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Background: The management of mild asthma has lacked an over-the-counter (OTC) option aside from inhaled epinephrine, which is available in the United States. However, inhaled epinephrine use without an inhaled corticosteroid may increase the risk of asthma death., Objective: To compare the cost-effectiveness of OTC as-needed budesonide-formoterol as a plausible alternative to inhaled epinephrine., Methods: We developed a probabilistic Markov model to compare OTC as-needed budesonide-formoterol inhaler use vs inhaled epinephrine use in adults with mild asthma from a US societal perspective over a lifetime horizon, with a 3% annual discount rate (2022 US dollars). Inputs were derived from the SYmbicort Given as-needed in Mild Asthma (SYGMA) trials, published literature, and commercial costs. Outcomes were quality-adjusted life-years (QALY), costs, incremental net monetary benefit (INMB), severe asthma exacerbations, well-controlled asthma days, and asthma-related deaths. Microsimulation was used to evaluate underinsured Americans living with mild asthma (n = 5,250,000)., Results: Inhaled epinephrine was dominated (with lower QALYs gains at a higher cost) by both as-needed budesonide-formoterol (INMB, $15,541 at a willingness-to-pay of $100,000 per QALY) and the no-OTC inhaler option (INMB, $1023). Adults using as-needed budesonide-formoterol had 145 more well-controlled asthma days, 2.79 fewer severe exacerbations, and an absolute risk reduction of 0.23% for asthma-related death compared with inhaled epinephrine over a patient lifetime. As-needed budesonide-formoterol remained dominant in all sensitivity and scenario analyses, with a 100% probability of being cost-effective compared with inhaled epinephrine in probabilistic sensitivity analysis., Conclusion: If made available, OTC as-needed budesonide-formoterol for treating mild asthma in underinsured adults without HCP management improves asthma outcomes, prevents fatalities, and is cost-saving., Competing Interests: Disclosures Dr Shaker has participated in research that has received funding from DBV; is a member of the Joint Task Force on Practice Parameters; serves as an associated editor for Annals of Allergy, Asthma, and Immunology; and is an editorial board member for the Journal of Allergy and Clinical Immunology In Practice. Dr Greenhawt is a consultant for Aquestive; is a member of physician and medical advisory boards for DBV Technologies, Nutricia, Novartis, Aquestive, Allergy Therapeutics, AstraZeneca, ALK-Abello, Bryn, and Prota; is an unpaid member of the scientific advisory council for the National Peanut Board and the medical advisory board of the International Food Protein Induced Enterocolitis Syndrome Association; is a member of the Brighton Collaboration Criteria Vaccine Anaphylaxis 2.0 working group; is the senior associate editor for the Annals of Allergy, Asthma, and Immunology, and is member of the Joint Taskforce on Allergy Practice Parameters. Dr Sadatsafavi has received honoraria from GlaxoSmithKline and AstraZeneca for unrelated activities; and received funding from AstraZeneca and GlaxoSmithKline for unrelated projects. Dr Abrams is an employee of the Public Health Agency of Canada. Dr Oppenheimer is a consultant for Amgen, Aimmune, Aquestive, GSK, and Sanofi; is a member of the Adjudication or Data Safety Monitoring Board for AstraZeneca, Amgen, Abbvie, Novartis, and GlaxoSmithKline; is the Executive Editor for the Annals of Allergy Asthma and Immunology; and is a reviewer for UpToDate. Dr Mosnaim receives current research grant support from GlaxoSmithKline, Novartis, and Sanofi-Regeneron; and has received past research grant support from AstraZeneca, ALK-Abello, Teva, and Genentech. The remaining authors have no conflicts of interest to report., (Copyright © 2023 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Rationale: Daily oral azithromycin therapy can reduce the risk of acute exacerbations of chronic obstructive pulmonary disease (COPD). However, given its adverse events and additional costs, it is not known whether adding long-term azithromycin as an adjunct therapy to inhaled pharmacotherapy is cost effective. Objectives: The objective of this study was to evaluate the cost-effectiveness of add-on azithromycin therapy in COPD as recommended by contemporary COPD management guidelines. Methods: We extended a previously validated Canadian COPD policy model to include azithromycin-related inputs and outcomes. The cost-effectiveness of azithromycin was evaluated over a 20-year time horizon in patients who continue to exacerbate despite receiving maximal inhaled therapies. The benefit of azithromycin was modeled as a reduction in exacerbation rates. Adverse events included cardiovascular death, hearing loss, gastrointestinal symptoms, and antimicrobial resistance. The incremental cost-effectiveness ratio (ICER) was calculated with costs in 2020 Canadian dollars ($) and quality-adjusted life-years (QALYs) discounted at 1.5% per year. The analysis was stratified among patient subgroups based on exacerbation histories. Results: In patients with a positive exacerbation history (one or more events in the previous 12 mo), azithromycin was associated with $49,732 costs, 7.65 QALYs, and 10.95 exacerbations per patient over 20 years. The corresponding values were $48,436, 7.62, and 11.86 for the reference group, resulting in an ICER of $43,200 per QALY gained. In patients defined as frequent exacerbators (two or more moderate or one or more severe events in the past 12 mo), the ICER was reduced to $8,862 per QALY gained. In patients with no history of exacerbation, azithromycin had lower QALYs and higher costs than the reference group. Conclusions: Add-on azithromycin is cost effective in patients with a recent history of exacerbations at commonly accepted willingness-to-pay thresholds of $50,000-$100,000/QALY. Guidelines should consider recommending add-on azithromycin for patients who had at least one moderate or severe exacerbation in the past year, albeit more information about treatment efficacy would strengthen this recommendation.

Background: Contemporary management of COPD relies on exacerbation history to risk-stratify patients for future exacerbations. Multivariable prediction models can improve the performance of risk stratification. However, the clinical utility of risk stratification can vary from one population to another., Research Question: How do two validated exacerbation risk prediction models (Acute COPD Exacerbation Prediction Tool [ACCEPT] and the Bertens model) compared with exacerbation history alone perform in different patient populations?, Study Design and Methods: We used data from three clinical studies representing populations at different levels of moderate to severe exacerbation risk: the Study to Understand Mortality and Morbidity in COPD (SUMMIT; N = 2,421; annual risk, 0.22), the Long-term Oxygen Treatment Trial (LOTT; N = 595; annual risk, 0.38), and Towards a Revolution in COPD Health (TORCH; N = 1,091; annual risk, 0.52). We compared the area under the receiver operating characteristic curve (AUC) and net benefit (measure of clinical utility) among three risk stratification algorithms for predicting exacerbations in the next 12 months. We also evaluated the effect of model recalibration on clinical utility., Results: Compared with exacerbation history, ACCEPT showed better performance in all three samples (change in AUC, 0.08, 0.07, and 0.10, in SUMMIT, LOTT, and TORCH, respectively; P ≤ .001 for all). The Bertens model showed better performance compared with exacerbation history in SUMMIT and TORCH (change in AUC, 0.10 and 0.05, respectively; P < .001 for both), but not in LOTT. No algorithm was superior in clinical utility across all samples. Before recalibration, the Bertens model generally outperformed the other algorithms in low-risk settings, whereas ACCEPT outperformed others in high-risk settings. All three algorithms showed the risk of harm (providing lower net benefit than not using any risk stratification). After recalibration, risk of harm was mitigated substantially for both prediction models., Interpretation: Exacerbation history alone is unlikely to provide clinical utility for predicting COPD exacerbations in all settings and could be associated with a risk of harm. Prediction models have superior predictive performance, but require setting-specific recalibration to confer higher clinical utility., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: The Acute Chronic Obstructive Pulmonary Disease (COPD) Exacerbation Prediction Tool (ACCEPT) was developed for individualised prediction of COPD exacerbations. ACCEPT was well calibrated overall and had a high discriminatory power, but overestimated risk among individuals without recent exacerbations. The objectives of this study were to 1) fine-tune ACCEPT to make better predictions for individuals with a negative exacerbation history, 2) develop more parsimonious models, and 3) externally validate the models in a new dataset., Methods: We recalibrated ACCEPT using data from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE, a three-year observational study, 1,803 patients, 2,117 exacerbations) study by applying non-parametric regression splines to the predicted rates. We developed three reduced versions of ACCEPT by removing symptom score and/or baseline medications as predictors. We examined the discrimination, calibration, and net benefit of ACCEPT 2·0 in the placebo arm of the Towards a Revolution in COPD Health (TORCH, a three-year randomised clinical trial of inhaled therapies in COPD, 1,091 patients, 1,064 exacerbations) study. The primary outcome for prediction was the occurrence of ≥2 moderate or ≥1 severe exacerbation in the next 12 months; the secondary outcomes were prediction of the occurrence of any moderate/severe exacerbation or any severe exacerbation., Findings: ACCEPT 2·0 had an area-under-the-curve (AUC) of 0·76 for predicting the primary outcome. Exacerbation history alone (current standard of care) had an AUC of 0·68. The model was well calibrated in patients with positive or negative exacerbation histories. Changes in AUC in reduced versions were minimal for the primary outcome as well as for predicting the occurrence of any moderate/severe exacerbations (ΔAUC<0·011), but more substantial for predicting the occurrence of any severe exacerbations (ΔAUC<0·020). All versions of ACCEPT 2·0 provided positive net benefit over the use of exacerbation history alone for some range of thresholds., Interpretation: ACCEPT 2·0 showed good calibration regardless of exacerbation history, and predicts exacerbation risk better than current standard of care for a range of thresholds. Future studies need to investigate the utility of exacerbation prediction in various subgroups of patients., Funding: This study was funded by a team grant from the Canadian Institutes of Health Research (PHT 178432)., Competing Interests: DS has received honorariums for COPD lectures sponsored by AstraZeneca, GSK, and Boehringer Ingelheim. All other authors declare no actual or perceived conflicts of interest., (© 2022 The Author(s).)