SYSTEMATIC REVIEW Theimpactofolodaterolontheriskof mortality and serious adverse events: a systematic review and meta-analysis

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1 British Journal of Clinical Pharmacology Br J Clin Pharmacol (2017) SYSTEMATIC REVIEW Theimpactofolodaterolontheriskof mortality and serious adverse events: a systematic review and meta-analysis Correspondence Chang-Hoon Lee, MD Associate Professor, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-Ro Jongno-Gu, Seoul, 03080, Republic of Korea. Tel.: ; Fax: ; kauri670@empal.com Received 14 April 2016; Revised 21 October 2016; Accepted 9December2016 Hyun Woo Lee, Hyung-Jun Kim and Chang-Hoon Lee Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, Republic of Korea Keywords adrenergic β 2 -receptor agonists, asthma, chronic obstructive pulmonary disease, mortality, olodaterol AIMS Olodaterol is a novel inhaled long-acting β 2 -agonist (LABA) that showed efficacy as a bronchodilator for patients with chronic obstructive pulmonary disease (COPD) and asthma. However, it is unclear whether olodaterol reduces mortality; the safety issues of olodaterol have not been fully evaluated. METHODS Randomized controlled trials comparing olodaterol with placebo for patients with COPD or asthma, which evaluated mortality or serious adverse events, were included. Eighteen trials reporting mortality and 26 trials reporting nonfatal serious adverse events were included. RESULTS Inhaled olodaterol did not reduce the risk of mortality (Peto fixed OR 1.31; 95% CI ) and had no significant impacts on nonfatal serious adverse events (Peto fixed OR 1.03; 95% CI ). CONCLUSIONS Inhaled olodaterol has no impact on mortality risk in clinical trials conducted on patients with COPD and asthma. However, the interpretation is limited by a high OR (1.31) and a wide CI that includes the hazardous effect. We could not find any relationship between inhaled olodaterol use and nonfatal serious adverse events. DOI: /bcp The British Pharmacological Society

2 Olodaterol and mortality WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Inhaled olodaterol is a recently developed long-acting β 2 -agonist that has a duration of action of >24 h. Olodaterol has shown clinical efficacy including improvement in lung function and quality of life. However, it is unclear if olodaterol reduces mortality. WHAT THIS STUDY ADDS Our systematic review shows that inhaled olodaterol does not reduce mortality risk in clinical trials conducted on patients with chronic obstructive pulmonary disease and asthma. The interpretation of the results is limited by a high odds ratio (1.31) and a wide confidence interval that includes the hazardous effect. We could not find any relationship between inhaled olodaterol use and nonfatal serious adverse events. Tables of Links TARGETS Enzymes [2] Beta adrenergic receptor kinase 2 LIGANDS Olodaterol These Tables list key protein targets and ligands in this article that are hyperlinked to corresponding entries in the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY [1], and are permanently archived in the Concise Guide to PHARMACOLOGY 2015/16 [2]. Introduction Inhaled long-acting β 2 -agonists (LABAs) represent an important class of drugs in the treatment of chronic obstructive pulmonary disease (COPD) and asthma [3, 4]. The bronchodilator effects of LABAs are mainly due to the relaxation of airway smooth muscle following increased production of camp by adenylyl cyclase, activation of protein kinase A and elevation of intracellular calcium levels [5]. Inhaled LABAs with or without inhaled corticosteroids (ICS) can reduce the risk of acute exacerbations of COPD and improve lung function and quality of life in COPD patients [6, 7]. In asthma, inhaled LABAs in combination with an ICS provide improved symptom control and decreased risk of exacerbation [8, 9]. Inhaled LABAs without ICS for chronic asthmatics also show efficacy in morning peak expiratory flow rate, asthma symptoms, quality of life and reduction of rescue medication [10]. However, for asthma patients, LABA alone without ICS is not recommended in the guidelines [4] becauseofconcernsregardingthepossibilityofincreaseinmortality [11]. Olodaterol (BI 1744 or BI 1744 CL) is a novel inhaled LABA that has a duration of action of >24 h [12]. It is distinguished from other inhaled β-agonists by its high selectivity for β 2 adrenergic receptors in the airway [13]. Various trials have suggested that olodaterol can significantly improve lung function and quality of life in patients with moderate to severe COPD [14 17], and it has also shown a bronchodilating effect in patients with moderate or severe persistent asthma [18, 19]. However, it is unclear if olodaterol reduces mortality risk, which is one of the major therapeutic targets, in either COPD patients or asthmatics. Rather, the number of deaths was greater in the olodaterol arm compared to placebo of several large randomized controlled trials (RCTs) that included COPD patients [16, 17, 20]. Although the risk of death was not significantly increased in an analysis of four olodaterol-related clinical trials [21], there has not been a systematic review including all relevant studies that evaluates the incidence of death and serious adverse events (SAEs) in COPD and asthma patients using olodaterol. Additionally, there has been concern that the incidence of death and acute exacerbation may be increased when asthma patients use LABAs [11]. Finally, the effect of olodaterol on SAEs has never been reported. We conducted this systematic review and meta-analysis to examine the impact of inhaled olodaterol on mortality andsaesinpatientswithcopdorasthma. Methods Search strategy and selection criteria We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and conference abstracts from the international congress of the American Thoracic Society, British Thoracic Society and European Respiratory Society up to 22 nd September 2015 using the search terms: Olodaterol, Striverdi, BI 1744 or BI 1744 CL, and 6-hydroxy-8-[(1R)-1-hydroxy-2-[[2-(4-methoxyphenyl)-1,1-dimethylethyl]amino]ethyl]-2H-1,4-benzoxazin-3(4H)-one. The inclusion criteria were as follows: (i) COPD or asthma patients older than 18 years; (ii) studies comparing olodaterol with placebo or olodaterol plus tiotropium with tiotropium; (iii) parallel or crossover RCTs; and (iv) studies presenting mortality or SAEs in published articles, ClinicalTrials.gov or conference abstracts. We defined the Br J Clin Pharmacol (2017)

3 H. W. Lee et al. olodaterol arm as patients who were randomly allocated to an olodaterol group or an olodaterol plus tiotropium group and the placebo arm as those in the placebo group or the tiotropium group. Searched studies were reviewed and selected according to the inclusion criteria. Study selection was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [22]. Any discrepancy of opinions in the inclusion or exclusion of the studies was resolved by referring to the original articles and discussing them as a group. Data extraction and assessment of the risk of bias We collected the baseline data of each study including study ID number, year of publication, study design, number of participants, inclusion criteria, and exclusion criteria. The extracted patient data were age, sex, smoking history (pack years), type of respiratory disease (COPD or asthma), prebronchodilator forced expired volume in 1 s (FEV 1 )and Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage (COPD patients only). We also noted the method of intervention in each study, the dose of olodaterol, the treatment duration and treatment regimen, the use of other concomitant drugs such as ICS and methylxanthines, and the type of inhalation device. The risk of bias in each study was assessed in seven dimensions according to the Cochrane risk of bias tool: (i) adequacy of random sequence generation; (ii) appropriateness of allocation concealment; (iii) sufficient blinding of participants and researchers; (iv) adequate blinding of outcome assessment; (v) completeness of outcome data; (vi) selective reporting; and (vii) other causes of bias. We resolved any disagreement in the risk of bias assessment by discussion. Primary and secondary outcomes The primary outcome was the risk of mortality in the olodaterol arm vs. the placebo arm (olodaterol vs. placebo or olodaterol + tiotropium vs. placebo + tiotropium; same dose of tiotropium was compared in each trial). The secondary outcome was comparison of the risk of nonfatal SAEs between the olodaterol and the placebo arms. In addition, total adverse events (AEs), AEs requiring hospitalization, and treatment-related AEs were analysed. Statistical analysis We conducted a metaregression analysis to estimate the odds ratio (OR) and 95% confidence interval (CI) using the Peto OR method and the fixed effect model. The chi-square test was used to find and measure quantitative heterogeneities among the pooled data. We assessed publication bias by funnel plot. We incorporated crossover trials in a meta-analysis by taking all participants and measurements from olodaterol periods as well as the placebo periods, and all studies were considered as if they were parallel trials. Subgroup analyses of mortality and nonfatal SAEs were conducted according to treatment regimens, type of respiratory disease, and use of other bronchodilators. Metaregression was performed to examine the correlation between the risk of mortality or nonfatal SAEs and the dose of olodaterol or the treatment duration, or prebronchodilator FEV 1. Meta-analysis, chi-square test for heterogeneity, and funnel plot were conducted with Review Manager, version 5.3 (Copenhagen: The Nordic Cochrane Center, The Cochrane Collaboration, 2014). Metaregression analysis was implemented by the STATA version 13.1 (STATA Corp., College Station, TX, USA). Results The database search protocol identified 48 articles in MEDLINE, 108 in EMBASE, 64 in the Cochrane Library, 54 in ClinicalTrials.gov, 34 in the American Thoracic Society abstracts, 18 in the British Thoracic Society abstracts and 32 in the European Respiratory Society abstracts. Among them, there were 26 that met the inclusion criteria (PRISMA guideline, Figure 1). Data regarding deaths were available for 18 of the 26 included trials, while all of trials reported data regarding SAEs. The risk of bias was generally low among the included trials (Figure S1). Publication bias was not indicated in the funnel plot for the olodaterol arm and mortality (Figure S2). Description of the included studies The included studies consisted of eight parallel trials and 18 crossover trials (Table 1). Most of the trials were published between 2014 and Among participants who were included, 9855 were in the olodaterol arm and 6736 were in the placebo arm. Olodaterol was compared with placebo in 17 trials, while olodaterol plus tiotropium was compared with tiotropium in nine trials. The dose of olodaterol was 2 20 μg, and the duration of treatment ranged from 1 day to 52 weeks. Crossover studies had washout periods of at least 2 weeks between interventions. All but two ( and ) trials permitted the use of an ICS as maintenance therapy during the study period. was predominantly used through all the included trials, but dry powder inhaler was also applied in the two trials ( and ). Olodaterol was always administered by soft mist inhaler and dry powder inhaler was used to administer tiotropium. There were COPD patients and 1673 asthma patients. COPD patients were aged 40 years or older with >10 pack years of smoking history, while the asthma patients were aged 18 years or older and had smoking histories of <5 or10 pack years. The mean age of COPD patients ranged between 60.6 and 69.3 years while that of asthma patients was between 28.9 and 45.3 years. The majority of COPD patients (53 95%) were men and the GOLD stage was 2 4. The mean prebronchodilator FEV 1 of COPD subjects ranged between 37% and 50%. COPD trials have a crossover or parallel design with various durations of intervention from 1 day to 1 year. However, all the asthma trials were conducted by a crossover method with relatively short duration, up to 16 weeks. The dose of ICS used by asthma patients was not mentioned in the report or article, although all the asthma trials included only stable patients who used moderate to high doses of ICS or low doses of ICS combined with an LABA Br J Clin Pharmacol (2017)

4 Olodaterol and mortality Figure 1 PRISMA flow chart for the meta-analysis Risk of mortality in the olodaterol arm compared to the placebo arm Eighteen studies were assessed to compare the risk of mortality between the olodaterol and the placebo arms (Figure 2). The olodaterol arm had a higher OR for death, but there was no statistically significant difference in the death rates (Peto fixed OR 1.31; 95% CI ). Heterogeneity was not observed (I 2 =0%,P = 0.94). Subgroup analyses according to the treatment regimen, type of respiratory disease, and use of an ICS or a methylxanthine showed similar results in each group (Figures S3 S6). No deaths were reported in asthma patients; however, in COPD patients, 75 (1%) patients in the olodaterol arm and 45 (1%) patients in the placebo arm died. No deaths were recorded in COPD patients who did not use concurrent methylxanthines. According to the metaregression analysis, there was no significant association between the risk of mortality (log OR) and treatment duration or olodaterol dosage (Table S1 and Figure S7). We observed no significant relationship between baseline FEV 1 and mortality in the metaregression analysis (data not shown). Risk of nonfatal SAEs in the olodaterol arm compared to placebo arm The meta-analysis (26 trials) indicated that the risk of nonfatal SAEs in the olodaterol arm was not significantly higher compared to the placebo arm (Peto fixed OR 1.03; 95% CI ; Figure 3). Heterogeneity among the trials was not suspected (I 2 =0%,P = 0.88). Subgroup analyses according to treatment regimen, type of respiratory disease, and use of an ICS or methylxanthine had similar results in each group (Figures S8 S11). About 0.4% of asthma patients experienced nonfatal SAEs, while 9% of COPD patients had at least 1 nonfatal SAE. Eight trials were excluded from the subgroup analysis of the use of other bronchodilators because data regarding the use of an ICS or a methylxanthine were not available. We did not find an association between the risk of SAEs (log OR) and treatment duration or olodaterol dosage (Table S2 and Figure S12). There was no significant relationship between baseline FEV 1 and SAEs (data not shown). The AEs considered as nonfatal are described in Table S3. Comparison of the risk of other AEs in the olodaterol and placebo arms The risk of total AEs was similar between olodaterol and placebo arms in the present meta-analysis (Peto fixed OR 1.00; 95% CI ; Figure S13). Statistically consistent results were observed in the 26 included studies (I 2 =0%,P =0.50). Only four trials were found to report AEs requiring hospitalization. The hospitalization rate was not significantly different between the two arms (Peto fixed OR 0.98; ; Figure S14). No evidence of heterogeneity for the rate of hospitalization was detected (I 2 =10%,P =0.33).Twelvetrialsrecorded the incidence of treatment-related AEs. The risk of Br J Clin Pharmacol (2017)

5 H. W. Lee et al. Table 1 Baseline characteristics of the included studies Study ID Published year Study design Number of included patients Mean age Male (%) Smoking status (pack years) Mean prebronchodilator FEV1 (L,%) GOLD stage Treatment duration Regimen Inhalation device COPD studies Crossover > , day Olodaterol vs. placebo Parallel > , weeks Olodaterol vs. placebo Parallel > , weeks Olodaterol vs. placebo Parallel > , weeks Olodaterol vs. placebo Parallel > , weeks Olodaterol vs. placebo Parallel > , weeks Olodaterol vs. placebo Parallel > , weeks Olodaterol vs. placebo Crossover > , weeks Olodaterol vs. placebo Crossover > , weeks Olodaterol vs. placebo Crossover >10 Not presented weeks Olodaterol vs. placebo Crossover >10 Not presented weeks Olodaterol vs. placebo Crossover > , weeks Olodaterol vs. placebo Crossover > , weeks Olodaterol vs. placebo Parallel > , weeks Olodaterio plus tiotropium Dry powder inhaler Parallel > , weeks Olodaterio plus tiotropium Dry powder inhaler Crossover > , weeks Olodaterol vs. placebo Olodaterio plus tiotropium Parallel >10 Not presented weeks Olodaterio plus tiotropium Parallel > , weeks Olodaterol vs. placebo b Olodaterio plus tiotropium Crossover > , weeks Olodaterol vs. placebo Olodaterio plus tiotropium Parallel > , weeks Olodaterio plus tiotropium c Subtotal Asthma studies Crossover <5 3.51, day Olodaterol vs. placebo (continues) 1170 Br J Clin Pharmacol (2017)

6 Olodaterol and mortality Table 1 (Continued) Inhalation device Treatment duration Regimen GOLD stage Mean prebronchodilator FEV 1 (L,%) Smoking status (pack years) Male (%) Mean age Number of included patients Study design Published year Study ID Crossover < , weeks Olodaterol vs. placebo Crossover < , weeks Olodaterol vs. placebo Crossover a 47.1 < , weeks Olodaterolvs. placebo Subtotal 1673 Total COPD = chronic obstructive pulmonary disease; FEV1 = forced expired volume in 1 s; GOLD = Global Initiative for Chronic Obstructive Lung Disease, a Age is described as median value and the range in the trial. b The published baseline data of and are described as a single table in which the data cannot be separately assessed. c The published baseline data of and are described as a single table in which the data cannot be separately assessed. treatment-related AEs did not differ according to the intervention (Peto fixed OR 0.93; 95% CI ; Figure S15). Major heterogeneity among trials was not detected (I 2 =34%,P =0.13). Discussion Inhaled olodaterol did not have a significant effect on the risk of mortality in a clinical trial population with COPD and asthma. Subgroup analysis showed that the OR for mortality in the olodaterol arm was not affected by dose, treatment regimen, treatment duration, type of respiratory disease or use of an additional bronchodilator. There was no significant association between the risk of mortality and the dose of olodaterol or treatment duration. Meta-analyses of nonfatal SAEs did not reveal any significantly harmful effect of olodaterol compared to placebo. Other AEs such as total AEs, AEs requiring hospitalization and treatment-related AEs did not differ according to the type of intervention. TheroleofLABAsinreducingtheriskofacuteexacerbations and improving FEV 1 or quality of life in patients with COPD has been well studied [6, 7]. In addition, in the TORCH trial, salmeterol was found to have a beneficial effect on survival in patients with moderate to severe COPD [23]. In the present study, inhaled olodaterol neither significantly reduced nor increased the risk of mortality within the context of clinical trials conducted on patients with COPD and asthma. Nonetheless, we cannot completely exclude the possibility of a higher mortality risk with inhaled olodaterol because the OR for mortality was 1.31 and the 95% CI ( ) was wide. In fact, for the studies involving asthma patients, no deaths were recorded in the treatment arms or the control arms. Considering that the reduction of mortality is one of the major therapeutic concerns for patients with COPD, a consistent OR of >1.00 is sufficient to raise concerns [3, 4, 24]. We could not find any systematic review with a metaanalysis conducted to investigate the relationship between olodaterol and mortality/nonfatal AEs. One pooled analysis reported that the incidence of death or SAEs was balanced across the intervention arms: placebo, formoterol and olodaterol [21]. This pooled analysis includes four trials ( , , , and ) that were conducted for 48 weeks. However, the pooled analysis also showed a high OR (>1) for mortality (Peto fixed OR 1.25; 95% CI ). Our systematic review included all the studies conducted for at least 4 weeks. It is possible that a study of longer duration could show the relationship between drug treatment and SAEs, including death. However, we think, in any case, 48 weeks is not enough for investigating the mortality outcome. At least 3 years are required to investigate the efficacy outcome of altering disease progression [25]. In addition, theoretically, the AEs of olodaterol can be triggered by a single dose. According to a recent review article, olodaterol reaches the maximum plasma concentration within minutes of inhalation, with a bioavailability of about 30% [26]. There were sudden AEs such as respiratory compromise, which could be Br J Clin Pharmacol (2017)

7 H. W. Lee et al. Figure 2 Mortality Figure 3 Serious adverse events induced within a short duration of drug treatment (1222.3). In the subgroup analysis, trials with longer duration (> 12 weeks) showed a result similar to that of the analysis for all trials. Inhaled olodaterol is delivered through a soft mist inhaler device. These devices can provide more efficient delivery of the aerosol to the lungs compared to conventional devices, which may be of benefit to patients who cannot generate 1172 Br J Clin Pharmacol (2017)

8 Olodaterol and mortality high inspiratory flow,eventhoughitmaypresentahigher risk of AEs for those who do generate high flow [27]. It is possible that a similar issue could arise with olodaterol. However, the high OR reported herein may also reflect some element of bias.first,wefailedtoshowasignificant association between the risk of mortality and the dose and duration of olodaterol treatment in the metaregression analysis, although more mortality cases were identified in trials with a study duration >12weeksthaninthosewithaduration<12 weeks. Second, the mortality rates of olodaterol group in the trials included in our systematic review were comparable to previous trials with other LABAs; 0 3% in trials comparing LABA and placebo, and 0 3% in trials comparing LABA + tiotropium and placebo + tiotropium [28, 29]. No deaths were observed in studies of asthmatics, which could be explained by the fact that asthma participants were younger (mean years old vs. mean years old in COPD participants) and had better lung function (mean FEV 1 %62 64% vs. mean FEV 1 %37 53% in COPD participants). In addition, the study duration of asthma trials was short (maximum 16 weeks). Notably, in COPD patients, deaths were reported in participants who were allowed to be treated with methylxanthines. Although an old study reported that theconcomitantuseofβ agonists and methylxanthines is capable of producing myocardial necrosis and an increase in the development of cardiac arrhythmias in several species of animals [30], we did not find any evidence in human studies suggesting an interaction between olodaterol and methylxanthines. Moreover, we were not aware of how many patients were actually treated with methylxanthines in the studies. The limitations of the present systematic review are as follows: first, SAEs and treatment-related AEs were not clearly defined among the included studies and were determined according to the subjective standard of each researcher. Second, we do not know exactly how many patients in each arm used other bronchodilators. Most of the trials reported the baseline pulmonary medications of the included patients, but we could not confirm that the patients used them in the same manner. In addition, the dose of ICS used by the asthma patients was not recorded in the included studies. Third, we cannot exclude the possibility of confounding between the severity of disease and use of ICS or methylxanthines in COPD patients. Fourth, many of the included trials did not describe the method of allocation concealment, and those studies were considered to have an unclear risk of selection bias. Fifth, the trials with 1-day treatment may have been too brief to demonstrate a difference in the mortality rates between two arms [25], even when they attempted to define it. Nonetheless, we chose to include these studies because cardiac events can be triggered by a single dose of a β-agonist [31]. Sixth, inclusion of crossover trials could lead to unitof-analysis error [32], although the meta-analysis including parallel studies alone showed similar results. Seventh, the causes of death were not assessed. Conclusions Inhaled olodaterol has no impact on mortality and nonfatal serious adverse events in clinical trials conducted on patients with COPD and asthma. However, the interpretation is limited by a high OR (1.31) and a wide CI for mortality that includes the hazardous effect. Further long-term, large clinical trials are needed for safety concerns. Competing Interests All authors have completed the Unified Competing Interest form at (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work. No funding or financial support. Contributors Study concept and design: C.H.L., H.W.L.; Acquisition of data: H.W.L., H.J.K.; Analysis and interpretation of data: H.W.L., H.J.K., C.H.L.; Drafting the manuscript: H.W.L., C.H.L.; Critical revision of the manuscript and important intellectual content: H.W.L., H.J.K., C.H.L.; Study supervision: C.H.L. References 1 Southan C, Sharman JL, Benson HE, Faccenda E, Pawson AJ, Alexander SP, et al. 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The Cochrane Collaboration Supporting Information Additional Supporting Information may be found in the online version of this article at the publisher s web-site: Table S1 Metaregression analysis to assess correlation of treatment duration and the dose of olodaterol with risk of mortality Table S2 Metaregression analysis to assess correlation of treatment duration and the dose of olodaterol with risk of serious adverse events Table S3 The list of adverse events considered as nonfatal serious adverse events of each included study Figure S1 Summary of the assessment of each risk of bias item (%) for each included study Figure S2 Funnel plot for detecting publication bias Figure S3 Subgroup analysis for the risk of mortality according to treatment regimen Figure S4 Subgroup analysis for the risk of mortality according to the type of respiratory disease Figure S5 Subgroup analysis for the risk of mortality according to the use of inhaled corticosteroid 1174 Br J Clin Pharmacol (2017)

10 Olodaterol and mortality Figure S6 Subgroup analysis for the risk of mortality according to the use of methylxanthine Figure S7 Metaregression for the association between treatment duration and dose of olodaterol, and the risk of mortality Figure S8 Subgroup analysis for the risk of serious adverse events according to treatment regimen Figure S9 Subgroup analysis for the risk of serious adverse events according to the type of respiratory diseases Figure S10 Subgroup analysis for the risk of serious adverse events according to the use of inhaled corticosteroid Figure S11 Subgroup analysis for the risk of serious adverse events according to the use of methylxanthine Figure S12 Metaregression for the association between treatment duration and dose of olodaterol, and the risk of serious adverse events Figure S13 Meta-analysis for the risk of total adverse events by olodaterol Figure S14 Meta-analysis for the risk of adverse events requiring hospitalization by olodaterol Figure S15 Meta-analysis for the risk of treatment-related adverse events by olodaterol Br J Clin Pharmacol (2017)