non-persistence identified as >30-day gap between fills) was evaluated using Cox models. RESULTS: 9942 patients (FF/UMEC/VI: 2782; MITT: 7160) were included. Adherence was significantly higher for FF/UMEC/VI versus MITT users (mean PDC, 0.66 vs. 0.48; p < 0.001), and FF/UMEC/VI users were twice as likely to be adherent (PDC ≥0.8) than MITT users (46.5% vs. 22.3%; risk ratio [95% CI]: 2.08 [1.85-2.30]; p < 0.001). After 12 months, significantly more FF/UMEC/VI users persisted on therapy than MITT users (35.7% vs. 13.9%; hazard ratio [95% CI]: 1.91 [1.81-2.01]; p < 0.001). CONCLUSIONS: COPD patients initiating single-inhaler FF/UMEC/VI had significantly improved adherence and persistence compared with MITT.

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).

Medium-dose ICS-containing FDCs reduce all-cause mortality in COPD patients: an in-depth analysis of dual and triple therapies.

OBJECTIVES: The recent publication of additional data retrieval for patients missing week 52 vital status in the original analyses of the ETHOS study provides the urgent need of updating previous network meta-analyses (NMA) to produce stronger evidence on mortality in patients receiving dual and triple FDCs according with the level of ICS dose. METHODS: A NMA was performed to compare the effect of ICS/LABA/LAMA, ICS/LABA, and LABA/LAMA FDCs administered via the same inhaler device in COPD patients. The number need to treat (NNT) was also calculated. RESULTS: When considering on-treatment all-cause of death (analyzed patients: 18,864), MD ICS/LABA/LAMA and MD ICS/LABA FDCs significantly reduced the risk of mortality vs. LABA/LAMA FDC (RR 0.59 95%CrI 0.35-0.97 and 0.61 95%CrI 0.38-0.99 respectively, P < 0.05); NNT ranged between 123 and 129. MD ICS/LABA/LAMA FDC also significantly reduced the risk of adjudicated cardiovascular mortality vs. LABA/LAMA FDC (RR 0.44 95%CI 0.19-0.97, P < 0.05). Low-dose (LD) ICS/LABA FDC did not significantly modulate mortality. CONCLUSION: MD ICS/LABA/LAMA and MD ICS/LABA FDCs were effective in reducing on-treatment all-cause of death, with MD ICS/LABA/LAMA FDC being effective also against adjudicated cardiovascular mortality. The protection against mortality was related with the level of ICS dose in the FDCs.

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 .