Exacerbation Rates In Patients Research Articles

Positioning of Tezepelumab in Severe Asthma.

Asthma is one of the most common chronic diseases and is estimated to be severe in 3%-10% of affected patients. There is a need for additional biologic treatments that are highly efficacious across the spectrum of severe uncontrolled asthma. Currently available drugs inhibit 1 or 2 specific cytokines or IgE antibodies and thus only partially suppress the complex type 2 (T2) inflammatory cascade. Biologics targeting more upstream molecules in the pathophysiological pathway of asthma could treat asthma more effectively. Tezepelumab is a human monoclonal immunoglobulin G2λ antibody that targets the cytokine thymic stromal lymphopoietin (TSLP). It is the first marketed biologic against an epithelial cell-derived cytokine, preventing binding of TSLP to its receptor and reducing the immune stimuli that TSLP can trigger in different asthma endotypes. Tezepelumab reduces downstream biomarkers of inflammation, such as blood and airway eosinophils, FeNO, IgE, IL-5, and IL-13. Tezepelumab provides a clinical benefit in severe asthma, reducing the annualized asthma exacerbation rate in patients with either high or low levels of biomarkers of T2 inflammation, although the effect is greater among those with high levels. The drug has been shown to improve asthma control, quality of life, and lung function and reduce airway hyperresponsiveness. Therefore, tezepelumab can be used across the spectrum of patients with severe uncontrolled asthma, especially in T2-high patients. This review includes a positioning statement by the authors, all of whom are members of the SEAIC Asthma Committee.

International Variation in Severe Exacerbation Rates in Patients With Severe Asthma

BackgroundExacerbation frequency strongly influences treatment choices in patients with severe asthma. Research QuestionWhat is the extent of the variability of exacerbations rate across countries and its implications in disease management? Study Design and MethodsWe retrieved data from the International Severe Asthma Registry, an international observational cohort of patients with a clinical diagnosis of severe asthma. We identified patients aged ≥18 years who did not initiate any biologics prior to baseline visit. A severe exacerbation was defined as the use of oral corticosteroids for ≥3 days or asthma-related hospitalization/emergency room visit. A series of negative binomial models were applied to estimate country-specific severe exacerbation rates during 365 days of follow-up, starting from a naïve model with country as the only variable, to an adjusted model with country as a random-effect term and patient and disease characteristics as independent variables. ResultsThe final sample included 7,510 patients from 17 countries (56% from the United States), contributing to 1,939 severe exacerbations (0.27/person-year). There was large between-country variation in observed severe exacerbation rate (min: 0.04 [Argentina], max:0.88 [Saudi Arabia], interquartile range [IQR]: 0.13–0.54), which remained substantial after adjusting for patient characteristics and sampling variability (IQR: 0.16–0.39). InterpretationIndividuals with similar patient characteristics but coming from different jurisdictions have varied severe exacerbation risks, even after controlling for patient and disease characteristics. This suggests unknown patient factors or system-level variations at play. Disease management guidelines should recognize such between-country variability. Risk prediction models that are calibrated for each jurisdiction will be needed to optimize treatment strategies. Clinical Trial Registration NumberN/A

Association Between Regular Moderate to Vigorous Physical Activity Initiation Following COPD Diagnosis and Mortality: An Emulated Target Trial Using Nationwide Cohort Data

Moderate to vigorous physical activity (MVPA) in patients with COPD affects their overall health outcomes, including symptom relief and improved quality of life. However, the magnitude of the effect of MVPA initiation on real-world clinical outcomes has not been well investigated. How does MVPA initiation affect mortality and severe exacerbation in patients who have not engaged in MVPA prior to COPD diagnosis? This study included patients with COPD aged≥ 40 years who were not performing MVPA prior to COPD diagnosis and who had at least one health screening visit prior to and following their COPD diagnosis between January 1, 2010, and December 31, 2018. The main exposure was MVPA, defined as vigorous aerobic exercise > 20min per day on≥ 3days per week or moderate aerobic exercise > 30min per day on≥ 5days per week. The primary end point was all-cause mortality, and the secondary end point was initial severe exacerbation as the time to event following COPD diagnosis. In total, 110,097 person-trials were included (27,564 MVPA increases and 82,533 control groups). No differences were observed between the covariates following matching. The adjusted hazards ratio of all-cause mortality for the MVPA group compared with the control group was 0.84 (95%CI, 0.79-0.89). In the subgroup analysis, patients aged > 65 years, female patients, those who had never smoked, and patients with a higher Charlson Comorbidity Index score displayed a stronger effect of MVPA on reducing mortality than younger male patients, those who had ever smoked, and patients with a lower Charlson Comorbidity Index score (Pinteraction< .05). The fully adjusted hazards ratio for the risk of severe exacerbation (MVPA group vscontrol) was 0.90 (95%CI, 0.87-0.94). Initiation of MVPA can potentially reduce mortality and severe exacerbations in patients with COPD, although personalized interventions and further clinical trials are necessary.

The rate of exacerbations in patients with asthma in Qatar: A retrospective study during 2019-2021.

Background: The prevalence of asthma is 9% among adults in Qatar, and its severity can be attributed to intrinsic and extrinsic factors such as environmental changes. As part of the project to investigate the association between air pollution and asthma severity, the rate of exacerbations in adult patients with asthma has been studied in Qatar. Methods: Retrospective data of patients with asthma (16-70 years) from January 2019 to December 2021 was retrieved from Cerner medical records. Frequencies of exacerbations in inpatient and outpatient departments were analyzed using means ± SD and median (IQR) for descriptive data and frequency and percentage for categorical data. Exacerbations were divided into single, double, and more than double for each quarter of the year (January 2019-December 2021) using SPSS and Minitab statistical packages. Results: A total of 6977 exacerbations visits (representing 6558 patients) were identified during the study period. The mean ± SD age was 41±14.3 years, with a female: male ratio of almost 1:1. The patients from the MENA region, including Qataris, presented 67% compared to 33% from the Indian subcontinent and other countries. The number of patient visits for hospitalization due to exacerbations showed a distinctive pattern during the three years. The highest record of asthmatics with exacerbations was observed in 2019 (42.7%) compared to half the rate in 2020 and 2021 (28.5%, 28.8%), respectively. The single exacerbation group was almost five times higher than 2 or >2 exacerbation groups in all years (2019-2021). Conclusion: This preliminary overview provides the rate of exacerbation episodes in patients with asthma in Qatar. One cause of these exacerbations can be attributed to air quality changes. The drop in the exacerbation rate observed in 2020-2021 could be explained by COVID-19 lockdown regulations or patients' adherence to prescribed meds. We aim to propose preventive and therapeutic strategies to alleviate asthmatics' symptoms and improve their quality of life.

Joint longitudinal model-based meta-analysis of FEV1 and exacerbation rate in randomized COPD trials.

Model-based meta-analysis (MBMA) is an approach that integrates relevant summary level data from heterogeneously designed randomized controlled trials (RCTs). This study not only evaluated the predictability of a published MBMA for forced expiratory volume in one second (FEV1) and its link to annual exacerbation rate in patients with chronic obstructive pulmonary disease (COPD) but also included data from new RCTs. A comparative effectiveness analysis across all drugs was also performed. Aggregated level data were collected from RCTs published between July 2013 and November 2020 (n = 132 references comprising 156 studies) and combined with data used in the legacy MBMA (published RCTs up to July 2013 - n = 142). The augmented data (n = 298) were used to evaluate the predictive performance of the published MBMA using goodness-of-fit plots for assessment. Furthermore, the model was extended including drugs that were not available before July 2013, estimating a new set of parameters. The legacy MBMA model predicted the post-2013 FEV1 data well, and new estimated parameters were similar to those of drugs in the same class. However, the exacerbation model overpredicted the post-2013 mean annual exacerbation rate data. Inclusion of year when the study started on the pre-treatment placebo rate improved the model predictive performance perhaps explaining potential improvements in the disease management over time. The addition of new data to the legacy COPD MBMA enabled a more robust model with increased predictability performance for both endpoints FEV1 and mean annual exacerbation rate.

Anti-epithelial-derived cytokines for severe asthma: Systematic review and meta-analysis

Therapies directed against epithelial-derived cytokines, often referred to as alarmins, have been studied in large randomized trials, and reports suggest possible benefit for non-type 2 as well as type 2 severe asthma. We performed a systematic review of Medline, Embase, Cochrane Central Register of Controlled Trials, Medline In-Process, and Web of Science databases from inception to March 2022. We performed a random-effects pairwise meta-analysis of randomized controlled trials addressing antialarmin therapy in severe asthma. Results use relative risk (RR) values and 95% confidence intervals (CIs). For continuous outcomes, we report mean difference (MD) values and 95% CIs. We define high eosinophils as ≥300 cells/μL and low eosinophils as <300 cells/μL. We used Cochrane-endorsed RoB 2.0 software to assess the risk of bias of trials, and we used the Grades of Recommendation Assessment, Development, and Evaluation (aka GRADE) framework to assess the certainty of the evidence. We identified 12 randomized trials including 2391 patients. Antialarmins probably reduce annualized exacerbation rates in patients with high eosinophils (RR 0.33 [95% CI 0.28 to 0.38]; moderate certainty). Antialarmins may reduce this rate in patients with low eosinophils (RR 0.59 [95% CI 0.38 to 0.90]; low certainty). Antialarmins improve FEV1 in patients with high eosinophils (MD 218.5 mL [95% CI 160.2 to 276.7]; high certainty). Antialarmin therapy probably does not improve FEV1 in patients with low eosinophils (MD 68.8 mL [95% CI 22.4 to 115.2]; moderate certainty). Antialarmins reduce blood eosinophils, total IgE, and fractional excretion of nitric oxide across studied subjects. Antialarmins are effective at improving lung function and probably reduce exacerbations in patients with severe asthma and blood eosinophils ≥300 cells/μL. The effect on patients with lower eosinophils is less certain.

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

Chronic obstructive pulmonary disease (COPD) exacerbations are associated with significant morbidity and mortality and increased economic healthcare burden for patients with COPD. Long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) dual therapy is recommended for patients receiving mono-bronchodilator therapy who experience exacerbations or ongoing breathlessness. This study compared two single-inhaler LAMA/LABA dual therapies, umeclidinium/vilanterol (UMEC/VI) and indacaterol/glycopyrronium (IND/GLY), on moderate-to-severe exacerbation rates in patients with COPD in England. This retrospective cohort study used linked primary care electronic health record data (Clinical Practice Research Datalink-Aurum) and secondary care data (Hospital Episode Statistics) to assess outcomes for patients with COPD who had a first prescription for single-inhaler UMEC/VI or IND/GLY (index date) between 1 January 2015 and 30 September 2019 (indexing period). Analyses compared UMEC/VI and IND/GLY on moderate-to-severe, moderate, and severe exacerbations, healthcare resource utilization (HCRU), and direct costs at 6, 12, 18, and 24 months, and time-to-first on-treatment exacerbation up to 24 months post-index date. Following inverse probability of treatment weighting (IPTW), non-inferiority and superiority of UMEC/VI versus IND/GLY were assessed. In total, 12,031 patients were included, of whom 8753 (72.8%) were prescribed UMEC/VI and 3278 (27.2%) IND/GLY. After IPTW, for moderate-to-severe exacerbations, weighted rate ratios were <1 at 6, 12, and 18 months and equal to 1 at 24 months for UMEC/VI; around the null value for moderate exacerbations and <1 at all timepoints for severe exacerbations. UMEC/VI showed lower HCRU incidence rates than IND/GLY for all-cause Accident and Emergency visits and COPD-related inpatient stays and associated all-cause costs at 6 months post-indexing. Time-to-triple therapy was similar for both treatments. UMEC/VI demonstrated non-inferiority to IND/GLY in moderate-to-severe exacerbation reduction at 6, 12 and 18 months. These results support previous findings demonstrating similarity between UMEC/VI and IND/GLY on reduction of moderate-to-severe exacerbations.

Effects of long-term tobramycin inhalation solution (TIS) once daily on exacerbation rate in patients with non-cystic fibrosis bronchiectasis

BackgroundUse of long-term tobramycin inhalation solution (TIS) has been shown beneficial in cystic fibrosis (CF) and earlier findings also suggest a benefit in non-CF bronchiectasis. We investigated the efficacy and safety of maintenance TIS once daily (OD) in frequent exacerbating bronchiectasis patients chronically infected by different pathogens sensitive for tobramycin.ObjectiveThe primary outcome was the frequency of exacerbations during the 12-month study period. Secondary outcomes were time to first exacerbation, change in lung function and quality of life (QoL), bacterial analysis and safety.Materials/patientsIn this multicenter RCT patients aged ≥ 18-year-old were included with confirmed bronchiectasis and ≥ 2 exacerbations in the preceding year. Patients were assigned (1:1) to receive TIS or placebo OD for 1-year.Results58 patients were included of which 52 were analyzed in the mITT analysis. TIS reduced exacerbation frequency with a RR of 0.74 (95% CI 0.49–1.14) (p = 0.15). Within the TIS population a decrease in number of exacerbations was found (2; p = 0.00), which was also seen in the placebo-treated patients (1.5; p = 0.00). In the TIS-treated patients the QoL improved (LRTI-VAS p = 0.02 Leicester Cough p = 0.02) without additional safety concerns. No differences were found for the other secondary outcomes.ConclusionLong-term TIS OD is a safe treatment modality and showed a non-significant reduced exacerbation frequency of 0.74 as compared to placebo in bronchiectasis patients chronically infected by tobramycin sensitive pathogens. TIS OD may be a potential therapeutic strategy in selected patients with bronchiectasis suffering from a high burden of disease.Trail registration number: The BATTLE study was registered at Clinical trials.gov number: NCT02657473. Date: 13 august 2016.

The BATTLE study: Effects of long-term tobramycin inhalation solution (TIS) once daily on exacerbation rate in patients with non-cystic fibrosis bronchiectasis. Study protocol of a double blind, randomized, placebo-controlled trial: study protocol

BackgroundPatients with bronchiectasis typically suffer from chronic symptoms such as a productive cough with or without exacerbations leading to hospitalization, causing reduced quality of life (QoL) and mortality. Long-term inhaled antibiotics to treat chronic bronchial infection is registered for use in cystic fibrosis (CF) bronchiectasis. However, in patients with non-CF bronchiectasis data on long-term antibiotics are limited. ObjectiveTo investigate the effectiveness of maintenance tobramycin inhalation solution (TIS) in bronchiectasis patients without cystic fibrosis. Study designThe BATTLE study is a randomized, double blind placebo controlled, multicenter study in the Netherlands performed in patients aged ≥18-year-old with confirmed bronchiectasis, at least two exacerbations in the preceding year, and minimal one positive sputum culture with gram negative pathogens or Staphylococcus aureus, sensitive to tobramycin in the preceding year and at baseline. Patients will be treated with TIS once daily (OD) or placebo (saline 0.9%) OD for 52 weeks followed by a run-out period of 4 weeks after the last dose. The primary outcome is the yearly rate of pulmonary exacerbations. Among secondary outcome parameters are time to exacerbation, lung function, QoL, microbiological evaluation and safety. DiscussionThe BATTLE study is designed to determine the efficacy and safety of maintenance TIS OD in bronchiectasis patients colonized by different pathogens and could lead to important new evidence for TIS therapy in this population.The BATTLE study is registered in Clinical trials.gov with registration number: NCT02657473.

CLINICAL OUTCOMES IN PATIENTS WITH SEVERE ASTHMA WHO HAD OR HAD NOT INITIATED BIOLOGIC THERAPY: RESULTS FROM THE CLEAR STUDY

CLINICAL OUTCOMES IN PATIENTS WITH SEVERE ASTHMA WHO HAD OR HAD NOT INITIATED BIOLOGIC THERAPY: RESULTS FROM THE CLEAR STUDY

Combination therapy with long-acting bronchodilators and the risk of major adverse cardiovascular events in patients with COPD: a systematic review and meta-analysis.

Accumulated high-quality data from randomised controlled trials (RCTs) indicate that long-acting muscarinic antagonist (LAMA)/long-acting β2 agonist (LABA) combination therapy significantly improves clinical symptoms and health status in patients with chronic obstructive pulmonary disease (COPD) and reduces exacerbation risk. However, there is a growing concern that LAMA/LABA therapy may increase the risk of cardiovascular disease in patients with COPD. The aim of this paper is to determine whether the use of LAMA/LABA combination therapy modifies the risk of cardiovascular disease in patients with COPD. Two reviewers independently searched Embase, PubMed and Cochrane Library to identify relevant RCTs of LAMA/LABA or LABA/LAMA/inhaled corticosteroids (ICS) for the management of patients with COPD that reported on cardiovascular end-points. The primary outcome was major adverse cardiovascular events (MACE), which was a composite of cardiovascular death, myocardial infarction or stroke. A total of 51 RCTs enrolling 91 021 subjects were analysed. Both dual LAMA/LABA (1.6% versus 1.3%; relative risk 1.42, 95% CI 1.11-1.81) and triple therapy (1.6% versus 1.4%; relative risk 1.29, 95% CI 1.03-1.61) significantly increased the risk of MACE compared with ICS/LABA. The excess risk was most evident in RCTs in which the average underlying baseline risk for MACE was >1% per year. Compared with LAMA only, LABA only or placebo, dual LAMA/LABA therapy did not significantly increase the risk of MACE, though these comparisons may have lacked sufficient statistical power. Compared with ICS/LABA, dual LAMA/LABA or triple therapy increases cardiovascular risk in patients with COPD. This should be considered in the context of the incremental benefits of these therapies for symptoms and exacerbation rates in patients with COPD, especially in those with a MACE risk of >1% per year.

Normalisation of airflow limitation in asthma: Post-hoc analyses of TRIMARAN and TRIGGER.

BackgroundIn asthma, persistent airflow limitation (PAL) is associated with poorer control, lung function decline and exacerbations. Using post‐hoc analyses we evaluated: the relationship between post‐salbutamol PAL at screening, airflow limitation (AL) during 52 weeks treatment with extrafine beclometasone dipropionate/formoterol fumarate/glycopyrronium (BDP/FF/G) versus BDP/FF and the risk of moderate/severe asthma exacerbations.MethodsTRIMARAN and TRIGGER were double‐blind studies comparing BDP/FF/G with BDP/FF (TRIMARAN medium‐dose ICS; TRIGGER high‐dose) in adults with uncontrolled asthma. Patients were subgrouped according to post‐salbutamol PAL status at screening, and AL over the 52‐week treatment period.ResultsMost patients with post‐salbutamol PAL at screening had AL at all on‐treatment visits (TRIMARAN 62.8%; TRIGGER 66.8%). A significantly higher proportion of patients had normalised airflow on ≥1 follow‐up visit when receiving BDP/FF/G than BDP/FF (TRIMARAN 44.1 vs. 33.1% [p = 0.003]; TRIGGER 40.1 vs. 26.0% [p < 0.001]). In patients with post‐salbutamol PAL at screening and normalised AL at ≥1 follow‐up visit, exacerbation rates were 15% (p = 0.105) and 19% (p = 0.039) lower in TRIMARAN and TRIGGER versus those with AL on all visits. There was a trend to lower exacerbation rates in patients receiving BDP/FF/G than BDP/FF, particularly in patients in whom AL was normalised.ConclusionIn these analyses, AL in asthma was associated with an increased exacerbation incidence. Inhaled triple therapy with extrafine BDP/FF/G was more likely to normalise airflow, and was associated with a trend to a lower exacerbation rate than BDP/FF, particularly in the subgroup of patients in whom treatment was associated with airflow normalisation.ClinicalTrials.gov: TRIMARAN, NCT02676076; TRIGGER, NCT02676089.

Effects of simvastatin on tissue factor pathway of blood coagulation in STATCOPE (Simvastatin in the prevention of COPD exacerbations) trial

BackgroundStatins are widely used to lower lipids and reduce cardiovascular events. In vitro studies and small studies in patients with hyperlipidemias show statins inhibit tissue factor (TF) and blood coagulation mechanisms. We assessed the effects of simvastatin on TF and coagulation biomarkers in patients entered in STATCOPE, a multicenter, randomized, placebo‐controlled trial of simvastatin (40 mg daily) versus placebo on exacerbation rates in patients with chronic obstructive pulmonary disease (COPD). MethodsIn 227 patients (114 simvastatin, 113 placebo; mean [± standard error of the mean] age 62 ± 0.53 years, 44.5% women) we measured (baseline, and 6 and 12 months): whole blood membrane TF‐procoagulant activity (TF‐PCA) and plasma factors VIIa, VII, VIII, fibrinogen, TF antigen, tissue factor pathway inhibitor (TFPI), thrombin‐antithrombin complexes (TAT), and D‐dimer. We excluded patients with diabetes, cardiovascular disease, and those taking or requiring a statin. ResultsIn the statin group, there was a small increase in TF‐PCA (from 25.18 ± 1.08 to 30.36 ± 1.10 U/ml; p = .03) over 12 months; factors VIIa and VIII, fibrinogen, TAT, and D‐dimer did not change. Plasma TFPI (from 52.4 ± 1.75 to 44.7 ± 1.78 ng/ml; p < .0001) and FVIIC (1.23 ± 0.04 to 1.15 ± 0.03 U/ml; p = .03) decreased and correlated with total cholesterol levels. No changes in biomarkers were observed with placebo. ConclusionsIn contrast to previous studies on statins, in COPD patients without diabetes, cardiovascular disease, or requiring a statin treatment, simvastatin (40 mg per day) did not decrease TF or factors VIIa and VIII, fibrinogen, TAT, or D‐dimer. The decreases in TFPI and factor VII reflect the decrease in serum lipids.

High Incidence of Thrombotic Thrombocytopenic Purpura Exacerbation Rate Among Patients With Morbid Obesity and Drug Abuse.

This study aims to identify the baseline patient characteristics, clinical presentation, and response to treatment of 11 patients who were diagnosed with thrombotic thrombocytopenic purpura (TTP) between 2014 and 2020 at Brookdale University Hospital Medical Center, Brooklyn, NY. Laboratory and clinical parameters were recorded for 29 patients who received plasmapheresis in this time period. Of 29 patients, 11 had confirmed TTP and one was diagnosed with hereditary TTP. Young, black, and female patients made up the majority of our patient population. A high prevalence of obesity and drug abuse were seen among our patients. Five out of 11 were obese and four of them were morbidly obese; six out of 11 patients were positive for the drug screen including cannabinoids (3), opiates (2), benzodiazepines (1), PCP (1), and methadone (1). Four patients with a positive drug screen had acute kidney injury (AKI), and plasmapheresis helped them enhance their kidney function. We observed a high incidence of AKI and high TTP exacerbation rates in patients who were drug abusers and those who were morbidly obese. There is a paucity of data on the relationship of TTP with obesityor drug abuse and this needs further study.

Blood eosinophils in COPD to inform inhaled corticosteroid use: Ready to be used in clinical practice

The GOLD report and the Canadian Thoracic Society Clinical Practice Guideline on pharmacotherapy in patients with COPD have incorporated blood eosinophils as a potential biomarker for treatment use in COPD patients. The first part of this review highlights situation where blood eosinophil is not useful. The second part reviews clinical trials (randomized control trial, withdrawal design) and an observational study (clinical database) in COPD patients with a history of exacerbations showing that inhaled corticosteroid-containing regimens reduces exacerbation rates in patients according to their level of blood eosinophils. This relationship between blood eosinophils and treatment response has been shown to follow a continuum. However, to be more practical, levels of blood eosinophils have been proposed for the clinician. The current evidence indicates that assessment of patient’s exacerbation risk and blood eosinophil count ⩾300 cells·μL− predict a high likelihood of clinical benefit with inhaled corticosteroid-containing regimens, and no or minimal benefit with eosinophils < 100-150 cells·μL−. The review concludes based on evidence that we must take action and stop waiting. Blood eosinophil level is a good predictive biomarker; it can discriminate which COPD patients are likely or not to respond to a specific therapy.

High-dose N-acetylcysteine for long-term, regular treatment of early-stage chronic obstructive pulmonary disease (GOLD I\u2013II): study protocol for a multicenter, double-blinded, parallel-group, randomized controlled trial in China

IntroductionThe presence of increased oxidative stress and airway inflammation has been proven in subjects with chronic obstructive pulmonary disease (COPD). Several studies have demonstrated that drugs with antioxidant and anti-inflammatory properties such as N-acetylcysteine (NAC) can reduce the rate of exacerbations in patients with COPD. However, the beneficial effects of NAC in early-stage COPD are minimally discussed. We are investigating whether high-dose NAC has therapeutic effects in Chinese patients with early-stage COPD.Method and analysisA randomized, double-blinded, placebo-controlled, parallel-group, multicenter clinical trial is evaluating the efficacy and safety of NAC for the long-term treatment of patients with early-stage COPD at 24 centers in China. Subjects aged 40–80 years and recruited by physicians or researchers with special training will be randomized to either NAC 600 mg twice daily group or matching placebo group for 2 years. Measurements will include forced expiratory volume in 1 s (FEV1), the number of COPD exacerbations, health-related quality, and pharmacoeconomic analysis.DiscussionCurrently, there are no randomized controlled trials with high-dose N-acetylcysteine (600 mg twice daily) for patients with mild-to-moderate COPD (GOLD I–II). We designed this multicenter randomized controlled trial (RCT) to assess the effectiveness, safety, and cost-effectiveness of long-term treatment with high-dose N-acetylcysteine. The results of this trial may guide clinical practice and change the standard of early COPD management.Trial registrationChinese Clinical Trial Registry ChiCTR-IIR-17012604. Registered on 07 September 2017.

Impact of mepolizumab on exacerbations in severe asthma: Results from a U.S. insurance claims data base.

Background: In controlled clinical studies, mepolizumab has been shown to reduce exacerbation rates and the use of oral corticosteroids as well as improve asthma control and health-related quality of life compared with placebo in patients with severe eosinophilic asthma. However, real-world data on the impact of mepolizumab on clinical outcomes are limited. Objective: To evaluate the effect of mepolizumab on asthma exacerbations and asthma exacerbation-related costs in patients with severe asthma in U.S. clinical practice. Methods: This retrospective cohort study used U.S. administrative claims data from patients ages ≥12 years and with severe asthma at mepolizumab treatment initiation (index date; identification period, January 2015-June 2017) who had received two or more mepolizumab administrations within 180 days of the index date and had no evidence of treatment with another asthma biologic. The exacerbation rate and exacerbation-related costs were assessed in both the 12 months before mepolizumab initiation (baseline period) and the following 12 months (follow-up period). A clinical trial-like cohort was identified, defined as patients with two or more baseline exacerbations and ≥10 administrations during follow-up. Results: A total of 201 patients were included in the overall population and 74 patients in the clinical trial-like cohort. Mepolizumab significantly reduced the exacerbation rate between the baseline and follow-up periods in both the overall population and the clinical trial-like cohort (p < 0.001), which corresponded to 33.6% and 48.6% reductions, respectively. The rate of exacerbations in patients who required hospitalization between the baseline and follow-up periods was also reduced by 35.3% (p = 0.080) and 68.2% (p = 0.015) in the overall population and in the clinical trial-like cohort, respectively. Cost data were inconclusive. Conclusion: This study, which used real-world data, demonstrated that mepolizumab is associated with reductions in asthma exacerbations, in line with the findings from controlled clinical studies. These results provided further evidence of the effectiveness of mepolizumab in a real-world setting.

Acute exacerbations of COPD versus IPF in patients with combined pulmonary fibrosis and emphysema

RationalePatients with combined pulmonary fibrosis and emphysema (CPFE) may develop acute exacerbations of IPF (AE-IPF) or COPD (AE-COPD). The incidence and the characteristics of exacerbations in patients with CPFE (e.g., COPD vs IPF) have not been well described.ObjectivesTo compare the incidence and rate of exacerbations in patients with CPFE vs. IPF and evaluate their effect on clinical outcomes.MethodsComprehensive clinical data from CPFE and IPF patients were retrospectively reviewed. Baseline characteristics including lung function data, oxygen requirements, and pulmonary hemodynamics, were collected. Acute exacerbation events in both groups were defined clinically and radiographically. In the CPFE group, two patterns of exacerbations were identified. AE-COPD was defined clinically by symptoms of severe airflow obstruction causing respiratory failure and requiring hospitalization. Radiographic data were also defined based on previously published literature. AE-IPF was defined clinically as an acute hypoxic respiratory failure, requiring hospitalization and treatment with high dose corticosteroids. Radiographically, patients had to have a change in baseline imaging including presence of ground-glass opacities, interlobular septal thickening or new consolidations; that is not fully explained by other etiologies.ResultsEighty-five CPFE patients were retrospectively compared to 112 IPF patients. Of 112 patients with IPF; 45 had AE-IPF preceding lung transplant (40.18%) compared to 12 patients in the CPFE group (14.1%) (p < 0.05). 10 patients in the CPFE group experienced AE-COPD (11.7%). Patients with AE-IPF had higher mortality and more likely required mechanical ventilation and extracorporeal membrane oxygenation (ECMO) compared to patients with AE-COPD, whether their underlying disease was IPF or CPFE.ConclusionsCPFE patients may experience either AE-IPF or AE-COPD. Patients with CPFE and AE-COPD had better outcomes, requiring less intensive therapy compared to patients with AE-IPF regardless if underlying CPFE or IPF was present. These data suggest that the type of acute exacerbation, AE-COPD vs AE-IPF, has important implications for the treatment and prognosis of patients with CPFE.

Prospective, Single-Arm, Longitudinal Study of Biomarkers in Real-World Patients with Severe Asthma

ARIETTA was a prospective, single-arm, noninterventional, multicenter study in patients with severe asthma. To examine the predictive and prognostic abilities of type 2 biomarkers for severe asthma outcomes. Adult patients with severe asthma receiving daily inhaled corticosteroids (fluticasone propionate ≥500 μg or equivalent) and ≥1 second controller medication were enrolled. Biomarker, clinical, and safety data were collected over 52 weeks. The primary endpoint was the asthma exacerbation rate over 52weeks in serum periostin-high (≥50 ng/mL at baseline) versus periostin-low subgroups (<50 ng/mL). Correlations between biomarker levels (periostin, blood eosinophils, IgE, and fractional exhaled nitric oxide [FeNO]) and between central and local laboratory measurements (blood eosinophils and IgE) were assessed. The study was terminated before planned enrollment was completed. Of 465 patients, 66.5% were female, 13.3% were receiving oral corticosteroids, 42.4% had ≥1 exacerbation in the previous year, 52.0% were periostin-high, and 87.5% had type 2 inflammation (blood eosinophils ≥150 cells/μL and/or FeNO ≥25 ppb and/or positive skin allergen test). Biomarker levels correlated poorly with each other. Central and local laboratory blood eosinophil and IgE measurements generally agreed. No difference was observed in exacerbation rates over 52 weeks between periostin-high and periostin-low patients (rate ratio, 0.93; 95% confidence interval, 0.67-1.28; P= .642). Results suggested higher exacerbation rates in patients with blood eosinophils ≥300 cells/μL and FeNO ≥25 ppb. No prognostic value for serum periostin related to exacerbations was detected. Higher blood eosinophils combined with increased FeNO were potentially associated with increased exacerbation rates.

BASELINE PERCENT PREDICTED FEV1 DOES NOT PREDICT A RESPONSE TO MEPOLIZUMAB IN PATIENTS WITH SEVERE EOSINOPHILIC ASTHMA: META-ANALYSIS FROM TWO PHASE 3 TRIALS

SESSION TITLE: Monday Electronic Posters 4 SESSION TYPE: Original Inv Poster Discussion PRESENTED ON: 10/21/2019 02:30 PM - 03:15 PM PURPOSE: The MENSA (NCT01691521) and MUSCA (NCT02281318) trials showed that mepolizumab consistently reduced annualized asthma exacerbation rates in patients with severe eosinophilic asthma. There are several risk factors for exacerbations, including decreased pulmonary function. The effect of the approved dose of mepolizumab, 100 mg subcutaneous (SC), on exacerbations according to a patient’s baseline % predicted FEV1 has not been examined. METHODS: This post-hoc subgroup analysis investigated the annual rate of clinically significant exacerbations (requiring administration of systemic glucocorticoids for ≥3 days or an emergency department visit/hospitalization) in patients receiving mepolizumab or placebo according to baseline % predicted FEV1 at screening in 3 categories (≤ 60, > 60 – ≤ 80 and > 80%). Exacerbation rates in the meta-analysis were measured at week 32 for MENSA and week 24 for MUSCA. Analyses were performed using negative binomial regression and treatment differences combined across studies using fixed-effects inverse-variance weighted meta-analysis. RESULTS: Of the 936 patients, 489 (52%), 354 (38%) and 93 (10%) were identified as having a ≤ 60, > 60 – ≤ 80 and > 80% predicted FEV1 at screening, respectively. Clinically relevant reductions in exacerbation rates were observed in the meta-analysis with 100 mg SC mepolizumab versus placebo, in patients from all categories of obstruction (rate ratio [mepolizumab/placebo]: ≤ 60% predicted FEV1 is 0.51[95% confidence interval [CI]: 0.39,0.66]; > 60 - ≤ 80% predicted FEV1 is 0.39[95% CI: 0.26,0.58]; > 80% predicted FEV1 is 0.37[95% CI: 0.19,0.73]). There was a numerical trend of an increase in the proportion of patients not having a clinically significant exacerbation with mepolizumab treatment, compared to placebo, with increasing baseline lung function (odds ratio [mepolizumab v placebo]: ≤ 60% predicted FEV1 is 2.67[95% CI: 1.79,3.98]; > 60 - ≤ 80% predicted FEV1 is 3.18[95% CI: 1.92,5.28]; > 80% predicted FEV1 is 4.90[95% CI: 1.54,15.62]). CONCLUSIONS: Mepolizumab produced clinically relevant reductions in the exacerbation rate versus placebo in patients with severe eosinophilic asthma irrespective of baseline % predicted FEV1. This suggests that baseline airway obstruction is not a factor that predicts a response to mepolizumab although patients with less severe lung function impairment may experience increasing relative benefit. This is aligned with DREAM that showed in a covariate modelling analysis, baseline % predicted FEV1 did not predict a response to intravenous mepolizumab. CLINICAL IMPLICATIONS: This abstract provides health care professionals with clinically relevant information on the efficacy of mepolizumab in severe eosinophilic asthma patients stratified by severity of airflow obstruction. DISCLOSURES: Employee relationship with GSK Please note: >$100000 Added 03/15/2019 by Frank Albers, source=Web Response, value=Salary Employee relationship with GSK Please note: >$100000 Added 03/18/2019 by Eric Bradford, source=Web Response, value=Salary Employee relationship with GSK Please note: >$100000 Added 03/18/2019 by Eric Bradford, source=Web Response, value=Ownership interest Employee relationship with GSK Please note: $5001 - $20000 Added 03/13/2019 by Stephen Mallett, source=Web Response, value=Shares Speaker/Speaker's Bureau relationship with Novartis Please note: $1001 - $5000 Added 03/19/2019 by Andrew Menzies-Gow, source=Web Response, value=Honoraria Speaker/Speaker's Bureau relationship with Teva Please note: $1001 - $5000 Added 03/19/2019 by Andrew Menzies-Gow, source=Web Response, value=Honoraria Advisory Committee Member relationship with Astra Zeneca Please note: $5001 - $20000 Added 03/19/2019 by Andrew Menzies-Gow, source=Web Response, value=Honoraria Advisory Committee Member relationship with Glaxo SmithKline Please note: $1001 - $5000 Added 03/19/2019 by Andrew Menzies-Gow, source=Web Response, value=Honoraria Scientific Medical Advisor relationship with Boehringer Ingelheim Please note: $1001 - $5000 Added 03/19/2019 by Andrew Menzies-Gow, source=Web Response, value=Honoraria Consultant relationship with Vectura Please note: $5001 - $20000 Added 03/19/2019 by Andrew Menzies-Gow, source=Web Response, value=Honoraria Advisory Committee Member relationship with Sanofi Please note: $1001 - $5000 Added 03/19/2019 by Andrew Menzies-Gow, source=Web Response, value=Honoraria Employee relationship with GlaxoSmithKline Please note: >$100000 Added 03/07/2019 by Jared Silver, source=Web Response, value=Salary Employee relationship with GlaxoSmithKline (estimated stock ownership by time of Chest) Please note: $20001 - $100000 Added 03/07/2019 by Jared Silver, source=Web Response, value=stock Employee relationship with GSK Please note: >$100000 Added 03/07/2019 by Steven Smith, source=Web Response, value=Salary Employee relationship with GSK Please note: $5001 - $20000 Added 03/07/2019 by Steven Smith, source=Web Response, value=Stock Employee relationship with GlaxoSmithKline Please note: >$100000 Added 03/18/2019 by Steven Yancey, source=Web Response, value=Salary