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Mario Cazzola,1 Nicola A Hanania,2 Clive P Page,3 Maria Gabriella Matera4 1Department of Experimental Medicine, University of Rome “Tor Vergata”, Rome, Italy; 2Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA; 3Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King’s College London, London, UK; 4Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, ItalyCorrespondence: Mario Cazzola, Department of Experimental Medicine, University of Rome “Tor Vergata”, Rome, Italy, Email mario.cazzola@uniroma2.itAbstract: Airway inflammation, driven by different types of inflammatory cells and mediators, plays a fundamental role in COPD and its progression. Neutrophils, eosinophils, macrophages, and CD4+ and CD8+ T lymphocytes are key players in this process, although the extent of their participation varies according to the patient’s endotype. Anti-inflammatory medications may modify the natural history and progression of COPD. However, since airway inflammation in COPD is relatively resistant to corticosteroid therapy, innovative pharmacological anti-inflammatory approaches are required. The heterogeneity of inflammatory cells and mediators in annethe different COPD endo-phenotypes requires the development of specific pharmacologic agents. Indeed, over the past two decades, several mechanisms that influence the influx and/or activity of inflammatory cells in the airways and lung parenchyma have been identified. Several of these molecules have been tested in vitro models and in vivo in laboratory animals, but only a few have been studied in humans. Although early studies have not been encouraging, useful information emerged suggesting that some of these agents may need to be further tested in specific subgroups of patients, hopefully leading to a more personalized approach to treating COPD.Keywords: anti-inflammatory drugs, COPD, inflammation, treatment

Nicola A Hanania,1 Scott H Bunner,2 Lindsay GS Bengtson,2 Afisi S Ismaila,3,4 Michael Bogart5 1Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA; 2Optum, Eden Prairie, MN, USA; 3Value Evidence and Outcomes, GSK, Collegeville, PA, USA; 4Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada; 5US Value Evidence & Outcomes, GSK, Research Triangle Park, NC, USACorrespondence: Afisi S Ismaila, Value Evidence and Outcomes, GSK, 1250 S. Collegeville Road, Collegeville, PA, 19426-0989, USA, Tel +1 919-3158229, Email afisi.s.ismaila@gsk.comPurpose: To examine the impact of initiating fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) in a single device on chronic obstructive pulmonary disease (COPD) exacerbations, COPD exacerbation-related costs, and all-cause and COPD-related healthcare resource utilization (HCRU) and costs in patients with COPD.Methods: Retrospective database analysis of patients with COPD aged ≥ 40 years who initiated FF/UMEC/VI between September 1, 2017, and December 31, 2018 (index date: first pharmacy claim for FF/UMEC/VI), following evidence of multiple-inhaler triple therapy (MITT) (≥ 30 consecutive days) in the year prior to index. COPD exacerbations, COPD exacerbation-related costs, and all-cause and COPD-related HCRU and costs were compared between the baseline period (12 months prior to and including index) and follow-up period (12 months following index).Results: Data from 912 patients (mean [SD] age: 71.2 [8.1], 51.2% female) were included in the analyses. Among the overall cohort, mean count of total COPD exacerbations (moderate or severe) per patient was statistically significantly lower in the follow-up period compared to baseline (1.2 vs 1.4, p=0.001). The proportion of patients with ≥ 1 COPD exacerbation (moderate or severe) was also statistically significantly lower in the follow-up period compared to baseline (56.4% vs 62.4%, p=0.001). All-cause and COPD-related HCRU were similar during follow-up compared to baseline, although the proportion of patients with COPD-related ambulatory visits was lower during follow-up (p< 0.001). COPD-related office visit costs, emergency room visit costs, and pharmacy costs were statistically significantly lower during follow-up compared to baseline (p< 0.001; p=0.019; p< 0.001, respectively).Conclusion: In a real-world setting, patients on MITT who subsequently initiated FF/UMEC/VI in a single device had significant reductions in the rate of COPD exacerbations (moderate or severe). Switching to FF/UMEC/VI also resulted in improvements in some HCRU and cost outcomes. These data support the use of FF/UMEC/VI among patients at high risk of exacerbation to reduce future risk and improve outcomes.Keywords: chronic obstructive pulmonary disease, exacerbations, healthcare utilization, multiple-inhaler triple therapy, FF/UMEC/VI, single-inhaler triple therapy

Hilary C Strollo,1 Seyed M Nouraie,1 Karin F Hoth,2 Craig M Riley,3 Chad Karoleski,1 Yingze Zhang,1 Nicola A Hanania,4 Russell P Bowler,5,6 Jessica Bon,1 Frank C Sciurba1 1University of Pittsburgh Medical Center, Department of Medicine, Department of Pulmonary Allergy and Critical Care Medicine, Pittsburgh, PA, USA; 2University of Iowa Carver College of Medicine, Department of Psychiatry, Iowa City, IA, USA; 3Chester County Hospital, University of Pennsylvania Health System, West Chester, PA, USA; 4Baylor College of Medicine, Department of Pulmonary, Critical Care and Sleep Medicine, Houston, TX, USA; 5National Jewish Health, Department of Medicine, Denver, CO, USA; 6University of Colorado School of Medicine, Denver, CO, USACorrespondence: Hilary C StrolloUniversity of Pittsburgh Medical Center, Department of Medicine, Department of Pulmonary Allergy and Critical Care Medicine, NW 628 UPMC Montefiore, 3459 Fifth Avenue, Pittsburgh, PA, 15213, USATel +1 412-692-2210Fax +1 412-692-4842Email strolloh2@upmc.eduRationale: Depression is a prevalent comorbidity of chronic obstructive pulmonary disease (COPD) that, along with COPD, has been associated with inflammation. An association between inflammation and depression in COPD has not been validated in a large COPD cohort.Methods: Individuals from the University of Pittsburgh SCCOR cohort and the COPDGene cohort with tobacco use history and airway obstruction (FEV1/FVC < 0.7) were evaluated using the Beck Depression Inventory II (BDI-II) and the Hospital Anxiety and Depression Scale (HADS), respectively. Participants completed symptom-related questionnaires and plasma IL-6 measurements. T-test, Fisher’s Exact tests and logistic regression were used for statistical analysis.Results: The SCCOR cohort included 220 obstructed participants: 44% female and 21.4% with elevated depressive symptoms. GOLD staging distribution was predominantly stage I and II. The COPDGene cohort included 745 obstructed participants: 44% female and 13.0% with elevated depressive symptoms. GOLD distribution was predominantly stage II and III. In the SCCOR cohort, correlation between IL-6 and depressive symptoms trended toward significance (p= 0.08). Multivariable modeling adjusted for FEV1, age, gender and medical comorbidities showed a significant association (OR = 1.70, 95% CI = 1.08– 2.69). IL-6 was significantly associated with elevated depressive symptoms in COPDGene in both univariate (p=0.001) and multivariable modeling (OR = 1.52, 95% CI =1.13– 2.04).Conclusion: Elevated plasma IL-6 levels are associated with depressive symptoms in individuals with COPD independent of airflow limitation and comorbid risk factors for depression. Our results suggest that systemic inflammation may play a significant and possibly bidirectional role in depression associated with COPD.Keywords: IL-6, depression, beck depression inventory, BDI, HADS, TNF-a, CRP, SCCOR, COPDGene

Arzu Ari,1 Karen Blain,2 Said Soubra,1 Nicola A Hanania3 1Department of Respiratory Care, Texas State University, Round Rock, TX, USA; 2Department of Respiratory Therapy, University of North Carolina Wilmington, Wilmington, NC, USA; 3Airways Clinical Research Center, Baylor College of Medicine, Houston, TX, USACorrespondence: Arzu Ari Email arzuari@txstate.eduAbstract: COVID-19 has affected millions of patients, caregivers, and clinicians around the world. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spreads via droplets and close contact from person to person, and there has been an increased concern regarding aerosol drug delivery due to the potential aerosolizing of viral particles. To date, little focus has been given to aerosol drug delivery to patients with COVID-19 treated at home to minimize their hospital utilization. Since most hospitals were stressed with multiple admissions and experienced restricted healthcare resources in the era of COVID-19 pandemic, treating patients with COPD at home became essential to minimize their hospital utilization. However, guidance on how to deliver aerosolized medications safely and effectively to this patient population treated at home is still lacking. In this paper, we provide some strategies and rationales for device and interface selection, delivery technique, and infection control for patients with COPD who are being treated at home in the era of COVID-19 and beyond.Keywords: coronavirus, COVID-19, SARS-CoV-2, aerosols, nebulizers, inhalers, homecare, infection control

Nicola A Hanania,1 Abebaw M Yohannes,2 Ayca Ozol-Godfrey,3 Michael Tocco,3 Thomas Goodin,3 Sanjay Sharma,3 Shahin Sanjar3 1Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX, 77030, USA; 2Department of Physical Therapy, Azusa Pacific University, Azusa, CA, USA; 3Sunovion Pharmaceuticals Inc., Marlborough, MA, USACorrespondence: Nicola A HananiaSection of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX, USATel +1 713-873-3454Email hanania@bcm.eduBackground: Anxiety and depression (A/D) are common in patients with chronic obstructive pulmonary disease (COPD) and are often associated with lower adherence to treatment and worse patient-related outcomes. However, studies on the impact of comorbid A/D on responses to bronchodilators are limited.Methods: This post hoc analysis of pooled data (N=861) from the GOLDEN 3 and 4 studies compared the efficacy and safety of nebulized glycopyrrolate (GLY) 25 μg in patients with moderate-to-very-severe COPD, grouped by self-reported A/D. Changes in forced expiratory volume in 1 second (FEV1) and health-related quality of life determined by St George’s Respiratory Questionnaire (SGRQ) scores in patients with or without comorbid A/D (A/D [+] or A/D [–]) were examined following 12 weeks of GLY 25 μg twice-daily (BID) or placebo treatment.Results: A/D (+) patients were predominantly female, younger, included a higher proportion of current smokers, and had higher baseline SGRQ scores compared with the A/D (–) group. At 12 weeks, GLY resulted in placebo-adjusted improvements from baseline in FEV1 of 46.9 mL (p=0.19; not significant) and 106.7 mL (p< 0.0001), in the A/D (+) and A/D (–) groups, respectively. Improvements were observed with GLY compared to placebo in SGRQ scores, regardless of baseline A/D status; the placebo-adjusted least squares mean change from baseline in SGRQ total scores was – 3.16 (p> 0.05) and – 3.34 (p< 0.001), for the A/D (+) and A/D (–) groups, respectively. Despite numerical improvements in SGRQ scores with GLY in the A/D (+) group, a higher response to placebo was observed. GLY was generally well tolerated throughout 12 weeks of treatment; incidence of adverse events was higher in the A/D (+) group compared with the A/D (–) group in both treatment arms.Conclusion: GLY 25 μg BID resulted in numerical improvements in FEV1, SGRQ total scores and SGRQ responder rates in patients with moderate-to-very-severe COPD, regardless of A/D status at baseline; significant improvements were noted only in the A/D (+) group. The results emphasize the importance of considering underlying comorbidities including A/D when evaluating the efficacy of COPD treatments.Keywords: anxiety, COPD, depression, LAMA, nebulized glycopyrrolate

Dharani K Narendra, Nicola A HananiaSection of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX, USAAbstract: Many patients with chronic obstructive pulmonary disease (COPD) continue to experience exacerbations despite receiving standard-of-care treatments. Novel approaches to COPD treatment focus on understanding and targeting molecular mechanisms of airway inflammation, airway obstruction, remodeling and lung destruction. Several identified phenotypes and endotypes of COPD will pave the future path for a more personalized approach to therapy. Although well known to be associated with neutrophilic inflammation, COPD may also be driven by eosinophilic inflammation both at stable states and during exacerbation. Targeting eosinophilic inflammation has been successful in managing severe eosinophilic asthma and may hold promise in certain phenotypes of COPD. The most promising biologic treatments at an advanced stage of development are agents blocking interleukin (IL)-5 or its receptor. This review examines our current understanding of the eosinophilic inflammation in COPD and the rationale for IL-5 targeting agents.Keywords: COPD, airway inflammation, eosinophils, IL-5, mepolizumab, benralizumab

Nicola A Hanania,1 Denis E O’Donnell21Department of Medicine, Section of Pulmonary and Critical Care, Baylor College of Medicine, Houston, TX, USA; 2Division of Respirology, Department of Medicine, Queen’s University, Kingston, Ontario, CanadaAbstract: Dyspnea is a distressing, debilitating, and near-ubiquitous symptom affecting patients with COPD. In addition to the functional consequences of dyspnea, which include activity limitation and reduced exercise tolerance, it is important to consider its psychological impact on patients with COPD, such as onset of depression or anxiety. Moreover, the anticipation of dyspnea itself can have a significant effect on patients’ emotions and behavior, with patients frequently self-limiting physical activity to avoid what has become the hallmark symptom of COPD. Dyspnea is, therefore, a key target for COPD treatments. Pharmacologic treatments can optimize respiratory mechanics, provide symptom relief, and reduce patients’ increased inspiratory neural drive to breathe. However, it is important to acknowledge the value of non-pharmacologic interventions, such as pulmonary rehabilitation and patient self-management education, which have proven to be invaluable tools for targeting the affective components of dyspnea. Furthermore, it is important to encourage maintenance of physical activity to optimize long-term patient outcomes. Here, we review the physiological and psychological consequences of activity-related dyspnea in COPD, assess the efficacy of modern management strategies in improving this common respiratory symptom, and discuss key unmet clinical and research needs that warrant further immediate attention.Keywords: dyspnea, chronic obstructive pulmonary disease, psychology, physiology, management

Nicola A Hanania,1 Sanjay Sethi,2 Arkady Koltun,3 Jonathan K Ward,4 Jacqui Spanton,4 Dik Ng4 1Asthma Clinical Research Center, Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA; 2Pulmonary, Critical Care, and Sleep Medicine, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, USA; 3Global Medical Affairs, Mylan Inc., Canonsburg, PA, USA; 4Mylan Global Respiratory Group, Mylan Pharma UK Ltd., Sandwich, Kent, UK Background: Formoterol fumarate inhalation solution (FFIS; Perforomist®) is a long-acting β2-agonist (LABA) marketed in the US as a nebulized COPD maintenance treatment. Because long-term LABA use was associated with a potential increased risk of exacerbation or death in asthma patients, the US Food and Drug Administration (FDA) requested a postmarketing commitment study to evaluate long-term safety in COPD patients. Methods: This was a multicenter, randomized, double-blind, placebo-controlled, noninferiority study. Patients (N=1,071; mean age, 62.6 years; 48.5% male; 89.7% white) with moderate-to-severe COPD on stable COPD therapy received FFIS (20 µg; n=541) or placebo (n=530) twice daily. The primary end point was the combined incidence of respiratory death, first COPD-related ER visit, or first COPD exacerbation-related hospitalization during 1 year post randomization. Noninferiority to placebo was concluded if the two-sided 90% CI of the HR of FFIS to placebo was

Anthony D D’Urzo,1 Mario Cazzola,2 Nicola A Hanania,3 Roland Buhl,4 M Reza Maleki-Yazdi5 1Department of Family and Community Medicine, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; 2Department of Experimental Medicine and Surgery, Tor Vergata University of Rome, Rome, Italy; 3Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA; 4Pulmonary Department, Mainz University Hospital, Mainz, Germany; 5Division of Respiratory Medicine, Women’s College Hospital, University of Toronto, Toronto, ON, Canada Abstract: COPD causes considerable health and economic burden worldwide, with incidence of the disease expected to continue to rise. Inhaled bronchodilators, such as long-acting muscarinic antagonists (LAMAs) and long-acting β2-agonists (LABAs), are central to the maintenance treatment of patients with COPD. Clinical studies have demonstrated that combined LAMA + LABA therapies improve efficacy while retaining a safety profile similar to LAMA or LABA alone. This has led to the development of several LAMA/LABA fixed-dose combination (FDC) therapies, which provide patients with the convenience of two active compounds in a single inhaler. GFF MDI (Bevespi Aerosphere®) is an FDC of glycopyrrolate/formoterol fumarate 18/9.6 µg formulated using innovative co-suspension delivery technology for administration via metered dose inhaler (MDI). GFF MDI was developed to make a treatment option available for patients who have a requirement or preference to use an MDI, rather than a dry powder or soft mist inhaler. Now that several LAMA/LABA FDCs have been approved for use in COPD, we review the impact of dual-bronchodilator treatment on COPD therapy and discuss recent clinical studies that are helping to develop a more comprehensive understanding of how LAMA/LABA FDCs can improve patient outcomes. Keywords: long-acting bronchodilator, LAMA, LABA, chronic obstructive pulmonary disease, fixed-dose combination, GFF MDI

James F Donohue,1 Vamsi K Bollu,2 Donald E Stull,3 Lauren M Nelson,4 Valerie SL Williams,4 Michael D Stensland,5 Nicola A Hanania6 1Department of Pulmonary Diseases and Critical Care Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 2Worldwide Health Economics and Outcomes Research, Bristol-Myers Squibb, Princeton, NJ, 3Data Analytics and Design Strategy, 4Psychometrics, RTI Health Solutions, Research Triangle Park, NC, 5Agile Outcomes Research, Inc., Rochester, MN, 6Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA Background: Symptom severity is the largest factor in determining subjective health in COPD. Symptoms (eg, chronic cough, dyspnea) are associated with decreased health-related quality of life (HRQoL). We evaluated the impact of arformoterol on HRQoL in COPD patients, measured by St George’s Respiratory Questionnaire (SGRQ). Post hoc growth mixture model (GMM) analysis examined symptom response profiles. Methods: We examined data from a randomized, double-blind, parallel-group, 12-month safety trial of twice-daily nebulized arformoterol 15 µg (n=420) versus placebo (n=421). COPD severity was assessed by Global Initiative for Chronic Obstructive Lung Disease (GOLD) status. GMM analysis identified previously unknown patient subgroups and examined the heterogeneity in response to SGRQ Symptoms scores. Results: SGRQ Total score improved by 4.24 points with arformoterol and 2.02 points with placebo (P=0.006). Significantly greater improvements occurred for arformoterol versus placebo in SGRQ Symptoms (6.34 vs 4.25, P=0.031) and Impacts (3.91 vs 0.97, P=0.001) scores, but not in Activity score (3.57 vs 1.75, P=0.057). GMM identified responders and nonresponders based on the SGRQ Symptoms score. End-of-study mean difference in SGRQ Symptoms scores between these latent classes was 20.7 points (P

Mario Cazzola,1 Nicola Alexander Hanania,2 William MacNee,3 Katja Rüdell,4 Claire Hackford,4 Nihad Tamimi4 1University of Rome ‘Tor Vergata’, Department of Medicine of Systems, Unit of Respiratory Clinical Pharmacology, Rome, Italy; 2Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX, USA; 3University of Edinburgh/MRC Centre for Inflammation Research, The Queen’s Medical Research Institute, Edinburgh, United Kingdom; 4Patient Reported Outcome Center of Excellence, Global Market Access, Primary Care Business Unit, Pfizer, Tadworth, United Kingdom Abstract: Patient-reported outcome (PRO) measures that quantify disease impact have become important measures of outcome in COPD research and treatment. The objective of this literature review was to comprehensively evaluate psychometric properties of available PRO instruments and the ability of each of them to characterize pharmaceutical treatment effects from published clinical trial evidence. Identified in this study were several PRO measures, both those that have been used extensively in COPD clinical trials (St George’s Respiratory Questionnaire and Chronic Respiratory Questionnaire) and new instruments whose full value is still to be determined. This suggests a great need for more information about the patient experience of treatment benefit, but this also may pose challenges to researchers, clinicians, and other important stakeholders (eg, regulatory agencies, pharmaceutical companies) who develop new treatment entities and payers (including but not limited to health technology assessment agencies such as the National Institute for Health and Care Excellence and the Canadian Agency for Drugs and Technologies in Health). The purpose of this review is to enable researchers and clinicians to gain a broad overview of PRO measures in COPD by summarizing the value and purpose of these measures and by providing sufficient detail for interested audiences to determine which instrument may be the most suitable for evaluating a particular research purpose. Keywords: COPD, patient reported outcome, health related quality of life, quality of life, psychometric properties

Abebaw M Yohannes,1 Martin J Connolly,2 Nicola A Hanania31Manchester Metropolitan University, Department of Health Professions, Manchester, UK; 2University of Auckland, Freemasons’ Department of Geriatric Medicine, Auckland, New Zealand; 3Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USAAbstract: Tiotropium bromide is an anticholinergic agent that has gained worldwide acceptance as a first-line, once daily maintenance therapy for patients with moderate-to-severe chronic obstructive pulmonary disease. The purpose of this review is to synthesize the evidence base in the past 10 years on the development of tiotropium and its efficacy compared to other able interventions such as long-acting beta agonists (LABAs), as well as to assess its safety profile and its effects on health-related outcomes in patients with COPD. Treatment with tiotropium bromide has generally improved patients’ health-related quality of life, reduced the number of patients suffering from acute exacerbations, decreased the number of hospitalizations, improved dyspnea, and reduced adverse events compared to placebo. In the past decade, several studies have examined the safety and efficacy of tiotropium in comparison to placebo and to LABAs (salmeterol, formoterol, and indacaterol) over periods ranging from 3 months to 48 months of follow-up. Head-to-head comparisons of tiotropium 18 µg (once daily) with salmeterol 50 µg (twice daily) in well-controlled trials demonstrated that tiotropium was superior in reducing acute exacerbation events and in improving quality of life. In a few short-term studies, indacaterol was comparable to tiotropium in its efficacy in improving health-related outcomes. Although the safety record of tiotropium has been exemplary in comparison to placebo, anticholinergic events such as dry mouth can be encountered in some patients. While the long-term safety of tiotropium when delivered in the HandiHaler® has been well documented, its delivery using the Respimat® Soft Mist Inhaler™ was associated with an elevated risk of cardiovascular complications, including increased mortality when compared to placebo. The exact mechanism for this is not known but is being investigated in a large multinational study that will evaluate the long-term safety of different doses of tiotropium delivered by the Respimat® soft mist inhaler versus the HandiHaler®. Further studies are required to investigate the efficacy and safety of tiotropium in comparison with novel LABAs such as indacaterol and vilanterol, and with other emerging novel anticholinergic agents such as aclidinium bromide and NVA237 (glycopyrronium bromide).Keywords: bronchodilator, tiotropium, salmeterol, indacaterol, LABA, chronic obstructive pulmonary disease

Marc L Decramer,1 Nicola A Hanania,2 Jan O Lötvall,3 Barbara P Yawn41Respiratory Division, University Hospital, KU Leuven, Belgium; 2Section of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, TX, USA; 3Krefting Research Centre, University of Gothenburg, Gothenburg, Sweden; 4Department of Research, Olmsted Medical Center, Rochester, MN, USABackground: Inhaled long-acting bronchodilators are the mainstay of pharmacotherapy for chronic obstructive pulmonary disease (COPD). Both the twice-daily long-acting ß2-adrenoceptor agonists (LABAs) salmeterol and formoterol and the once-daily LABA indacaterol are indicated for use in COPD. This review examines current evidence for the safety of LABAs in COPD, focusing on their effect on exacerbations and deaths.Methods: We searched PubMed for placebo-controlled studies evaluating long-term (≥24 weeks) use of formoterol, salmeterol, or indacaterol in patients with stable COPD, published between January 1990 and September 2012. We summarized data relating to exacerbations and adverse events, particularly events related to COPD.Results: From 20 studies examined (8774 LABA-treated patients), there was no evidence of an association between LABA treatment and increased exacerbations, COPD-related adverse events, or deaths. Where analyzed as an efficacy outcome, LABA treatment was generally associated with significant or numerical reductions in COPD exacerbations compared with placebo. Incidences of COPD-related adverse events were similar for active and placebo treatments. The incidence of adverse events typically associated with the ß2-agonist drug class such as skeletal muscle tremors and palpitations was low (often

Carole Drexel1, Anne Jacobson2, Nicola A Hanania3, Ben Whitfield4, Jay Katz5, Thomas Sullivan51Potomac Center for Medical Education, Columbia, MD, USA; 2Potomac Center for Medical Education, Port St John, FL, USA; 3Baylor College of Medicine, Houston, TX, USA; 4CE Outcomes, LLC, Birmingham, AL, USA; 5Rockpointe, Columbia, MD, USABackground: Major clinical gaps impede the evidence-based treatment of chronic obstructive pulmonary disease (COPD) in the primary care setting. Studies are needed to measure the effectiveness of continuing medical education (CME) on improving physician competency and performance toward evidence-based COPD care.Methods: Between September 26, 2009 and December 12, 2009, 769 primary care physicians participated in a series of 12 regional, live, interactive, case-based, multiformat, half-day CME programs on COPD. A subgroup of randomly selected participants (n = 50) and demographically matched nonparticipants (n = 50) completed surveys that included case vignettes, a validated tool for measuring physician performance in clinical practice. Cohen's d was used to calculate the magnitude of difference between participants and nonparticipants in the delivery of evidence-based care.Results: Physicians who participated in CME programs were 50% more likely to provide evidence-based COPD care than physicians who did not participate. Compared with nonparticipants, participating physicians were more likely to recognize COPD correctly in a patient presenting with dyspnea (74% versus 94%, P = 0.007), recognize that women may have a greater susceptibility than men to the toxic effects of smoking (54% versus 90%, P < 0.001), and identify the mechanisms of action of emerging therapies (33% versus 65%, P = 0.003).Conclusion: Physicians who participated in a half-day regional CME program on COPD diagnosis, staging, and treatment were significantly more likely than nonparticipants to deliver evidence-based COPD care. With multiformat, interactive, focused educational interventions, physicians can make diagnostic and therapeutic choices in the primary care setting that align more closely with current guidelines and clinical evidence in COPD management.Keywords: COPD, continuing medical education, practice patterns, outcomes measurement, case vignettes, effect size