The effect of inhaler prescription on the development of lung cancer in COPD: a nationwide population-based study.

BACKGROUND: COPD is associated with the development of lung cancer. A protective effect of inhaled corticosteroids (ICS) on lung cancer is still controversial. Hence, this study investigated the development of lung cancer according to inhaler prescription and comorbidties in COPD. METHODS: A retrospective cohort study was conducted based on the Korean Health Insurance Review and Assessment Service database. The development of lung cancer was investigated from the index date to December 31, 2020. This cohort included COPD patients (≥ 40 years) with new prescription of inhalers. Patients with a previous history of any cancer during screening period or a switch of inhaler after the index date were excluded. RESULTS: Of the 63,442 eligible patients, 39,588 patients (62.4%) were in the long-acting muscarinic antagonist (LAMA) and long-acting ß2-agonist (LABA) group, 22,718 (35.8%) in the ICS/LABA group, and 1,136 (1.8%) in the LABA group. Multivariate analysis showed no significant difference in the development of lung cancer according to inhaler prescription. Multivariate analysis, adjusted for age, sex, and significant factors in the univariate analysis, demonstrated that diffuse interstitial lung disease (DILD) (HR = 2.68; 95%CI = 1.86-3.85), a higher Charlson Comorbidity Index score (HR = 1.05; 95%CI = 1.01-1.08), and two or more hospitalizations during screening period (HR = 1.19; 95%CI = 1.01-1.39), along with older age and male sex, were independently associated with the development of lung cancer. CONCLUSION: Our data suggest that the development of lung cancer is not independently associated with inhaler prescription, but with coexisting DILD, a higher Charlson Comorbidity Index score, and frequent hospitalization.

Long-acting B-2 agonists (LABA) or long-acting muscarinic antagonists (LAMA): which one may be the first option in group A COPD patients?

INTRODUCTION: Long-acting muscarinic antagonists (LAMA) or beta-2 agonists (LABA) have been recommended for symptom control in group A COPD patients as a first-line bronchodilator treatment in GOLD guidelines. However, there is no mention of priority/superiority between the two treatment options. We aimed to compare the effectiveness of these treatments in this group. METHODS: The study cohort was formed of all subjects from six pulmonology clinics with an initial diagnosis of COPD who were new users of a LAMA or LABA from January 2020 to December 2021. Seventy-six group A COPD patients, in whom LABA or LAMA therapy had been started in the last 1 month as a first-line treatment, were included in our study. Participants were evaluated with spirometry, COPD Assessment Test (CAT), mMRC scale, and St. George Respiratory Questionnaire (SGRQ) for three times (baseline, 6-12th months). RESULTS: There were 76 group A COPD patients with LAMA (67.1%) and LABA (32.9%). The number of patients who improved in CAT score at the end of the first year was significantly higher in patients using LAMA than those using LABA (p = 0.022); the improvement at minimum clinically important difference (MCID) in CAT score of LAMA group at 1st year was also significant (p = 0.044). SGRQ total and impact scores were found to be statistically lower at 1st year compared to baseline in patients using LAMA (p = 0.010 and 0.006, respectively). Significant improvement was detected in CAT and SGRQ scores at the 6th month visit in the LAMA group having emphysema (p = 0.032 and 0.002, respectively). CONCLUSION: According to significant improvements in CAT and SGRQ score, LAMA may be preferred over LABA as a bronchodilator agent in group A COPD patients, especially in emphysema-dominant phenotype.

SABINA + Hong Kong: a territory wide study of prescribing trends and outcomes associated with the use of short-acting ß2 agonists in the Chinese population.

BACKGROUND: Excessive use of short-acting ß2 agonists (SABA) in patients with asthma continues to be a notable concern due to its link to higher mortality rates. Global relevance of SABA overuse in asthma management cannot be understated, it poses significant health risk to patients with asthma and imposes burden on healthcare systems. This study, as part of global SABINA progamme, aimed to describe the prescribing patterns and clinical outcomes associated with SABA use in the Chinese population. METHODS: Retrospective cohort study was conducted using anonymized electronic healthcare records of Clinical Data Analysis and Reporting System (CDARS) from Hong Kong Hospital Authority (HA). Patients newly diagnosed with asthma between 2011 and 2018 and aged ≥12 years were included, stratified by SABA use (≤2, 3-6, 7-10, or ≥11 canisters/year) during one-year baseline period since asthma diagnosis date. Patients were followed up from one-year post-index until earliest censoring of events: outcome occurrence and end of study period (31 December 2020). Cox proportional regression and negative binomial regression were used to estimate the mortality risk and frequency of hospital admissions associated with SABA use respectively, after adjusting for age, sex, Charlson Comorbidity Index (CCI), and inhaled corticosteroid (ICS) dose. Outcomes include all-cause, asthma-related, and respiratory-related mortality, frequency of hospital admissions for any cause, and frequency of hospital admissions due to asthma. RESULTS: 17,782 patients with asthma (mean age 46.7 years, 40.8% male) were included and 59.1% of patients were overusing SABA (≥ 3 canisters per year). Each patient was prescribed a median of 5.61 SABA canisters/year. SABA overuse during baseline period was associated with higher all-cause mortality risk compared to patients with ≤2 canisters/year. Association was dose-dependent, highest risk in those used ≥11 canisters/year (adjusted hazard ratio: 1.42, 95% CI: 1.13, 1.79) and 3-6 canisters/year (adjusted hazard ratio: 1.22, 95% CI: 1.00, 1.50). Higher SABA prescription volume associated with increased frequency of hospital admissions with greatest risk observed in 7-10 canisters/year subgroup (adjusted rate ratio: 4.81, 95% CI: 3.66, 6.37). CONCLUSIONS: SABA overuse is prevalent and is associated with increased all-cause mortality risk and frequency of hospital admissions among the patients with asthma in Hong Kong.

Triple Inhaled Therapy at Two Glucocorticoid Doses in Moderate-to-Very-Severe COPD.

BACKGROUND: Triple fixed-dose regimens of an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting ß2-agonist (LABA) for chronic obstructive pulmonary disease (COPD) have been studied at single dose levels of inhaled glucocorticoid, but studies at two dose levels are lacking. METHODS: In a 52-week, phase 3, randomized trial to evaluate the efficacy and safety of triple therapy at two dose levels of inhaled glucocorticoid in patients with moderate-to-very-severe COPD and at least one exacerbation in the past year, we assigned patients in a 1:1:1:1 ratio to receive twice-daily inhaled doses of triple therapy (inhaled glucocorticoid [320 µg or 160 µg of budesonide], a LAMA [18 µg of glycopyrrolate], and a LABA [9.6 µg of formoterol]) or one of two dual therapies (18 µg of glycopyrrolate plus 9.6 µg of formoterol or 320 µg of budesonide plus 9.6 µg of formoterol). The primary end point was the annual rate (the estimated mean number per patient per year) of moderate or severe COPD exacerbations, as analyzed in the modified intention-to-treat population with the use of on-treatment data only. RESULTS: The modified intention-to-treat population comprised 8509 patients. The annual rates of moderate or severe exacerbations were 1.08 in the 320-µg-budesonide triple-therapy group (2137 patients), 1.07 in the 160-µg-budesonide triple-therapy group (2121 patients), 1.42 in the glycopyrrolate-formoterol group (2120 patients), and 1.24 in the budesonide-formoterol group (2131 patients). The rate was significantly lower with 320-µg-budesonide triple therapy than with glycopyrrolate-formoterol (24% lower: rate ratio, 0.76; 95% confidence interval [CI], 0.69 to 0.83; P<0.001) or budesonide-formoterol (13% lower: rate ratio, 0.87; 95% CI, 0.79 to 0.95; P = 0.003). Similarly, the rate was significantly lower with 160-µg-budesonide triple therapy than with glycopyrrolate-formoterol (25% lower: rate ratio, 0.75; 95% CI, 0.69 to 0.83; P<0.001) or budesonide-formoterol (14% lower: rate ratio, 0.86; 95% CI, 0.79 to 0.95; P = 0.002). The incidence of any adverse event was similar across the treatment groups (range, 61.7 to 64.5%); the incidence of confirmed pneumonia ranged from 3.5 to 4.5% in the groups that included inhaled glucocorticoid use and was 2.3% in the glycopyrrolate-formoterol group. CONCLUSIONS: Triple therapy with twice-daily budesonide (at either the 160-µg or 320-µg dose), glycopyrrolate, and formoterol resulted in a lower rate of moderate or severe COPD exacerbations than glycopyrrolate-formoterol or budesonide-formoterol. (Funded by AstraZeneca, ETHOS ClinicalTrials.gov number, NCT02465567.).

Step-Up Therapy in Black Children and Adults with Poorly Controlled Asthma.

BACKGROUND: Morbidity from asthma is disproportionately higher among black patients than among white patients, and black patients constitute the minority of participants in trials informing treatment. Data indicate that patients with inadequately controlled asthma benefit more from addition of a long-acting beta-agonist (LABA) than from increased glucocorticoids; however, these data may not be informative for treatment in black patients. METHODS: We conducted two prospective, randomized, double-blind trials: one involving children and the other involving adolescents and adults. In both trials, the patients had at least one grandparent who identified as black and had asthma that was inadequately controlled with low-dose inhaled glucocorticoids. We compared combinations of therapy, which included the addition of a LABA (salmeterol) to an inhaled glucocorticoid (fluticasone propionate), a step-up to double to quintuple the dose of fluticasone, or both. The treatments were compared with the use of a composite measure that evaluated asthma exacerbations, asthma-control days, and lung function; data were stratified according to genotypic African ancestry. RESULTS: When quintupling the dose of fluticasone (to 250 µg twice a day) was compared with adding salmeterol (50 µg twice a day) and doubling the fluticasone (to 100 µg twice a day), a superior response occurred in 46% of the children with quintupling the fluticasone and in 46% of the children with doubling the fluticasone and adding salmeterol (P = 0.99). In contrast, more adolescents and adults had a superior response to added salmeterol than to an increase in fluticasone (salmeterol-low-dose fluticasone vs. medium-dose fluticasone, 49% vs. 28% [P = 0.003]; salmeterol-medium-dose fluticasone vs. high-dose fluticasone, 49% vs. 31% [P = 0.02]). Neither the degree of African ancestry nor baseline biomarkers predicted a superior response to specific treatments. The increased dose of inhaled glucocorticoids was associated with a decrease in the ratio of urinary cortisol to creatinine in children younger than 8 years of age. CONCLUSIONS: In contrast to black adolescents and adults, almost half the black children with poorly controlled asthma had a superior response to an increase in the dose of an inhaled glucocorticoid and almost half had a superior response to the addition of a LABA. (Funded by the National Heart, Lung, and Blood Institute; BARD ClinicalTrials.gov number, NCT01967173.).

Controlled Trial of Budesonide-Formoterol as Needed for Mild Asthma.

BACKGROUND: In double-blind, placebo-controlled trials, budesonide-formoterol used on an as-needed basis resulted in a lower risk of severe exacerbation of asthma than as-needed use of a short-acting ß2-agonist (SABA); the risk was similar to that of budesonide maintenance therapy plus as-needed SABA. The availability of data from clinical trials designed to better reflect clinical practice would be beneficial. METHODS: We conducted a 52-week, randomized, open-label, parallel-group, controlled trial involving adults with mild asthma. Patients were randomly assigned to one of three treatment groups: albuterol (100 µg, two inhalations from a pressurized metered-dose inhaler as needed for asthma symptoms) (albuterol group); budesonide (200 µg, one inhalation through a Turbuhaler twice daily) plus as-needed albuterol (budesonide maintenance group); or budesonide-formoterol (200 µg of budesonide and 6 µg of formoterol, one inhalation through a Turbuhaler as needed) (budesonide-formoterol group). Electronic monitoring of inhalers was used to measure medication use. The primary outcome was the annualized rate of asthma exacerbations. RESULTS: The analysis included 668 of 675 patients who underwent randomization. The annualized exacerbation rate in the budesonide-formoterol group was lower than that in the albuterol group (absolute rate, 0.195 vs. 0.400; relative rate, 0.49; 95% confidence interval [CI], 0.33 to 0.72; P<0.001) and did not differ significantly from the rate in the budesonide maintenance group (absolute rate, 0.195 in the budesonide-formoterol group vs. 0.175 in the budesonide maintenance group; relative rate, 1.12; 95% CI, 0.70 to 1.79; P = 0.65). The number of severe exacerbations was lower in the budesonide-formoterol group than in both the albuterol group (9 vs. 23; relative risk, 0.40; 95% CI, 0.18 to 0.86) and the budesonide maintenance group (9 vs. 21; relative risk, 0.44; 95% CI, 0.20 to 0.96). The mean (±SD) dose of inhaled budesonide was 107±109 µg per day in the budesonide-formoterol group and 222±113 µg per day in the budesonide maintenance group. The incidence and type of adverse events reported were consistent with those in previous trials and with reports in clinical use. CONCLUSIONS: In an open-label trial involving adults with mild asthma, budesonide-formoterol used as needed was superior to albuterol used as needed for the prevention of asthma exacerbations. (Funded by AstraZeneca and the Health Research Council of New Zealand; Novel START Australian New Zealand Clinical Trials Registry number, ACTRN12615000999538.).

Short-acting ß2-agonist prescription patterns in patients with asthma in Turkey: results from SABINA III.

BACKGROUND: Over-reliance on short-acting ß2-agonists (SABAs) is associated with poor asthma outcomes. However, the extent of SABA use in Turkey is unclear owing to a lack of comprehensive healthcare databases. Here, we describe the demographics, disease characteristics and treatment patterns from the Turkish cohort of the SABA use IN Asthma (SABINA) III study. METHODS: This observational, cross-sectional study included patients aged ≥ 12 years with asthma from 24 centres across Turkey. Data on sociodemographics, disease characteristics and asthma treatments were collected using electronic case report forms. Patients were classified by investigator-defined asthma severity (guided by the 2017 Global Initiative for Asthma [GINA]) and practice type (primary/specialist care). The primary objective was to describe SABA prescription patterns in the 12 months prior to the study visit. RESULTS: Overall, 579 patients were included (mean age [standard deviation; SD]: 47.4 [16.1] years; 74.3% female), all of whom were treated by specialists. Most patients had moderate-to-severe asthma (82.7%, GINA steps 3-5), were overweight or obese (70.5%), had high school or university/post-graduate education (51.8%) and reported fully reimbursed healthcare (97.1%). The mean (SD) asthma duration was 12.0 (9.9) years. Asthma was partly controlled/uncontrolled in 56.3% of patients, and 46.5% experienced ≥ 1 severe exacerbation in the preceding 12 months. Overall, 23.9% of patients were prescribed ≥ 3 SABA canisters in the previous 12 months (considered over-prescription); 42.9% received no SABA prescriptions. As few patients had mild asthma, only 5.7% were prescribed SABA monotherapy. Therefore, most patients (61.5%) were prescribed SABA in addition to maintenance therapy, with 42.8% receiving ≥ 3 SABA canisters in the previous 12 months. Inhaled corticosteroids (ICS), ICS + a long-acting ß-agonist fixed-dose combination and oral corticosteroids were prescribed to 14.5%, 88.3% and 28.5% of all patients, respectively. Additionally, 10.2% of patients purchased SABA over the counter, of whom 27.1% purchased ≥ 3 canisters in the preceding 12 months. CONCLUSIONS: Despite all patients being treated by specialists and most receiving fully reimbursed healthcare, nearly a quarter of patients received prescriptions for ≥ 3 SABA canisters in the previous 12 months. This highlights a public health concern and emphasizes the need to align clinical practices with the latest evidence-based recommendations.

Extrafine triple therapy and asthma exacerbation seasonality: TRIMARAN and TRIGGER post hoc analyses.

BACKGROUND: Previous studies have shown seasonal variation in asthma exacerbations, peaking over the winter months. A single-inhaler triple therapy containing extrafine formulations of the inhaled corticosteroid (ICS) beclomethasone dipropionate (BDP), long-acting ß2-agonist formoterol fumarate (FF), and long-acting muscarinic antagonist glycopyrronium (G) is in development for asthma. OBJECTIVE: We sought to evaluate whether calendar season impacted the relative effect of BDP/FF/G versus BDP/FF on moderate and severe asthma exacerbations. METHODS: TRIMARAN and TRIGGER were double-blind 52-week studies comparing BDP/FF/G with BDP/FF (TRIMARAN medium-dose ICS; TRIGGER high-dose) in adults with uncontrolled asthma (Asthma Control Questionnaire-7 score ≥1.5), prebronchodilator FEV1 less than 80% predicted, history of 1 or more asthma exacerbation, who had been receiving ICS/long-acting ß2-agonist for at least 4 weeks before entry. Moderate and severe asthma exacerbations were captured throughout each study. In these post hoc analyses, the annual moderate and severe exacerbation rate was calculated for each month, with rate ratios determined from events grouped by season. RESULTS: In patients who received BDP/FF alone, there was a marked seasonal effect on the occurrence of asthma exacerbations, with the rate highest in the winter months. However, the addition of the long-acting muscarinic antagonist component to BDP/FF reduced this seasonal variation, especially during the winter, such that the relative effect of BDP/FF/G versus BDP/FF was greatest in the winter (significant 20.3% reduction [P = .0008]). Reductions in the other seasons ranged between 8.6% and 12.0%. CONCLUSIONS: These post hoc analyses indicate that inhaled triple therapy with extrafine BDP/FF/G reduces seasonal peaks in moderate and severe exacerbations, and confirm the overall utility of adding long-acting muscarinic antagonist to ICS/long-acting ß2-agonist in the management of asthma.

Prolonged ß2-adrenergic agonist treatment improves glucose homeostasis in diet-induced obese UCP1-/- mice.

Prolonged supplementation with the ß2-agonist clenbuterol improves glucose homeostasis in diabetic rodents, likely via ß2-adrenoceptor (ß2-AR)-mediated effects in the skeletal muscle and liver. However, since rodents have, in contrast to-especially diabetic-humans, substantial quantities of brown adipose tissue (BAT) and clenbuterol has affinity to ß1- and ß3-ARs, the contribution of BAT to these improvements is unclear. Therefore, we investigated clenbuterol-mediated improvements in glucose homeostasis in uncoupling protein 1-deficient (UCP1-/-) mice, lacking thermogenic BAT, versus wild-type (WT) mice. Anesthetized WT and UCP1-/- C57Bl/6 mice were injected with saline or clenbuterol and whole body oxygen consumption was measured. Furthermore, male WT and UCP1-/- C57Bl/6 mice were subjected to 17-wk of chow feeding, high-fat feeding, or high-fat feeding with clenbuterol treatment between weeks 13 and 17. Body composition was measured weekly with MRI. Oral glucose tolerance and insulin tolerance tests were performed in week 15 and 17, respectively. Clenbuterol increased oxygen consumption approximately twofold in WT mice. This increase was blunted in UCP1-/- mice, indicating clenbuterol-mediated activation of BAT thermogenesis. High-fat feeding induced diabetogenic phenotypes in both genotypes. However, low-dose clenbuterol treatment for 2 wk significantly reduced fasting blood glucose by 12.9% in WT and 14.8% in UCP1-/- mice. Clenbuterol treatment improved glucose and insulin tolerance in both genotypes compared with HFD controls and normalized to chow-fed control mice independent of body mass and composition alterations. Clenbuterol improved whole body glucose homeostasis independent of UCP1. Given the low human abundancy of BAT, ß2-AR agonist treatment provides a potential novel route for glucose disposal in diabetic humans.NEW & NOTEWORTHY Improvements in whole body glucose homeostasis of rodents upon prolonged ß2-adrenergic agonist supplementation could potentially be attributed to UCP1-mediated BAT thermogenesis. Indeed, we show that acute injection with the ß2-AR agonist clenbuterol induces BAT activation in mice. However, we also demonstrate that prolonged clenbuterol supplementation robustly improves whole body glucose and insulin tolerance in a similar way in both DIO WT and UCP1-/- mice, indicating that ß2-AR agonist supplementation improves whole body glucose homeostasis independent of UCP1-mediated BAT thermogenesis.

Time-to-treatment window and cross-sex potential of ß2-adrenergic receptor-induced mitochondrial biogenesis-mediated recovery after spinal cord injury.

Mitochondrial dysfunction is a well-characterized consequence of spinal cord injury (SCI). We previously reported that treatment with the FDA-approved ß2-adrenergic receptor agonist formoterol beginning 8 h post-SCI induces mitochondrial biogenesis (MB) and improves body composition and locomotor recovery in female mice. To determine the time-to-treatment window of formoterol, female mice were subjected to 80 kdyn contusion SCI and daily administration of vehicle or formoterol (0.3 mg/kg) beginning 24 h after injury. This delayed treatment paradigm improved body composition in female mice by 21 DPI, returning body weight to pre-surgery weight and restoring gastrocnemius mass to sham levels; however, there was no effect on locomotor recovery, as measured by the Basso-Mouse Scale (BMS), or lesion volume. To assess the cross-sex potential of formoterol, injured male mice were treated with vehicle or formoterol (0.3 or 1.0 mg/kg) beginning 8 h after SCI. Formoterol also improved body composition post-SCI in male mice, restoring body weight and muscle mass regardless of dose. Interestingly, however, improved BMS scores and decreased lesion volume was observed only in male mice treated with 0.3 mg/kg. Additionally, 0.3 mg/kg formoterol induced MB in the gastrocnemius and injured spinal cord, as evidenced by increased MB protein expression and mitochondrial number. These data indicate that formoterol treatment improves recovery post-SCI in both male and female mice in a dose- and initiation time-dependent manner. Furthermore, formoterol-induced functional recovery post-SCI is not directly associated with peripheral effects, such as muscle mass and body weight.

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

BACKGROUND: Recently, the addition of inhaled corticosteroid (ICS) to long-acting muscarinic antagonist (LAMA) and long-acting beta-agonist (LABA) combination therapy has been recommended for patients with COPD who have severe symptoms and a history of exacerbations because it reduces the exacerbations. In addition, a reducing effect on mortality has been shown by this treatment. However, the evidence is mainly based on one large randomized controlled trial IMPACT study, and it remains unclear whether the ICS add-on treatment is beneficial or not. Recently, a large new ETHOS trial has been performed to clarify the ICS add-on effects. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety including ETHOS trial. METHODS: We searched relevant randomized control trials (RCTs) and analyzed the exacerbations, quality of life (QOL), dyspnea symptom, lung function and adverse events including pneumonia and mortality, as the outcomes of interest. RESULTS: We identified a total of 6 RCTs in ICS add-on protocol (N = 13,579). ICS/LAMA/LABA treatment (triple therapy) significantly decreased the incidence of exacerbations (rate ratio 0.73, 95% CI 0.64-0.83) and improved the QOL score and trough FEV1 compared to LAMA/LABA. In addition, triple therapy significantly improved the dyspnea score (mean difference 0.33, 95% CI 0.18-0.48) and mortality (odds ratio 0.66, 95% CI 0.50-0.87). However, triple therapy showed a significantly higher incidence of pneumonia (odds ratio 1.52, 95% CI 1.16-2.00). In the ICS-withdrawal protocol including 2 RCTs, triple therapy also showed a significantly better QOL score and higher trough FEV1 than LAMA/LABA. Concerning the trough FEV1, QOL score and dyspnea score in both protocols, the differences were less than the minimal clinically important difference. CONCLUSION: Triple therapy causes a higher incidence of pneumonia but is a more preferable treatment than LAMA/LABA due to the lower incidence of exacerbations, higher trough FEV1 and better QOL score. In addition, triple therapy is also superior to LABA/LAMA due to the lower mortality and better dyspnea score. However, these results should be only applied to patients with symptomatic moderate to severe COPD and a history of exacerbations. CLINICAL TRIAL REGISTRATION: PROSPERO; CRD42020191978.

Prevalence of overuse of short-acting beta-2 agonists (SABA) and associated factors among patients with asthma in Germany.

BACKGROUND: Overuse of short-acting beta-2 agonists (SABA), which do not treat the underlying inflammation of asthma, is linked to poor clinical outcomes such as increased exacerbation risk. This study, as part of the SABINA program, estimated the prevalence of SABA overuse and associated variables in outpatients in Germany. METHODS: This retrospective study used anonymized electronic healthcare data from the Disease Analyzer database (IQVIA). A total of 15,640 patients aged ≥ 12 years with asthma who received ≥ 1 SABA prescription(s) between July 2017 and June 2018 in 924 general physician and 22 pneumologist (PN) practices were included. SABA overuse was defined as ≥ 3 prescribed inhalers (~ 200 puffs each) during the study period. The associations between SABA overuse and physician specialty, Global Initiative for Asthma (GINA) steps (based on asthma medications), age, sex, and inhaled corticosteroid (ICS)/long-acting beta agonist (LABA) use were estimated using multivariable regression for patients with probable moderate (GINA step 2) and probable severe (GINA steps 3-5) asthma. RESULTS: Annually, 36% of all patients (GINA steps 1-5) in general and 38% in PN practices received ≥ 3 SABA inhalers. The risk of SABA overuse was 14% higher in patients treated by a general practitioner vs. a PN; 34% and 85% higher in GINA steps 4 and 5, respectively, vs. GINA step 3; and 40% higher in male vs. female patients. CONCLUSIONS: SABA overuse is prevalent among patients with asthma across all GINA steps in Germany, which may indicate suboptimal asthma control. Further studies are needed to investigate the reasons behind SABA overuse.

Efficacy of umeclidinium/vilanterol according to the degree of reversibility of airflow limitation at screening: a post hoc analysis of the EMAX trial.

BACKGROUND: In patients with chronic obstructive pulmonary disease (COPD), the relationship between short-term bronchodilator reversibility and longer-term response to bronchodilators is unclear. Here, we investigated whether the efficacy of long-acting bronchodilators is associated with reversibility of airflow limitation in patients with COPD with a low exacerbation risk not receiving inhaled corticosteroids. METHODS: The double-blind, double-dummy EMAX trial randomised patients to umeclidinium/vilanterol 62.5/25 µg once daily, umeclidinium 62.5 µg once daily, or salmeterol 50 µg twice daily. Bronchodilator reversibility to salbutamol was measured once at screening and defined as an increase in forced expiratory volume in 1 s (FEV1) of ≥ 12% and ≥ 200 mL 10-30 min post salbutamol. Post hoc, fractional polynomial (FP) modelling was conducted using the degree of reversibility (mL) at screening as a continuous variable to investigate its relationship to mean change from baseline in trough FEV1 and self-administered computerised-Transition Dyspnoea Index (SAC-TDI) at Week 24, Evaluating Respiratory Symptoms-COPD (E-RS) at Weeks 21-24, and rescue medication use (puffs/day) over Weeks 1-24. Analyses were conducted across the full range of reversibility (-850-896 mL); however, results are presented for the range -100-400 mL because there were few participants with values outside this range. RESULTS: The mean (standard deviation) reversibility was 130 mL (156) and the median was 113 mL; 625/2425 (26%) patients were reversible. There was a trend towards greater improvements in trough FEV1, SAC-TDI, E-RS and rescue medication use with umeclidinium/vilanterol with higher reversibility. Improvements in trough FEV1 and reductions in rescue medication use were greater with umeclidinium/vilanterol compared with either monotherapy across the range of reversibility. Greater improvements in SAC-TDI and E-RS total scores were observed with umeclidinium/vilanterol versus monotherapy in the middle of the reversibility range. CONCLUSIONS: FP analyses suggest that patients with higher levels of reversibility have greater improvements in lung function and symptoms in response to bronchodilators. Improvements in lung function and rescue medication use were greater with umeclidinium/vilanterol versus monotherapy across the full range of reversibility, suggesting that the dual bronchodilator umeclidinium/vilanterol may be an appropriate treatment for patients with symptomatic COPD, regardless of their level of reversibility.

A scintigraphy study of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler in patients with moderate-to-very severe chronic obstructive pulmonary disease.

BACKGROUND: Triple therapy with inhaled corticosteroids/long-acting muscarinic antagonists/long-acting ß2-agonists (ICS/LAMA/LABA) is recommended for patients with chronic obstructive pulmonary disease (COPD) with continued symptoms or exacerbations, despite treatment with LAMA/LABA or ICS/LABA. The pulmonary, extrathoracic, and regional lung deposition patterns of a radiolabeled ICS/LAMA/LABA triple fixed-dose combination budesonide/glycopyrrolate/formoterol fumarate (BGF 320/18/9.6 µg), delivered via a single Aerosphere metered dose inhaler (MDI) were previously assessed in healthy volunteers and showed good deposition to the central and peripheral airways (whole lung deposition: 37.7%). Here, we report the findings assessing BGF in patients with moderate-to-very severe COPD. METHODS: This phase I, single-dose, open-label gamma scintigraphy imaging study (NCT03906045) was conducted in patients with moderate-to-very severe COPD. Patients received two actuations of BGF MDI (160/9/4.8 µg per actuation) radiolabeled with technetium­99­pertechnetate, not exceeding 5 MBq per actuation. Immediately following each inhalation, patients performed a breath-hold of up to 10 s, then exhaled into an exhalation filter. Gamma scintigraphy imaging of the anterior and posterior views of the lungs and stomach, and a lateral head and neck view, were performed immediately after exhalation. The primary objective of the study was to assess the pulmonary deposition of BGF. Secondary objectives assessed the deposited dose of radiolabeled BGF in the oropharyngeal and stomach regions, on the actuator, and on the exhalation filter in addition to regional airway deposition patterns in the lungs. RESULTS: The mean BGF emitted dose deposited in the lungs was 32.1% (standard deviation [SD] 15.6) in patients with moderate-to-very severe COPD, 35.2% (SD 12.8) in patients with moderate COPD, and 28.7% (SD 18.4) in patients with severe/very severe COPD. Overall, the mean normalized outer/inner ratio was 0.55 (SD 0.19), while the standardized central/peripheral ratio was 2.21 (SD 1.64). CONCLUSIONS: Radiolabeled BGF 320/18/9.6 µg was efficiently delivered and deposited throughout the entire lung, including large and small airways, in patients with moderate-to-very severe COPD, with similar deposition in patients with moderate COPD and patients with severe/very severe COPD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03906045. Registered 8 April 2019, https://clinicaltrials.gov/ct2/show/NCT03906045.

Efficacy and safety of single-inhaler extrafine triple therapy versus inhaled corticosteroid plus long-acting beta2 agonist in eastern Asian patients with COPD: the TRIVERSYTI randomised controlled trial.

BACKGROUND: A single-inhaler extrafine triple combination of beclometasone dipropionate (BDP), formoterol fumarate (FF) and glycopyrronium (G) has been developed for maintenance therapy of chronic obstructive pulmonary disease (COPD). This study evaluated the efficacy and safety of BDP/FF/G in patients in three eastern Asian areas: China, Republic of Korea and Taiwan. METHODS: TRIVERSYTI was a double-blind, randomised, active-controlled, parallel-group study in patients with COPD, post-bronchodilator forced expiratory volume in 1 s (FEV1) < 50% predicted, ≥ 1 exacerbation in the previous 12 months, and receiving inhaled maintenance medication. Patients received either extrafine BDP/FF/G 100/6/10 µg via pressurised metered-dose inhaler, or non-extrafine budesonide/formoterol (BUD/FF) 160/4.5 µg via dry-powder inhaler, both administered as two puffs twice-daily for 24 weeks. The co-primary objectives (analysed in the overall population) were to demonstrate superiority of BDP/FF/G over BUD/FF for change from baseline in pre-dose morning and 2-h post-dose FEV1 at Week 24 (these were analysed as key secondary objectives in the China subgroup). The rate of moderate/severe COPD exacerbations was a secondary endpoint. RESULTS: Of 708 patients randomised, 88.8% completed. BDP/FF/G was superior to BUD/FF for pre-dose and 2-h post-dose FEV1 at Week 24 [adjusted mean differences 62 (95% CI 38, 85) mL and 113 (87, 140) mL; both p < 0.001]. The annualised moderate/severe exacerbation rate was 43% lower with BDP/FF/G [rate ratio 0.57 (95% CI 0.42, 0.77); p < 0.001]. Adverse events were reported by 61.1% and 67.0% patients with BDP/FF/G and BUD/FF. Results were similar in the China subgroup. CONCLUSIONS: In patients with COPD, FEV1 < 50% and an exacerbation history despite maintenance therapy, treatment with extrafine BDP/FF/G improved bronchodilation, and was more effective at preventing moderate/severe COPD exacerbations than BUD/FF. Trial registration CFDA CTR20160507 (registered 7 Nov 2016, http://www.chinadrugtrials.org.cn/index.html ).

The ß-Adrenergic Agonist Albuterol Improves Pulmonary Vascular Reserve in Heart Failure With Preserved Ejection Fraction.

RATIONALE: Pulmonary vascular resistance fails to decrease appropriately during exercise in patients with heart failure with preserved ejection fraction (HFpEF). Interventions that enhance pulmonary vasodilation might be beneficial in this cohort but could also worsen left atrial hypertension, exacerbating lung congestion. Intravenous ß-agonists reduce pulmonary vascular resistance but are not suitable for chronic use. OBJECTIVE: We hypothesized that the inhaled ß-adrenergic agonist albuterol would improve pulmonary vasodilation during exercise in patients with HFpEF, without increasing left heart filling pressures. METHODS AND RESULTS: We performed a randomized, double-blind, placebo-controlled trial testing the effects of inhaled albuterol on resting and exercise hemodynamics in subjects with HFpEF using high-fidelity micromanometer catheters and expired gas analysis. The primary end point was pulmonary vascular resistance during exercise. Subjects with HFpEF (n=30) underwent resting and exercise hemodynamic assessment and were then randomized 1:1 to inhaled, nebulized albuterol or placebo. Rest and exercise hemodynamic testing was then repeated. Albuterol improved the primary end point of exercise pulmonary vascular resistance as compared with placebo (-0.6±0.5 versus +0.1±0.7 WU; P=0.003). Albuterol enhanced cardiac output reserve and right ventricular pulmonary artery coupling, reduced right atrial and pulmonary artery pressures, improved pulmonary artery compliance, and enhanced left ventricular transmural distending pressure (all P <0.01), with no increase in pulmonary capillary hydrostatic pressures. CONCLUSIONS: Albuterol improves pulmonary vascular reserve in patients with HFpEF without worsening left heart congestion. Further study is warranted to evaluate the chronic efficacy of ß-agonists in HFpEF and other forms of pulmonary hypertension. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov . Unique identifier: NCT02885636.

Switching to nebulised short acting bronchodilators does not increase the risk of arrhythmia in patients hospitalized with a COPD exacerbation.

If short acting ß2-agonists and muscarinic antagonists (SABA/SAMA) may have proarrhythmic effects during acute COPD exacerbations (AECOPD) is still unknown. The primary objective of the study was to investigate the incidence of new onset arrhythmias in hospitalized patients shifted to SABA/SAMA during an AECOPD compared with continuing chronic inhaled therapy. Secondary objectives were to assess the clinical characteristics of patients shifted to SABA/SAMA and risk factors for arrhythmia. This was a retrospective, observational, study enrolling consecutive patients hospitalized with an AECOPD. Incidence of arrhythmias was obtained reviewing digital records. Patients with chronic arrhythmias or home-treated with SABA/SAMA were excluded. 235 patients (63.8% males) were included, and 10/182 patients shifted to SABA/SAMA experienced arrhythmias, while no events were observed in patients on chronic inhaled therapy (p = 0.122). Shifted patients had a more severe AECOPD and history of paroxysmal atrial fibrillation was an independent risk factor for arrhythmia (OR 14.010, IC95%: 2.983-65.800; p = 0.001). In conclusion, shifting patients to SABA/SAMA appears not to increase the risk for arrhythmia during severe AECOPD. However, the pharmacological approach in patients with a history of paroxysmal arrhythmia should be carefully evaluated and monitored.

Discovery of a novel class of inhaled dual pharmacology muscarinic antagonist and ß2 agonist (MABA) for the treatment of chronic obstructive pulmonary disease (COPD).

The targeting of both the muscarinic and ß-adrenergic pathways is a well validated therapeutic approach for the treatment of chronic obstructive pulmonary disease (COPD). In this communication we report our effort to incorporate two pharmacologies into a single chemical entity, whose characteristic must be suitable for a once daily inhaled administration. Contextually, we aimed at a locally acting therapy with limited systemic absorption to minimize side effects. Our lung-tailored design of bifunctional compounds that combine the muscarinic and ß-adrenergic pharmacologies by the elaboration of the muscarinic inhibitor 7, successfully led to the potent, pharmacologically balanced muscarinic antagonist and ß2 agonist (MABA) 13.

Medication adherence in patients with asthma using once-daily versus twice-daily ICS/LABAs.

OBJECTIVE: This real-world observational study compared medication adherence and persistence among patients with asthma receiving the once-daily inhaled corticosteroid/long-acting ß2-agonist (ICS/LABA) fluticasone furoate/vilanterol (FF/VI) versus the twice-daily ICS/LABAs budesonide/formoterol (B/F) and fluticasone propionate/salmeterol (FP/SAL). METHODS: This retrospective cohort study conducted using IQVIATM Health Plan Claims Data included patients with asthma ≥18 years of age initiating ICS/LABA therapy with FF/VI, B/F, or FP/SAL between January 1, 2014 and June 30, 2016 (index date). Patients had ≥12 months and ≥3 months of continuous eligibility pre- and post-index date, respectively. Patients receiving FF/VI were separately matched 1:1 with patients receiving B/F or FP/SAL using propensity score matching (PSM) and multivariable regression to balance baseline covariates between cohorts. The primary endpoint was medication adherence, measured by proportion of days covered (PDC). Secondary endpoints included proportion of patients achieving PDC ≥ 0.5 and PDC ≥ 0.8 and persistence with index medication, measured by time to discontinuation (>45-day gap in therapy). RESULTS: After PSM, 3,764 and 3,339 patients receiving FF/VI were matched with patients receiving B/F or FP/SAL, respectively. Mean PDC was significantly higher for FF/VI versus B/F (0.453 vs 0.345; adjusted p < 0.001) and FP/SAL (0.446 vs 0.341; adjusted p < 0.001). The proportion of patients achieving PDC ≥ 0.5 or PDC ≥ 0.8, and treatment persistence were significantly higher for FF/VI versus B/F and FP/SAL (all p < 0.001). CONCLUSIONS: In this real-world study, patients initiating FF/VI had better adherence and lower risk of discontinuing treatment versus B/F or FP/SAL, suggesting that once-daily ICS/LABA treatment might improve adherence and persistence compared with twice-daily alternatives.

Assessing asthma control: comparison of electronic-recorded short-acting beta-agonist rescue use and self-reported use utilizing the asthma control test.

Background: Question 4 (Q4) of the Asthma Control Test (ACT) asks patients to report their SABA use over the prior 4 weeks, a criterion for evaluating the impairment domain of asthma control. Biases in recall may lead to a misclassification of asthma control and has implications for asthma control determination and management strategies.Objective: To correlate objective electronic-recorded short-acting beta-agonist (SABA) use with self-reported use via Q4 of the ACT.Methods: Patients ≥18 years of age with a self-reported diagnosis of asthma were enrolled in a digital health electronic medication monitoring (EMM) platform, which recorded the date and time of SABA actuations and prompted the completion of the ACT. The correlations between ACT Q4 responses and EMM-recorded SABA use were evaluated using Spearman's rank correlation coefficients.Results: 1,062 patients (mean age: 35.4 years, mean ACT: 16.3) were included in analyses. Higher Q4 scores, indicating lower SABA use, were moderately and negatively correlated with EMM-recorded SABA use (ρ = -0.59 [95% CI: -0.63, -0.54]). Thirty-five percent of patients underreported SABA use when comparing Q4 to EMM-recorded SABA use.Conclusions: While ACT Q4 and EMM-recorded use were moderately correlated, underreported SABA use on the ACT highlights the need for objective measures of SABA use in asthma control assessments. The use of EMM-recorded SABA data has the potential for clinicians to more accurately determine asthma control, guide changes to controller therapy, and estimate imminent exacerbation risk.