Primary Care Severe Asthma Registry and Education Project (PCSAR-EDU): Phase 1 - an e-Delphi for registry definitions and indices of clinician behaviour.

INTRODUCTION: Although most asthma is mild to moderate, severe asthma accounts for disproportionate personal and societal costs. Poor co-ordination of care between primary care and specialist settings is recognised as a barrier to achieving optimal outcomes. The Primary Care Severe Asthma Registry and Education (PCSAR-EDU) project aims to address these gaps through the interdisciplinary development and evaluation of both a 'real-world' severe asthma registry and an educational programme for primary care providers. This manuscript describes phase 1 of PCSAR-EDU which involves establishing interdisciplinary consensus on criteria for the: (1) definition of severe asthma; (2) generation of a severe asthma registry and (3) definition of an electronic-medical record data-based Clinician Behaviour Index (CBI). METHODS AND ANALYSIS: In phase 1, a modified e-Delphi activity will be conducted. Delphi panellists (n≥13) will be invited to complete a 30 min online survey on three separate occasions (i.e., three separate e-Delphi 'rounds') over a 3-month period. Expert opinion will be collected via an open-ended survey ('Open' round 1) and 5-point Likert scale and ranking surveys ('Closed' round 2 and 3). A fourth and final Delphi round will occur via synchronous meeting, whereby panellists approve a finalised ideal 'core criteria list', CBI and corresponding item weighting. ETHICS AND DISSEMINATION: Ethical approval has been obtained for the activities involved in phase 1 from the University of Toronto's Human Research Ethics Programme (approval number 39695). Future ethics approvals will depend on information gathered in the proceeding phase; thus, ethical approval for phase 2 and 3 of this study will be sought sequentially. Findings will be disseminated through conference presentations, peer-reviewed publications and knowledge translation tools.

Importance of distinguishing between asthma and chronic obstructive pulmonary disease in primary care.

OBJECTIVE: To facilitate distinction between asthma and chronic obstructive pulmonary disease (COPD) in day-to-day primary care practice, and provide practical treatment strategies using spirometric cases to outline how to recognize the clinical and spirometric overlap between asthma and COPD. SOURCES OF INFORMATION: The approaches described here were developed using evidence-based guidelines and the expertise of the authors, including research findings by the authors in the areas of asthma, COPD management, and spirometric testing in primary care. MAIN MESSAGE: There are patients with clinical or spirometric features of both asthma and COPD. Both asthma and COPD are associated with some degree of inflammation of the respiratory tract, mediated by the increased expression of inflammatory proteins. However, there are clear differences between asthma and COPD in the pattern of inflammation that occurs in the lungs. Diagnostic confusion between COPD and asthma is most likely to arise in older patients with respiratory complaints, particularly against a background that includes cigarette smoke or workplace exposure. Both asthma and COPD are clinical diagnoses based on patient history, symptoms, physical examination findings, and objective measures of lung function. Postbronchodilator spirometry is always needed to confirm a new diagnosis of COPD and should also be performed prebronchodilator for the diagnosis of asthma. However, in many cases, the interpretation of spirometry results is not straightforward. CONCLUSION: Understanding the nature and extent of the spirometric overlap between asthma and COPD is critical for tailoring a therapeutic strategy that is based on factors that include medical and family history, signs and symptoms, and a clear interpretation of spirometry data. This information will be leveraged differently for individual patients to arrive at the correct clinical diagnosis and to select the most appropriate therapy.

Importance de distinguer l'asthme de la maladie pulmonaire obstructive chronique en première ligne.

OBJECTIF: Faciliter la distinction entre l'asthme et la maladie pulmonaire obstructive chronique (MPOC) en pratique de première ligne de tous les jours, et fournir des stratégies thérapeutiques pratiques à l'aide de cas de spirométrie pour illustrer comment reconnaître le chevauchement clinique et spirométrique entre l'asthme et la MPOC. SOURCES D'INFORMATION: Les approches décrites ici s'appuient sur les lignes directrices factuelles et sur l'expertise des auteurs, y compris des observations de recherches menées par les auteurs dans les domaines de l'asthme, de la prise en charge de la MPOC et des examens de spirométrie en première ligne. MESSAGE PRINCIPAL: Certains patients présentent des caractéristiques cliniques communes à l'asthme et à la MPOC. Ces deux maladies sont associées à un certain degré d'inflammation des voies respiratoires, médiée par l'expression accrue de protéines inflammatoires. Il existe toutefois des différences évidentes entre l'asthme et la MPOC pour ce qui est de l'inflammation présente dans les poumons. La confusion diagnostique entre la MPOC et l'asthme survient le plus souvent chez les patients âgés qui se plaignent de symptômes respiratoires, surtout en contexte de tabagisme ou d'exposition professionnelle. Les diagnostics cliniques d'asthme et de MPOC sont fondés sur les antécédents du patient, les symptômes, l'examen physique et les mesures objectives de la fonction respiratoire. La spirométrie après bronchodilatation est toujours nécessaire pour confirmer un nouveau diagnostic de MPOC et elle doit également être réalisée avant la bronchodilatation pour poser un diagnostic d'asthme. Dans de nombreux cas, toutefois, il n'est pas évident d'interpréter les résultats de la spirométrie. CONCLUSION: Il est essentiel de bien comprendre la nature et la portée du chevauchement spirométrique entre l'asthme et la MPOC afin de concevoir une stratégie thérapeutique qui s'appuie sur des facteurs qui incluent les antécédents médicaux et familiaux, les signes et les symptômes, et l'interprétation claire des données de spirométrie. Cette information sera utilisée différemment auprès de chaque patient pour arriver au bon diagnostic clinique et sélectionner le traitement le plus approprié.

Aclidinium bromide/formoterol fumarate as a treatment for COPD: an update.

Introduction: Aclidinium/formoterol is a long-acting muscarinic antagonist (LAMA) and long-acting ß2-agonist (LABA) dual bronchodilator used as a maintenance treatment for patients with chronic obstructive pulmonary disease (COPD). The efficacy of aclidinium/formoterol has been demonstrated consistently in patients with moderate-to-severe COPD versus placebo and monocomponents, with a comparable safety profile.Areas covered: This review examines recent research findings that expand our understanding of the impact of aclidinium/formoterol on the burden of COPD. Reviewed outcomes include improvements in lung function, respiratory symptoms, health-related quality of life, exercise tolerance, exacerbation rates, and clinically important deteriorations. In addition, the reported cardiovascular safety of aclidinium and current LAMA/LABA treatment recommendations are discussed.Expert opinion: Aclidinium/formoterol reduces disease burden in patients with COPD, including those that are treatment-naïve, without a significant increase in safety risk compared with monotherapies. Furthermore, evidence supports an improvement in lung function over a 24-hour period with aclidinium/formoterol treatment versus monotherapy and placebo, which may offer an advantage over some once-daily LAMA/LABA combinations. In summary, the recent evidence discussed in this review adds weight to the use of LAMA/LABA combinations as an initial therapy for certain patients newly diagnosed with COPD.

Airway hyperresponsiveness in patients with normal spirometry results and symptoms compatible with asthma: Primary care retrospective chart review.

OBJECTIVE: To evaluate the proportion of patients with symptoms suggestive of asthma and normal lung function who exhibit airway hyperreactivity with methacholine challenge testing (MCT) in primary care. DESIGN: Retrospective chart review. SETTING: Primary care lung clinic in Toronto, Ont. PARTICIPANTS: A total of 69 patients presenting to the lung clinic who had symptoms compatible with asthma, normal spirometry test results, and were referred for MCT. MAIN OUTCOME MEASURES: Descriptive statistics, frequency counts, independent t tests, and 2 tests were used to examine differences in the proportion of clinical and demographic variables identified in patients with or without a positive MCT result. Effect size was determined between MCT-positive and MCT-negative patients for both categorical ( coefficient) and continuous (Hedges g) data. RESULTS: Twenty-one patients (30.4%) had positive MCT results, and 48 patients (69.6%) had negative MCT results. Family history of asthma and reduced baseline and postbronchodilator forced expiratory volume in 1 second were associated with a positive MCT result. CONCLUSION: The findings of this study provide insight into the utility of simple spirometry for asthma diagnosis and the need to further clarify the role of MCT in the primary care setting.

Variation Among Spirometry Interpretation Algorithms.

Several algorithms exist to facilitate spirometric interpretation in clinical practice, yet there is a lack of consensus on how spirometric criteria for asthma, COPD, and restrictive disorders should be incorporated into spirometry interpretation algorithms suitable for use in day-to-day primary care management. The purpose of this review was to identify and describe the variability that exists among spirometry interpretation algorithms and how this might be relevant to the interpretation of spirometric data of common conditions encountered in primary care. MEDLINE, Embase, and mainstream search engines were used to identify all English-language spirometry interpretation algorithm-related material between January 1990 and December 2018. Eight variations in spirometry interpretation algorithms were identified via specific a priori assumptions that each spirometry interpretation algorithm should contain content consistent with national and international guidelines related to spirometry interpretation. Of the 26 spirometry interpretation algorithms identified, 5 were deemed impractical for day-to-day use in primary care (19%), 23 lacked a logic string leading to the postbronchodilator FEV1/FVC (88%), 4 relied on postbronchodilator change in FEV1 to distinguish between asthma and COPD (15%), 24 lacked a prompt for bronchodilator challenge when FEV1/FVC was considered to be at a normal level (92%), 12 did not indicate whether the data represented a prebronchodilator or postbronchodilator scenario (46%), 7 did not include a logic string that considers mixed obstructive/restrictive defect (27%), 23 did not contain a prompt to refer for methacholine challenge testing when spirometry appeared normal (88%), and 2 spirometry interpretation algorithms did not include a logic string leading to restrictive disorder (8%). Our review suggests that there is considerable variability among spirometry interpretation algorithms available as diagnostic aids and that there is a need for standardization of spirometry interpretation algorithms in primary care.

An Evaluation Of Single And Dual Long-Acting Bronchodilator Therapy As Effective Interventions In Maintenance Therapy-Naïve Patients With COPD.

Background: Ideally, treatment recommendations for maintenance therapy-naïve patients with COPD should be based on studies conducted specifically in this population. We have reviewed evidence from previous studies of pharmacological treatments in maintenance therapy-naïve patients with COPD and performed a new post-hoc analysis of dual bronchodilator treatment in this population, aiming to assess the effectiveness of these interventions. Materials and methods: A literature review identified clinical trials that included analyses of patients with COPD who were maintenance therapy-naïve with long-acting ß2-agonists (LABA) or long-acting muscarinic antagonists (LAMA). Additionally, a post-hoc subgroup analysis was conducted for maintenance therapy-naïve patients with COPD in two large phase III, randomized, double-blind, 24-week trials investigating the efficacy of aclidinium bromide/formoterol fumarate (AB/FF) fixed-dose combination versus monotherapy or placebo (ACLIFORM [NCT01462942] and AUGMENT [NCT01437397]). Results: Treatment-naïve patients with COPD often represent a population of patients at the earliest stage at which most patients seek treatment. Of nine relevant studies identified, all reported positive findings for efficacy of LABA, LAMA, or LABA/LAMA treatment in maintenance therapy-naïve populations. Improvements were observed in lung function, symptoms, and health status versus monotherapy or placebo. Post-hoc analysis of ACLIFORM and AUGMENT demonstrated that AB/FF was effective in improving lung function in patients who had received no prior maintenance therapy. AB/FF showed improvements in 1 hr post-dose FEV1, trough FEV1, and patient-reported outcomes versus placebo and monotherapies. Combined with reviews of previous studies in maintenance therapy-naïve patients, these findings suggest that earlier intervention with a dual bronchodilator maintenance therapy, such as AB/FF, may provide significantly greater benefits than LAMA or LABA mono-bronchodilator therapy as a first maintenance treatment for COPD. Conclusion: These data show that therapeutic intervention is effective in treatment-naïve patients. Intervention with dual bronchodilator therapy as a first maintenance treatment for COPD may provide greater benefits than LAMA or LABA monotherapy.

Weighing the evidence for pharmacological treatment interventions in mild COPD; a narrative perspective.

There is increasing focus on understanding the nature of chronic obstructive pulmonary disease (COPD) during the earlier stages. Mild COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 1 or the now-withdrawn GOLD stage 0) represents an early stage of COPD that may progress to more severe disease. This review summarises the disease burden of patients with mild COPD and discusses the evidence for treatment intervention in this subgroup.Overall, patients with mild COPD suffer a substantial disease burden that includes persistent or potentially debilitating symptoms, increased risk of exacerbations, increased healthcare utilisation, reduced exercise tolerance and physical activity, and a higher rate of lung function decline versus controls. However, the evidence for treatment efficacy in these patients is limited due to their frequent exclusion from clinical trials. Careful assessment of disease burden and the rate of disease progression in individual patients, rather than a reliance on spirometry data, may identify patients who could benefit from earlier treatment intervention.

Prevalence and Characteristics of Asthma-Chronic Obstructive Pulmonary Disease Overlap in Routine Primary Care Practices.

Rationale: Adults may exhibit characteristics of both asthma and chronic obstructive pulmonary disease (COPD), a situation recently described as asthma-COPD overlap (ACO). There is a paucity of information about ACO in primary care.Objectives: To estimate the prevalence and describe characteristics of individuals with ACO in primary care practices among patients currently diagnosed with asthma, COPD, or both; and to compare the prevalence and characteristics of ACO among the three source populations.Methods: The Respiratory Effectiveness Group conducted a cross-sectional study of individuals ≥40 years old and with ≥2 outpatient primary care visits over a 2-year period in the UK Optimum Patient Care Research Database. Patients were classified into one of three source populations based on diagnostic codes: 1) COPD only, 2) both asthma and COPD, or 3) asthma only. ACO was defined as the presence of all of the following 1) age ≥40 years, 2) current or former smoking, 3) post-bronchodilator airflow limitation (forced expiratory volume in 1 second/forced vital capacity <0.7), and 4) ≥12% and ≥200 ml reversibility in post-bronchodilator forced expiratory volume in 1 second.Results: Among 2,165 individuals (1,015 COPD only, 395 with both asthma and COPD, and 755 asthma only), the overall prevalence of ACO was 20% (95% confidence interval, 18-23%). Patients with ACO had a mean age of 70 years (standard deviation, 11 yr), 60% were men, 73% were former smokers (the rest were current smokers), and 66% were overweight or obese. Comorbid conditions were common in patients with ACO, including diabetes (53%), cardiovascular disease (36%), hypertension (30%), eczema (23%), and rhinitis (21%). The prevalence of ACO was higher in patients with a diagnosis of both asthma and COPD (32%) compared with a diagnosis of COPD only (20%; P < 0.001) or asthma only (14%; P < 0.001). Demographic and clinical characteristics of ACO varied across these three source populations.Conclusions: One in five individuals with a diagnosis of COPD, asthma, or both asthma and COPD in primary care settings have ACO based on the Respiratory Effectiveness Group ACO Working group criteria. The prevalence and characteristics of patients with ACO varies across the three source populations.

Aclidinium bromide in fixed-dose combination with formoterol fumarate in the management of COPD: an update on the evidence base.

Aclidinium bromide/formoterol fumarate (AB/FF) 400/12 µg is a twice-daily long-acting muscarinic receptor antagonist and long-acting ß2 agonist (LAMA/LABA) dual-bronchodilator maintenance therapy used to relieve symptoms and reduce future risk of exacerbations in adults with chronic obstructive pulmonary disease (COPD). To date, there have been several clinical studies and post hoc analyses of AB/FF, assessing treatment outcomes in patients with moderate-to-severe COPD. These studies have looked at a range of outcomes, including lung function parameters, patient-reported symptom scores, quality-of-life measures assessing impaired health and perceived well-being, and the frequency, duration, and severity of exacerbations. In light of the major 2017 revision to the Global initiative for chronic Obstructive Lung Disease (GOLD) recommendations, and the subsequent updates, we present an update on the latest evidence supporting the efficacy and safety of AB/FF. This review discusses the clinical relevance of the improvements in lung function, symptoms, quality of life, and exacerbations in patients with COPD reported in the phase III and IV trials of AB/FF. Given the current concerns over unnecessary inhaled corticosteroid (ICS) use in COPD, we also touch briefly on the use of blood eosinophils as a biomarker for identifying those patients with COPD already using LAMA/LABA therapy for whom the addition of ICS might be of benefit.

Efficacy of aclidinium/formoterol 400/12 µg, analyzed by airflow obstruction severity, age, sex, and exacerbation history: pooled analysis of ACLIFORM and AUGMENT.

BACKGROUND: Aclidinium/formoterol 400/12 µg is a twice-daily maintenance bronchodilator for COPD. This post hoc study evaluated aclidinium/formoterol vs aclidinium 400 µg, formoterol 12 µg, or placebo in patient subgroups. PATIENTS AND METHODS: Data were pooled from two 24-week Phase III clinical trials (ACLIFORM and AUGMENT). Patients (N=3,394) were analyzed by baseline airflow obstruction severity (moderate/severe), age (<65/≥65 years), sex, and exacerbation history (0/≥1 exacerbation in the previous 12 months). Changes from baseline vs placebo and mono-therapies were evaluated: morning pre-dose (trough) and morning 1-hour post-dose FEV1, Transition Dyspnea Index (TDI), and moderate/severe exacerbation rates (healthcare resource utilization [HCRU] and EXAcerbations of Chronic pulmonary disease Tool [EXACT] criteria). RESULTS: Aclidinium/formoterol improved the post-dose FEV1 vs placebo and monotherapy in all subgroups (all P<0.01) and trough FEV1 vs placebo (P<0.001) and formoterol (P<0.05) across all subgroups. Improvements in trough FEV1 were observed vs aclidinium in patients with severe airflow obstruction, patients aged <65 years, males, and patients with exacerbation history (P<0.05). Improvements in TDI were observed vs placebo in all subgroups (all P<0.001), monotherapies for patients with moderate (formoterol P<0.05) or severe airflow obstruction (aclidinium P<0.05), patients aged <65 years (aclidinium P<0.01, formoterol P<0.05), males (formoterol P<0.05), and patients with no exacerbation history (formoterol P<0.05). HCRU exacerbation rates were lower for aclidinium/formoterol vs placebo in patients with no exacerbation history (P<0.01). EXACT exacerbation rates were lower for aclidinium/formoterol in patients with moderate airflow obstruction vs placebo and aclidinium, patients aged <65 years vs placebo and ≥65 years vs formoterol, males vs placebo, and patients with no exacerbation history vs placebo (all P<0.05). CONCLUSION: Aclidinium/formoterol significantly improved post-dose FEV1, trough FEV1, and TDI vs placebo across all subgroups and vs monotherapy in many subgroups. These findings further support the benefits of aclidinium/formoterol for all patients with COPD.

New developments in optimizing bronchodilator treatment of COPD: a focus on glycopyrrolate/formoterol combination formulated by co-suspension delivery technology.

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 ß2-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.

Practical considerations when prescribing a long-acting muscarinic antagonist for patients with COPD.

COPD is characterized by persistent airflow limitation, progressive breathlessness, cough, and sputum production. Long-acting muscarinic antagonists (LAMAs) are one of the recommended first-choice therapeutic options for patients with COPD, and several new agents have been developed in recent years. A literature search identified 14 published randomized, placebo-controlled studies of the efficacy and safety of LAMAs in patients with COPD, with improvements seen in lung function, exacerbations, breathlessness, and health status. A greater weight of evidence currently exists for glycopyrronium (GLY) and tiotropium than for umeclidinium and aclidinium, especially in terms of exacerbation reductions. To date, there have been few head-to-head clinical studies of the different LAMAs. Available data indicate that GLY and aclidinium have similar efficacy to tiotropium in terms of improving lung function, dyspnea, exacerbations, and health status. Overall, evidence demonstrates that currently available LAMAs provide effective and generally well-tolerated therapy for patients with COPD. Delivery devices for the different LAMAs vary, which may affect individual patient's adherence to and preference for treatment. Subtle differences between individual therapeutic options may be important to individual patients and the final treatment choice should involve physician's and patient's experiences and preferences.

Reduction in clinically important deterioration in chronic obstructive pulmonary disease with aclidinium/formoterol.

BACKGROUND: 'Clinically important deterioration' (CID) is a composite endpoint measuring worsening of the key clinical features of chronic obstructive pulmonary disease (COPD), namely lung function, patient-reported outcomes, and exacerbations. ACLIFORM and AUGMENT were two 24-week, randomized, double-blind, phase III studies assessing twice-daily (BID) aclidinium bromide (AB) 400 µg/formoterol fumarate (FF) 12 µg. This pooled post-hoc analysis assessed the effects of AB/FF 400/12 µg on both first and sustained CID events versus placebo and monotherapies in patients with moderate to severe COPD. METHODS: A first CID event was defined as the occurrence of a moderate/severe exacerbation or the worsening from baseline in ≥1 of the following: trough forced expiratory volume in 1 second (FEV1; ≥100 mL), Transition Dyspnea Index (TDI) focal score (≥1 unit), or St George's Respiratory Questionnaire (SGRQ) total score (≥4 units). A 'sustained' CID was defined as a worsening maintained at all subsequent visits from appearance to week 24 or a moderate/severe exacerbation at any time. CID events were assessed at three visits (weeks 4, 12, and 24); trough FEV1 was also measured at weeks 1 and 18. RESULTS: AB/FF 400/12 µg reduced the risk of a first CID event by 45% versus placebo (hazard ratio [HR] 0.55, p < 0.001), 18% versus FF 12 µg (HR 0.82, p < 0.01), and 15% versus AB 400 µg (HR 0.85, p < 0.05). Similarly, AB/FF 400/12 µg reduced the risk of a sustained CID event by 48% versus placebo (HR 0.52, p < 0.001) and 22% versus FF 12 µg (HR 0.78, p < 0.01). AB/FF 400/12 µg reduced the risk of a first or sustained CID event for all four components versus placebo (trough FEV1 and TDI, first and sustained CID, all p < 0.001; SGRQ first CID p < 0.001; SGRQ sustained CID, p < 0.01; exacerbations first and sustained CID, both p < 0.05) and TDI and SGRQ versus FF 12 µg (TDI, first and sustained CID both p < 0.05; SGRQ first CID p < 0.01), and SGRQ versus AB 400 µg (first CID, p < 0.05). CONCLUSIONS: AB/FF 400/12 µg BID may provide greater airway stability and fewer exacerbations or deteriorations in lung function, health status, or dyspnea compared with placebo or monotherapies. TRIAL REGISTRATION: Clinicaltrials.gov NCT01462942 (ACLIFORM); registered 26 October 2011. Clinicaltrials.gov NCT01437397 (AUGMENT); registered 19 September 2011.

Safety of inhaled glycopyrronium in patients with COPD: a comprehensive analysis of clinical studies and post-marketing data.

BACKGROUND: Chronic use of inhaled anticholinergics by patients with chronic obstructive pulmonary disease (COPD) has raised long-term safety concerns, particularly cardiovascular. Glycopyrronium is a once-daily anticholinergic with greater receptor selectivity than previously available agents. METHODS: We assessed the safety of inhaled glycopyrronium using data pooled from two analysis sets, involving six clinical studies and over 4,000 patients with COPD who received one of the following treatments: glycopyrronium 50 µg, placebo (both delivered via the Breezhaler device), or tiotropium 18 µg (delivered via the HandiHaler device). Data were pooled from studies that varied in their duration and severity of COPD of the patients (ie, ≤12 weeks duration with patients having moderate or severe COPD; and >1 year duration with patients having severe and very severe COPD). Safety comparisons were made for glycopyrronium vs tiotropium or placebo. Poisson regression was used to assess the relative risk for either active drug or placebo (and between drugs where placebo was not available) for assessing the incidence of safety events. During post-marketing surveillance (PMS), safety was assessed by obtaining reports from various sources, and disproportionality scores were computed using EMPIRICA. In particular, the cardiac safety of glycopyrronium during the post-marketing phase was evaluated. RESULTS: The overall incidence of adverse events and deaths was similar across groups, while the incidence of serious adverse events was numerically higher in placebo. Furthermore, glycopyrronium did not result in an increased risk of cerebro-cardiovascular events vs placebo. There were no new safety reports during the PMS phase that suggested an increased risk compared to results from the clinical studies. Moreover, the cardiac safety of glycopyrronium during the PMS phase was also consistent with the clinical data. CONCLUSION: The overall safety profile of glycopyrronium was similar to its comparators indicating no increase in the overall risk for any of the investigated safety end points.