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Use of Aclidinium Did Not Increase the Risk of Death Respiratory Medicine 152 (2019) 37–43 Contents lists available at ScienceDirect Respiratory Medicine journal homepage: www.elsevier.com/locate/rmed Use of aclidinium did not increase the risk of death in a noninterventional T cohort study in the Clinical Practice Research Datalink (CPRD), United Kingdom ∗ Cristina Rebordosaa, , Jaume Aguadoa, Estel Planaa, Steven Thomasb, Ana Francesc, Alejhandra Leic, Esther García-Gilc, Javier Nuevod, Susana Perez-Gutthanna, Jordi Castellsaguea a RTI Health Solutions, Av. Diagonal 605, 9-1, 08028, Barcelona, Spain b RTI Health Solutions, 200 Park Offices Drive, Research Triangle Park, NC, 27709, United States c AstraZeneca, Avda. Diagonal, 615 2nd floor, 08028, Barcelona, Spain d AstraZeneca, Serrano Galvache 56, 28033, Madrid, Spain ARTICLE INFO ABSTRACT Keywords: Background: Aclidinium bromide is an inhaled long-acting muscarinic antagonist (LAMA). Although the initial Aclidinium potential increased cardiovascular and mortality risk among users of tiotropium has been ruled out by several LAMA observational studies, and clinical trials, there are still concerns related to the use of newer LAMA medications. Mortality The current study aimed to evaluate the risk of death among users of aclidinium and other LAMAs. United Kingdom Methods: We conducted a cohort and nested case-control study among patients with COPD aged 40 years or older to compare the risk of all-cause mortality among users of aclidinium and other COPD medications with the risk among users of long-acting β2 agonists (LABA), in the Clinical Practice Research Datalink (CPRD) in the United Kingdom (2012–2017). Results: Mortality rates per 1,000 person-years were 32.9 for aclidinium, 43.8 for tiotropium, 38.0 for other LAMA, 47.1 for LABA/ICS, and 38.1 for LABA. The RR of death compared with current use of LABA was 0.54 (confidence interval [95% CI], 0.40–0.72) for aclidinium, 0.96 (95% CI, 0.76–1.21) for tiotropium, 0.76(95% CI, 0.58–0.99) for other LAMA, and 1.08 (95% CI, 0.90–1.31) for LABA/ICS. Decreased risk for death observed among users of aclidinium was driven by overall current single use (RR = 0.41; 95% CI, 0.22–0.79), which corresponded to 26% of the aclidinium users (< 15 cases) and not by multiple use (RR = 1.02; 95% CI, 0.71–1.48). Conclusion: Use of aclidinium, tiotropium, other LAMA, or LABA/ICS was not associated with an increased risk of all-cause mortality as compared with the use of LABAs. 1. Introduction patients classified under COPD severity C and D (Global Initiative for Chronic Obstructive Lung Disease [2]. Cardiovascular and mortality Long-acting muscarinic antagonists (LAMAs) are widely used among safety concerns for tiotropium, the first LAMA approved in Europe, patients with chronic obstructive pulmonary disease (COPD). As many were not confirmed in large long-term clinical trials (UPLIFT and as 35% of patients with COPD in the United Kingdom (UK) in 2013 had TIOSPIR) [3,4]. However, cardiovascular safety and mortality remains used LAMAs in the previous year [1]. LAMAs are recommended as first- as a potential risk for other LAMAs, including aclidinium [5,6,7,8]. line therapy and at the same level as long-acting beta agonists (LABAs) This is the first of a series of observational post-authorisation safety in patients with COPD severity B and are preferable over LABA among studies (PASS) performed in the routine clinical practice to evaluate the Abbreviations: BMI, body mass index; CAT, COPD assessment test; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CPRD, Clinical Practice Research Datalink; FEV1, forced expiratory volume in 1 s; GOLD, Global Initiative for Chronic Obstructive Lung Disease; HES, Hospital Episode Statistics database; ICD, International Classification of Diseases; ICS, inhaled corticosteroids; LABA, long-acting β2 agonist; LAMA, long-acting muscarinic antagonists; LRTA, leukotriene receptor antagonists; mMRC, modified Medical Research Council; ONS, Office for National Statistics; PASS, post-authorisation safety study; ppFEV1, percentpre- dicted forced expiratory volume in 1 s; RR, relative risks; SABA, short-acting beta2-agonist; SAMA, short-acting muscarinic antagonist; SD, standard deviation ∗ Corresponding author. Av. Diagonal 605, 9-1, 08028, Barcelona, Spain. E-mail address: crebordosa@rti.org (C. Rebordosa). https://doi.org/10.1016/j.rmed.2019.04.018 Received 11 December 2018; Received in revised form 14 March 2019; Accepted 22 April 2019 Available online 26 April 2019 0954-6111/ © 2019 Elsevier Ltd. All rights reserved. C. Rebordosa, et al. Respiratory Medicine 152 (2019) 37–43 cardiovascular safety of aclidinium, a LAMA approved in the European exposure were also performed to evaluate different exposure windows Union in 2012. To put the results of this study in the context of a po- and differences in adherence and compliance that would lead tomod- pulation that frequently use multiple medications, this study compared ification of the estimated duration of use. Current use was classified aclidinium with LABAs as well as with other COPD medications. The into current single or multiple use depending on whether patients were studies are being performed sequentially as the number of users of concurrently treated with other study medications at the index date. aclidinium are accrued in the UK, the country where the study is being Current single use was further subclassified as switching if patients had performed. This first study aimed to compare all-cause mortality in recent use of other study medications at the index date. patients with COPD initiating treatment with aclidinium bromide and Sociodemographic and clinical characteristics such as age, sex, other selected COPD medications with all-cause mortality in patients obesity, smoking, comorbidities, and comedications were ascertained with COPD initiating treatment with LABAs. Cardiovascular mortality based on information before the cohort entry date. COPD severity was and other major cardiovascular events (stroke and acute myocardial defined according to the GOLD classification categories A, B,C,orD infarction) will be evaluated in future studies when a higher number of (Tables S–1) based on the percent predicted forced expiratory volume users of aclidinium has been accrued in the UK. in 1 s [FEV1], symptoms (modified Medical Research Council grade, COPD assessment test score, or breathlessness), and exacerbation his- 2. Materials and methods tory [11] both before or at the cohort entry date and before or at the index date. When no data on expected FEV1 were recorded, the percent This is a case-control study nested in a population-based cohort of predicted FEV1 was calculated by applying formulas from the Global adult patients aged 40 years or older with a recorded diagnosis of COPD Lung Function Initiative (European Respiratory Society Task Force TF initiating treatment with aclidinium, tiotropium, other LAMA (glyco- 2009-03) to establish improved lung function reference values [12]. pyrronium and umeclidinium), LABA/inhaled corticosteroids (LABA/ Crude and age- and sex-standardised mortality rates and 95% con- ICS), or LABA identified in the Clinical Practice Research Datalink fidence intervals (CIs) were estimated for current use of eachstudy (CPRD) in the UK from 01 September 2012 through 01 March 2017. For medication using the age and sex distribution of person-time in current a subset of practices where linkage data was available, the study also users of aclidinium bromide as the standard population. Conditional included information from the Office for National Statistics (ONS) and logistic regression was used to estimate crude and adjusted relative the Hospital Episode Statistics database (HES). COPD diagnoses were risks (RRs) and 95% CIs of all-cause mortality for the risk factors and all identified through outpatient diagnosis recorded in CPRD GOLDor medication-use comparisons of interest. Crude RRs obtained from the inpatient diagnosis recorded in HES (ICD-10 codes J40-J44) at any time matched sample were adjusted by the matching factors by design (i.e., before the cohort entry date or up to 30 days after the cohort entry date. age, sex and year of cohort entry). The final multivariable regression Patients with COPD with or without prior history of asthma could enter models included variables considered clinically relevant, those that the study, and asthma history was evaluated as a potential confounder changed the coefficient by approximately 5% from the models com- in the analysis. Patients were included if they were new users of the paring current single use and current use of aclidinium bromide, and study medications, defined as having a prescription of the study med- the variables with a relative risk of 2 or more or 0.5 or less in the ication within the study period and no prescription of this medication in univariate analysis. the last 6 months, and if they had at least 1 year of prior enrollment in the CPRD before cohort entry date. Patients with life-threatening con- 3. Results ditions (cancer, HIV, respiratory failure, end-stage renal disease, organ transplant, drug or alcohol abuse, coma, or congenital anomalies) at The study included 3,555 new users of aclidinium, 19,413 new users baseline were excluded from the study. New users were followed from of tiotropium, 5,308 new users of other LAMA, 21,718 new users of the cohort entry date (i.e., the day of the first prescription within the LABA/ICS, and 4,797 new users of LABA (Fig. 1). The percentage of study period) until the earliest of the following dates: death (index eligible patients was approximately 82% among users of aclidinium and date), disenrollment from the practice, date the practice stops con- users of other LAMA and was much lower among users of the rest of the tributing data, or end of the study period. study medications, particularly among users of LABA/ICS (14.4%). The All patients included in the cohort that had a confirmed death event main reason for exclusion was not being a new user during the study and death date, either through an electronic algorithm or review of period.
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