Effect of tiotropium on COPD exacerbations: A systematic review

Accepted Manuscript Effect of tiotropium on COPD exacerbations: A systematic review David M.G. Halpin, Claus Vogelmeier, Michael P. Pieper, Norbert Metzdorf, Frank Richard, Antonio Anzueto PII:

S0954-6111(16)30030-0

DOI:

10.1016/j.rmed.2016.02.012

Reference:

YRMED 4868

To appear in:

Respiratory Medicine

Received Date: 2 September 2015 Revised Date:

17 February 2016

Accepted Date: 23 February 2016

Please cite this article as: Halpin DMG, Vogelmeier C, Pieper MP, Metzdorf N, Richard F, Anzueto A, Effect of tiotropium on COPD exacerbations: A systematic review, Respiratory Medicine (2016), doi: 10.1016/j.rmed.2016.02.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Effect of tiotropium on COPD exacerbations: A systematic review David M. G. Halpina,*, Claus Vogelmeierb, Michael P. Pieperc, Norbert Metzdorfd, Frank Richardd, and Antonio Anzuetoe,f

Royal Devon and Exeter Hospital, University of Exeter Medical School, Exeter, UK

b

Department of Medicine, Pulmonary and Critical Care Medicine, University Medical

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a

Center Giessen and Marburg, Philipp University of Marburg, Member of the German

c

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Center for Lung Research, Marburg, Germany

Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG,

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Biberach, Germany d

Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany

e

Department of Medicine, Division of Pulmonary Diseases/Critical Care Medicine,

The University of Texas Health Science Center at San Antonio, San Antonio, TX,

f

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USA

The South Texas Veterans Health Care System, Audie L. Murphy Memorial

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Veterans Hospital Division, San Antonio, TX, USA

* Corresponding author. Department of Respiratory Medicine, Royal Devon and

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Exeter Hospital, Barrack Road, Exeter EX2 5DW, United Kingdom. Tel: +44 (0)1392 402133; fax: +44 (0)1392 402828. E-mail address: [email protected].

Running title: Effect of tiotropium on COPD exacerbations

Non-standard abbreviations: ICS: inhaled corticosteroids.

ACCEPTED MANUSCRIPT Abstract Background: Exacerbation frequency is related to disease progression, quality of life, and prognosis in COPD. Earlier diagnosis, along with interventions aimed at preventing exacerbations and delaying progression, may help reduce the global

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burden of disease. Long-acting inhaled bronchodilators are effective at maintaining symptom relief and are recommended as first-choice therapy for more symptomatic patients and those at risk of exacerbation.

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Methods: As prevention of exacerbations is a priority goal in COPD management and a number of different long-acting bronchodilators are available, we conducted a systematic

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review of exacerbation data from randomized controlled trials (published January 2000 to May 2014) comparing the effect of tiotropium versus placebo and/or other maintenance therapies.

Results: Exacerbations were a primary endpoint in 12 publications (five studies: four

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comparing tiotropium with placebo; one with active comparator) and a secondary endpoint in 17 publications (seven studies: six comparing tiotropium with placebo; one with active comparator). Overall, tiotropium was associated with a longer time to

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first exacerbation event and fewer exacerbations (including severe exacerbations/ hospitalizations) compared with placebo and long-acting β2-agonists. Tiotropium also

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showed similar efficacy to glycopyrronium and a fixed long-acting muscarinic antagonist/long-acting β2-agonist combination (glycopyrronium/indacaterol), although not all studies were powered to demonstrate differences in exacerbation outcomes. Exacerbation outcomes were comparable with both formulations of tiotropium (HandiHaler® 18 µg/Respimat® 5 µg). Conclusions: The results of this comprehensive systematic review demonstrate

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ACCEPTED MANUSCRIPT tiotropium is beneficial in reducing exacerbation risk versus placebo or other maintenance treatments. Keywords: Anticholinergic; Antimuscarinic; COPD; Long-acting muscarinic

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antagonist

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Introduction COPD is characterized by airflow obstruction, and bronchodilators are central to its management [1]. The aims of pharmacological therapy for COPD are to prevent and

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control symptoms, reduce the frequency and severity of exacerbations, and improve health status and exercise tolerance [1]. Short-acting bronchodilators can produce substantial improvements in lung function, but long-acting bronchodilators are more

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effective at maintaining symptom relief [1]. Improvements in FEV1 produced by

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bronchodilation correlate with improvements in breathlessness and health status as well as reduced exacerbation rates [2].

Exacerbations are an important component of COPD [3,4], significantly impacting on the burden of disease [5], leading to a worsening health status and increased risk of

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future exacerbations and death [6,7]. Exacerbations are also strong predictors of disease progression, quality of life, and prognosis [7,8]. Some patients may be more

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prone to exacerbations [4], and the prevention of exacerbations is a priority goal in

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COPD management [1].

Current maintenance therapies for patients at risk of exacerbations include longacting anticholinergics (also called long-acting muscarinic antagonists [LAMAs]), long-acting β2-agonists (LABAs), LABAs combined with inhaled corticosteroids (ICS), and phosphodiesterase type 4 inhibitors [9,10]. For patients at risk of exacerbations in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) groups C and D, a long-acting anticholinergic or a fixed combination of ICS/LABA is recommended as first-choice therapy [1], while for symptomatic patients at lower risk of exacerbations 3

ACCEPTED MANUSCRIPT (group B), a LAMA or LABA is recommended. There is now more evidence to inform these choices, and we have therefore undertaken a systematic review of the effects of tiotropium therapy compared with placebo and/or other maintenance therapies in patients with COPD. Unlike other publications (for example, Karner, et al. [11]), this

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review includes for the first time all published randomized controlled trials with

exacerbation outcomes as prespecified endpoints and with tiotropium as an active

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treatment arm.

Tiotropium is a once-daily LAMA shown to reduce exacerbations and improve other

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important outcomes of COPD [12–15]. Tiotropium is approved and marketed as a dry-powder formulation delivered via the HandiHaler® device (18 µg; Boehringer Ingelheim Pharma GmbH and Co KG, Ingelheim am Rhein, Germany) [16] and as an aqueous solution delivered via the Respimat® inhaler (5 µg; two puffs of 2.5 µg once

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daily; Boehringer Ingelheim Pharma GmbH and Co KG, Ingelheim am Rhein,

Methods

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Germany) in many countries [17].

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A systematic literature search (January 2000 to May 2014) of electronic databases was conducted to identify all COPD trials in which exacerbations were a prespecified endpoint and tiotropium was an active treatment arm. As there is no standardized definition of a COPD exacerbation due to the heterogeneity of causes, symptoms and severities [18], our literature search did not limit studies to a specific definition. (For definitions of exacerbation used in selected studies, see Table E1 in the online supplement.) The total hits from the search were assessed for their relevance (based

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ACCEPTED MANUSCRIPT on titles/abstracts), and publications that were deemed potentially relevant were obtained in full and assessed.

Articles were included if they reported on double-blind, randomized, controlled trials

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of ≥6 months’ duration. Both placebo- and active-controlled (i.e., vs. other

maintenance therapies) trials were eligible if exacerbation data were included as a primary or secondary endpoint; blinded studies with additional open-label tiotropium

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arm(s) were included if appropriate. Prospective studies and subgroup analyses of trials were permitted, provided the data were new and not duplicated elsewhere.

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Non-blinded open-label studies, review articles, methodology papers, retrospective studies, pooled analyses, case studies, conference findings, congress abstracts, pharmacoeconomic studies, and meeting reports were excluded. The search was limited to trials in humans. The literature search results and article selection were

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reviewed and verified by the authors to ensure their accuracy.

Exacerbation outcomes included time to first event (exacerbation/hospitalization due

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to exacerbation), exacerbation rate, and the proportion of patients with events

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(exacerbations/hospitalizations due to exacerbation).

Results

Summary of search findings

The search returned a total of 236 hits (Fig. 1). Of these, 195 publications were excluded based on the title/abstract and identification of duplicates. The remaining 41 publications were deemed potentially relevant based on the title and/or abstract. Of 5

ACCEPTED MANUSCRIPT these, a further 14 publications were excluded based on duration of study (i.e., <6 months [n = 6]), retrospective nature of study (n = 1), non-appropriate comparator (n = 1), open-label study (n = 2), pooled analysis (n = 3), and lack of data on specific treatments (n = 1). Two additional recent publications were identified during the

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search [19,20]. In total, 29 publications were deemed relevant for inclusion in the final analysis [12,14,15,19–44]. Refer to online supplement, Tables E2 and E3, for details

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of study durations and population size.

Figure 1 Systematic Review of Published Manuscripts Reporting Exacerbation Data

a

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in Trials Comparing Tiotropium With Placebo and/or Other Maintenance Therapies. Two additional articles included following a final check on any relevant, recently

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published articles (since May 204 end of search period and submission date).

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ACCEPTED MANUSCRIPT Exacerbations were a primary study endpoint (including subgroup analyses and prospective studies) in 12 publications [12,15,21,23,24,30,35,37,38,42–44] and a secondary study endpoint (including subgroup analyses and prospective studies) in

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17 publications [14,19,20,22,25–29,31–34,36,39].

Six studies included an entry criterion that patients must have had one or more

exacerbations in the year prior to entry [15,21,29,30,42–44], and one study required

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one or more exacerbations in the 2 years prior to entry [26].

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The exacerbation data reported included time to first event, exacerbation rate, and proportion of patients with an event (online supplement, Tables E2 and E3); severe (hospitalized) exacerbation data have been detailed where available. Of the 209 publications that were excluded, 26 reported exacerbations as “other endpoint.”

[43,45,46].

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Additional data from open-label comparisons are included for information only

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Effect of tiotropium versus placebo

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Sixteen publications comparing tiotropium with placebo investigated the use of HandiHaler® (18 µg) [14,24–28,30–32,34–37,39–41], and four reported the effects of Respimat® (5 µg [two puffs of 2.5 µg once daily] and/or 10 µg) [12,22,23,38].

Time to first exacerbation event There were 14 publications (including subgroup analyses) that compared tiotropium with placebo, with time to first exacerbation as the endpoint [12,14,22– 25,27,28,30,35,36,38,40,41]. Tiotropium was associated with a significantly (p < 7

ACCEPTED MANUSCRIPT 0.05) prolonged time to first exacerbation in nine studies [12,14,23–25,30,35,36,40] (online supplement, Table E2). In three studies, the time to first hospitalization (severe exacerbation) was also significantly (p < 0.05) prolonged in patients treated with tiotropium compared with placebo (Fig. 2; online supplement, Table E2)

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[12,14,35].

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Figure 2 Hazard Ratios for an Exacerbation of COPD in Patients Receiving

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Tiotropium Versus Placebo.

Exacerbation rate or proportion of patients with exacerbations Twenty publications (including subgroup analyses) compared the effect of tiotropium with placebo on the rate of exacerbations or proportion of patients experiencing an exacerbation event [12,14,22–28,30–32,34–41]. Fewer patients treated with tiotropium experienced one or more exacerbations [12,23–25,30,35–38]; these 8

ACCEPTED MANUSCRIPT differences reached statistical significance in nine publications [12,23–25,30,35–38]. In addition, the number/rate of exacerbations [14,22–25,27,28,30–32,34,36–40] and exacerbation days [14,24,30,36,37,40] were reduced and the probability of remaining

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exacerbation-free [23] was higher in patients receiving tiotropium versus placebo.

In total, 16 publications examined the effect of tiotropium on severe exacerbations or hospitalizations due to an exacerbation [12,14,23–28,30,31,34–37,39,41]; in five

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studies, significantly fewer patients experienced a severe/hospitalized exacerbation in the tiotropium arms versus placebo [24,25,35,37,39]. In addition, two studies

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[24,25] demonstrated that patients receiving tiotropium had significantly fewer hospitalization days due to a severe exacerbation versus those receiving placebo (online supplement, Table E2). However, in two studies [14,26], the number of hospitalizations and hospitalization days due to a severe exacerbation did not differ

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Subgroup analyses

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between tiotropium and placebo (online supplement, Table E2).

In general, the eight subgroup analyses comparing tiotropium with placebo displayed

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similar trends for exacerbation reductions to those observed in the primary studies, although not all outcomes were statistically significant [27,28,31,32,34,37–39]. In prespecified subgroup analyses of the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) trial, tiotropium significantly reduced the rate of exacerbations in patients with COPD aged <50 years (p = 0.02) [34]. Tiotropium reduced the number of exacerbations per patient-year by 16% versus control in patients naïve to maintenance therapy prior to the study; however, this failed to reach statistical significance (p = 0.08) [41]. 9

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In a post hoc subanalysis of the Veteran Affairs Study (despite not being adequately powered), tiotropium reduced the likelihood of having at least one exacerbation versus placebo in the entire patient group (rate ratio [95% confidence interval (CI)]:

Effect of tiotropium versus active comparators

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Tiotropium monotherapy versus salmeterol

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African American and Caucasian subgroups (p = 0.34) [37].

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0.81 [0.66–0.99]; p = 0.037), with no statistically significant difference between the

Two publications (including subgroup analyses) directly compared tiotropium with salmeterol [15,42]. In the Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD®) trial, tiotropium significantly prolonged the time to first exacerbation (187 vs. 145 days; hazard ratio [HR] [95% CI], 0.83 [0.77–0.90]; p < 0.001) and

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severe exacerbation (HR [95% CI], 0.72 [0.61–0.85]; p < 0.001) in patients with moderate to very severe COPD when compared with salmeterol [15] (Fig. 3; online

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supplement, Table E3).

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Figure 3 Hazard Ratios for an Exacerbation of COPD in Patients Receiving Tiotropium Versus an Active Comparator. a Reciprocal HR and 95% for tiotropium versus tiotropium plus fluticasone-salmeterol were derived and not as reported in the Aaron et al, 2007 [21] (the reported unadjusted of HR [95% CI], 0.80 [0.60–1.08] are inconsistent with the results presented in the text and are therefore a likely error in the original publication [21]); b The reciprocal HR and 95% CIs for tiotropium versus active comparator were derived and not statistically reported in the original publications where values for active comparator versus tiotropium were given. 10

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In addition, tiotropium reduced the annual rate of exacerbations versus salmeterol (0.64 vs. 0.72; rate ratio [95% CI], 0.89 [0.83–0.96]; p = 0.002), as well as the annual

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rate of moderate exacerbations (0.54 vs. 0.59; rate ratio [95% CI], 0.93 [0.86–1.00]; p = 0.048) and severe exacerbations (0.09 vs. 0.13; rate ratio [95% CI], 0.73 [0.66– 0.82]; p < 0.001) (online supplement, Table E3). Of those patients who experienced

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an exacerbation in this trial, 44% had moderate (GOLD stage 2) COPD at trial onset.

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In subgroup analyses of POET-COPD®, tiotropium significantly prolonged the time to first exacerbation (HR [95% CI], 0.88 [0.79–0.99]; p = 0.028) and first severe exacerbation (HR [95% CI], 0.66 [0.48–0.91]; p = 0.012), reduced rates of severe exacerbations (rate ratio [95% CI], 0.70 [0.57–0.85]; p < 0.001) in GOLD stage 2 patients [42], significantly prolonged the time to first exacerbation (HR [95% CI], 0.79 [0.65–0.97; p = 0.028), and reduced the annual exacerbation rate (rate ratio [95% CI],

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ACCEPTED MANUSCRIPT 0.77 [0.63–0.94]; p = 0.012) in maintenance therapy-naïve patients when compared with salmeterol [42].

Tiotropium monotherapy versus indacaterol

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One publication compared tiotropium with indacaterol [29]. In the second,

prespecified superiority analysis, the annualized rate of exacerbations was shown to be higher with indacaterol than with tiotropium (0.90 vs. 0.73; rate ratio [95% CI],

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1.24 [1.12–1.37]; p < 0.0001), showing superiority of tiotropium [29]. In addition, the time to first moderate or severe exacerbation was longer with tiotropium (HR [95%

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CI], 1.20 [1.07–1.33]; p = 0.0012) over a 1-year period [29]. The HR and 95% CIs presented here for tiotropium versus indacaterol for time to first moderate or severe exacerbation were derived by inverting the HRs and CIs reported in the referenced publication (HR [95% CI], 0.83 [0.75–0.93]; p = 0.0012) (Fig. 3; online supplement,

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Table E3).

In a separate subgroup analysis of patients with exacerbations treated with ICS

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and/or antibiotics, exacerbation rates were higher in the indacaterol group than in the tiotropium group [29]. However, in patients stratified by ICS at baseline, the rates of

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severe exacerbations were not significantly different between the two groups. Overall, fewer patients in the tiotropium group experienced an exacerbation during the study than those in the indacaterol group.

Tiotropium monotherapy versus dual and/or triple therapy

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ACCEPTED MANUSCRIPT Six publications compared tiotropium with dual (either LABA/LAMA or LABA/ICS) and/or triple therapy (online supplement, Table E3) [19–21,33,43,44].

The Effect of QVA149 Versus NVA237 and Tiotropium on COPD Exacerbations

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(SPARK) study compared tiotropium versus a combination of glycopyrronium

50 µg/indacaterol 110 µg (QVA149) and glycopyrronium alone (NVA237) in patients at risk of an exacerbation [44]. Overall, the incidence of severe exacerbations was

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low, with no significant differences observed between tiotropium and the glycopyrronium/indacaterol combination; however, in patients receiving

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glycopyrronium alone, there was an increase in severe exacerbations compared with tiotropium (rate ratio [95% CI], 1.43 [1.05–1.97]; p = 0.025; online supplement, Table E3). The rate of moderate or severe exacerbations was not significantly lower with the glycopyrronium/indacaterol combination versus tiotropium (rate ratio [95% CI],

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0.90 [0.79–1.02]; p = 0.10), nor with glycopyrronium alone versus tiotropium (rate ratio [95% CI], 1.03 [0.91–1.16]; p = 0.68).

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Two publications reporting three studies compared the LAMA/LABA combination of umeclidinium/vilanterol with tiotropium [19,20]. In one 24-week blinded study, in

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which the time to first COPD exacerbation event was an additional endpoint, the risk of an exacerbation was reduced with the LAMA/LABA combination compared with tiotropium (HR [95% CI], 0.5 [0.3–1.0]; p = 0.044); however, the number of patients with events was low in both treatment groups (n = 16 [4%] vs. 29 [6%], respectively) [20]. Furthermore, a numerically greater proportion of patients who experienced an exacerbation were receiving additional ICS treatment in the umeclidinium/vilanterol group (n = 12 [75%]) compared with tiotropium (n = 20 [69%]) [20]. In contrast, in two 13

ACCEPTED MANUSCRIPT other blinded studies, the risk of a COPD exacerbation was numerically higher in the umeclidinium/vilanterol group when compared with tiotropium, though these results were not significant (HR [95% CI], 1.2 [0.5–2.6]; p = 0.71; and HR [95% CI], 1.9 [1.0–

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3.6]; p = 0.06, respectively) [19].

When compared with the salmeterol plus fluticasone combination, tiotropium was not associated with significant differences either in the rate of exacerbations (rate ratio

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[95% CI], 0.97 [0.84–1.12]; p = 0.656) or the rate of hospitalizations (13% vs. 16%; p = 0.085) in patients with COPD and a clinical history of exacerbations (online

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supplement, Table E3) [43]. In a second study, there were no significant differences in exacerbation rates with tiotropium plus salmeterol/fluticasone combination versus tiotropium alone (p = 0.531) (online supplement, Table E3) [33].

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In a multicenter trial of patients with moderate or severe COPD who had at least one exacerbation treated with corticosteroids or antibiotics in the 12 months prior to randomization [21], neither dual therapy with tiotropium and salmeterol, nor triple

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therapy with tiotropium, salmeterol, and fluticasone, was associated with any significant differences in the proportion of patients experiencing at least one

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exacerbation, time to first exacerbation event, or mean number of exacerbations when compared with tiotropium alone. However, unlike dual therapy, triple therapy was associated with a significant reduction in the rate of severe exacerbations requiring hospitalization compared with tiotropium monotherapy (relative risk, 0.53; p = 0.01) (online supplement, Table E3).

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ACCEPTED MANUSCRIPT Additional information from open-label comparisons

Tiotropium monotherapy versus glycopyrronium and placebo One publication compared open-label tiotropium with glycopyrronium bromide [44,45],

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and another compared each agent with placebo [45].

In the SPARK study, when tiotropium was compared with glycopyrronium, there were

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no significant differences for the annual rates of moderate or severe exacerbations

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(0.93 vs. 0.95) or severe exacerbations (0.08 vs. 0.12) [44].

In a 1-year open-label study, tiotropium reduced the risk of exacerbations (time to first moderate or severe exacerbation) by 34% compared with placebo (HR [95% CI], 0.66 [0.52–0.85]; p = 0.001) [45]. The risk reduction was 39% with glycopyrronium versus placebo (HR [95% CI], 0.61 [0.46–0.82]; p = 0.001). While glycopyrronium

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was associated with a 35% reduction in the rate of moderate or severe exacerbations compared with placebo (0.54 vs. 0.80; rate ratio [95% CI], 0.66 [0.50–0.87]; p =

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0.003), the effect of tiotropium was not significantly different from placebo (rate ratio [95% CI], 0.80 [0.59, 1.11]; p = 0.179). Both glycopyrronium and tiotropium were

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superior to placebo in reducing moderate exacerbations treated with systemic corticosteroids (odds ratio [95% CI], 0.61 [0.43–0.87; p = 0.006 and 0.62 [0.41–0.93]; p = 0.021, respectively) or antibiotics (odds ratio [95% CI], 0.69 [0.50–0.96]; p = 0.026 and 0.65 [0.44–0.95]; p = 0.026, respectively) [45].

Tiotropium monotherapy versus indacaterol and placebo One publication compared open-label tiotropium with indacaterol and placebo [46]. Over 26 weeks, tiotropium was associated with numerical reductions in 15

ACCEPTED MANUSCRIPT exacerbations versus placebo (HR [95% CI], 0.76 [0.56–1.03]; p = 0.080) but did not significantly reduce the rate of exacerbations compared with placebo (rate ratio [95% CI], 0.70 [0.48–1.03]; p = 0.070). Indacaterol 150 µg did appear to have a significant benefit over placebo in terms of time to first COPD exacerbation (HR [95% CI], 0.69

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[0.51–0.94]; p = 0.019) and the rate of exacerbations (rate ratio [95% CI], 0.67 [0.46– 0.99]; p = 0.044) in this study.

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Discussion

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Clinicians need clear advice from guidelines and initiatives such as GOLD on the best first-choice therapies for managing patients with COPD, particularly when considering outcomes such as effects on exacerbation rates. Tiotropium is the most widely studied LAMA and, as such, there is a considerable amount of data available. However, to our knowledge, this is the first systematic review of all published

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randomized, controlled trials designed to assess exacerbations outcomes (as prespecified endpoints) in patients with COPD who were receiving tiotropium via

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therapies).

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HandiHaler® or Respimat® (compared with placebo and/or other maintenance

Overall, tiotropium appears to be associated with a longer time to first exacerbation event and fewer exacerbations (including severe exacerbations/hospitalizations) than either placebo or active comparator treatment. To date, there are limited data available to suggest an additional clinical benefit (in terms of exacerbation reduction) when using LAMA/LABA combinations or a LABA/ICS in combination with a LAMA.

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ACCEPTED MANUSCRIPT Generally, exacerbation outcomes were comparable with both formulations of tiotropium (HandiHaler® 18 µg/Respimat® 5 µg), a finding in line with evidence from the TIOtropium Safety and Performance In Respimat® (TIOSPIR®) study (N = 17,135), which demonstrated similar exacerbation efficacy and safety profiles for the

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two formulations [47].

Both LAMAs and LABAs are effective treatments for patients with COPD and are

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widely used in clinical practice; however, differences in exacerbation outcomes

between various treatments have been demonstrated in the literature. For example,

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tiotropium, a once-daily LAMA, significantly decreased the annual rate of exacerbations for patients with moderate to very severe COPD compared with salmeterol, a twice-daily LABA [15]. A trend for lower rates of exacerbations was evident with tiotropium compared with indacaterol, a once-daily LABA [29], and

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indacaterol did not show non-inferiority to tiotropium in terms of the annual rate of exacerbations. These findings indicate that tiotropium may be more effective than LABAs in terms of exacerbation reduction, irrespective of once-daily or twice-daily

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regimens, suggesting that the effect is not simply related to sustained bronchodilation. It has been postulated that differences in duration and mechanism of action may

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account for their exacerbation outcome profiles; however, evidence is currently lacking and further prospective, randomized studies are needed to compare directly the exacerbation efficacy of these agents.

Potential mechanisms that may contribute to the preventive effects of tiotropium on COPD exacerbations might include inhibition of the action of acetylcholine in the lung, which may lead to suppression of acetylcholine-mediated release of chemotactic 17

ACCEPTED MANUSCRIPT substances involved in the modulation of inflammatory responses [48]. Inhibition of acetylcholine may translate into additional effects beyond that of bronchodilation (i.e., anti-inflammatory effects), and the reduction of proliferation and mucus secretion

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[48–51].

Although beyond the scope of this review, an important clinical question is whether the exacerbation-prevention properties of tiotropium can be considered a class effect.

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While LAMAs all demonstrate a high affinity and potency toward the muscarinic M3 receptor, tiotropium has been shown to have a much longer dissociation from the

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receptors than either aclidinium or glycopyrronium [50,52]. Tiotropium therefore provides an effective and long-lasting (>24-hour) blockade of the M3 receptors [53,54]. In line with these kinetic properties, preclinical data suggest that tiotropium should provide the greatest level of bronchoprotection of all three LAMAs when

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applied at equieffective doses [50]. It is speculative as to whether LAMAs have antiinflammatory effects: most of the studies suggesting that LAMAs have antiinflammatory and anti-remodeling properties have been conducted in vitro, and

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clinical studies showing definite anti-inflammatory activity for any LAMA are lacking. Few studies have directly compared the exacerbation efficacy of LAMAs, and this is

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worthy of further investigation.

Unlike LAMAs, which mediate their bronchodilator effects through inhibition of cholinergic pathways, LABAs mediate their effects, in part, through stimulation of β2adrenergic receptors. Recent studies suggest that genetic variation in these receptors may play an important role in treatment response [55], with some 18

ACCEPTED MANUSCRIPT genotypes associated with a limited response to β2-adrenergic drugs and others a full response; however, in clinical practice these genotypes are difficult to identify.

There are both strengths and limitations of this systematic review that should be

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considered when evaluating the findings. A total of 29 publications were selected for review, including large studies that were specifically powered to evaluate

exacerbations [12,15,47], and studies that were large and of a long enough duration

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to evaluate exacerbations in subgroup analyses [14,15]. In terms of limitations, the results are generally reported in a descriptive manner, and direct comparisons

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between trials are not conclusive due to differences in study designs and other potential methodological shortcomings. The lack of standardization in endpoints and outcomes between trials precluded the ability to pool data from different studies and perform a formal meta-analysis of the exacerbation data. Definitions used to describe

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an exacerbation event, including severity, differed between trials, and it is unknown whether these differences may have influenced results; however, there appears to be

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consistency in the results of the individual studies reviewed here.

Since our search was restricted to English-language papers and mainstream journals

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(electronic search of the main databases), we cannot discount the possibility that some studies may have been excluded from this review; however, due to the comprehensive and rigorous literature search process, we are confident that all key studies published at the time were captured and included.

Although not all studies were powered to show differences in exacerbation outcomes, current evidence indicates that tiotropium appears to demonstrate benefits over 19

ACCEPTED MANUSCRIPT placebo and the LABAs salmeterol and indacaterol, while providing results comparable with the LAMA glycopyrronium and the fixed LAMA/LABA combination QVA149 (glycopyrronium/indacaterol).

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Conflicts of interest

DMGH has received personal fees and non-financial support from AstraZeneca,

Boehringer Ingelheim and Novartis, and personal fees from GlaxoSmithKline and

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Pfizer. CV has received personal fees from Almirall, AstraZeneca, Boehringer

Ingelheim, Chiesi, Cytos, GlaxoSmithKline, Janssen, Mundipharma, Novartis and

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Takeda, and grants and personal fees from Grifols. MPP and NM are employees of Boehringer Ingelheim. FR was an employee of Boehringer Ingelheim at the time of manuscript submission. AA has received personal fees from AstraZeneca, Bayer-

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Schering Pharma, Boehringer Ingelheim, Dey Pharma, GlaxoSmithKline and Pfizer.

Acknowledgements and funding

This study was funded jointly by Boehringer Ingelheim and Pfizer. Writing assistance

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was provided by Leigh Prevost and Natalie Dennis from PAREXEL, which was

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funded jointly by Boehringer Ingelheim and Pfizer.

All authors contributed to drafting the article and critically revising the content of the manuscript, and made the decision to submit this work for publication. All authors read and approved the final manuscript.

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References

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ACCEPTED MANUSCRIPT 14. Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008;359(15):1543-54. 15. Vogelmeier C, Hederer B, Glaab T, Schmidt H, Rutten-van Molken MP, Beeh KM, et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med 2011;364(12):1093-103.

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20. Maleki-Yazdi MR, Kaelin T, Richard N, Zvarich M, Church A. Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in chronic obstructive pulmonary disease: results of a 24-week, randomized, controlled trial. Respir Med 2014;108(12):1752-60. 21. Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med 2007;146(8):545-55.

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22. Abrahams R, Moroni-Zentgraf P, Ramsdell J, Schmidt H, Joseph E, Karpel J. Safety and efficacy of the once-daily anticholinergic BEA2180 compared with tiotropium in patients with COPD. Respir Med 2013;107(6):854-62.

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23. Bateman E, Singh D, Smith D, Disse B, Towse L, Massey D, et al. Efficacy and safety of tiotropium Respimat SMI in COPD in two 1-year randomized studies. Int J Chron Obstruct Pulmon Dis 2010;5:197-208. 24. Brusasco V, Hodder R, Miravitlles M, Korducki L, Towse L, Kesten S. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax 2003;58(5):399-404. 25. Casaburi R, Mahler DA, Jones PW, Wanner A, San PG, ZuWallack RL, et al. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J 2002;19(2):217-24. 26. Chan CK, Maltais F, Sigouin C, Haddon JM, Ford GT. A randomized controlled trial to assess the efficacy of tiotropium in Canadian patients with chronic obstructive pulmonary disease. Can Respir J 2007;14(8):465-72. 22

ACCEPTED MANUSCRIPT 27. Decramer M, Celli B, Kesten S, Lystig T, Mehra S, Tashkin DP. Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial. Lancet 2009;374(9696):1171-8. 28. Decramer M, Molenberghs G, Liu D, Celli B, Kesten S, Lystig T, et al. Premature discontinuation during the UPLIFT study. Respir Med 2011;105(10):1523-30.

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29. Decramer ML, Chapman KR, Dahl R, Frith P, Devouassoux G, Fritscher C, et al. Oncedaily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallel-group study. Lancet Respir Med 2013;1(7):524-33. 30. Dusser D, Bravo ML, Iacono P. The effect of tiotropium on exacerbations and airflow in patients with COPD. Eur Respir J 2006;27(3):547-55.

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31. Fukuchi Y, Fernandez L, Kuo HP, Mahayiddin A, Celli B, Decramer M, et al. Efficacy of tiotropium in COPD patients from Asia: a subgroup analysis from the UPLIFT trial. Respirology 2011;16(5):825-35.

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32. Hanania NA, Sharafkhaneh A, Celli B, Decramer M, Lystig T, Kesten S, et al. Acute bronchodilator responsiveness and health outcomes in COPD patients in the UPLIFT trial. Respir Res 2011;12:6. 33. Hanania NA, Crater GD, Morris AN, Emmett AH, O'Dell DM, Niewoehner DE. Benefits of adding fluticasone propionate/salmeterol to tiotropium in moderate to severe COPD. Respir Med 2012;106(1):91-101.

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34. Morice AH, Celli B, Kesten S, Lystig T, Tashkin D, Decramer M. COPD in young patients: a pre-specified analysis of the four-year trial of tiotropium (UPLIFT). Respir Med 2010;104(11):1659-67.

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35. Niewoehner DE, Rice K, Cote C, Paulson D, Cooper JA, Jr., Korducki L, et al. Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial. Ann Intern Med 2005;143(5):317-26.

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36. Powrie DJ, Wilkinson TM, Donaldson GC, Jones P, Scrine K, Viel K, et al. Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD. Eur Respir J 2007;30(3):472-8. 37. Rice KL, Leimer I, Kesten S, Niewoehner DE. Responses to tiotropium in AfricanAmerican and Caucasian patients with chronic obstructive pulmonary disease. Transl Res 2008;152(2):88-94. 38. Tang Y, Massey D, Zhong NS. Evaluation of the efficacy and safety of tiotropium bromide (5 microg) inhaled via Respimat in Chinese patients with chronic obstructive pulmonary disease. Chin Med J (Engl) 2013;126(19):3603-7. 39. Tashkin D, Celli B, Kesten S, Lystig T, Decramer M. Effect of tiotropium in men and women with COPD: results of the 4-year UPLIFT trial. Respir Med 2010;104(10):1495504.

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ACCEPTED MANUSCRIPT 40. Tonnel AB, Perez T, Grosbois JM, Verkindre C, Bravo ML, Brun M. Effect of tiotropium on health-related quality of life as a primary efficacy endpoint in COPD. Int J Chron Obstruct Pulmon Dis 2008;3(2):301-10. 41. Troosters T, Celli B, Lystig T, Kesten S, Mehra S, Tashkin DP, et al. Tiotropium as a first maintenance drug in COPD: secondary analysis of the UPLIFT trial. Eur Respir J 2010;36(1):65-73.

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42. Vogelmeier C, Fabbri LM, Rabe KF, Beeh KM, Schmidt H, Metzdorf N, et al. Effect of tiotropium vs. salmeterol on exacerbations: GOLD II and maintenance therapy naive patients. Respir Med 2013;107(1):75-83.

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43. Wedzicha JA, Calverley PM, Seemungal TA, Hagan G, Ansari Z, Stockley RA. The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am J Respir Crit Care Med 2008;177(1):19-26.

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44. Wedzicha JA, Decramer M, Ficker JH, Niewoehner DE, Sandstrom T, Taylor AF, et al. Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study. Lancet Respir Med 2013;1(3):199-209. 45. Kerwin E, Hebert J, Gallagher N, Martin C, Overend T, Alagappan VK, et al. Efficacy and safety of NVA237 versus placebo and tiotropium in patients with COPD: the GLOW2 study. Eur Respir J 2012;40(5):1106-14.

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46. Donohue JF, Fogarty C, Lotvall J, Mahler DA, Worth H, Yorgancioglu A, et al. Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium. Am J Respir Crit Care Med 2010;182(2):155-62. 47. Wise RA, Anzueto A, Cotton D, Dahl R, Devins T, Disse B, et al. Tiotropium Respimat inhaler and the risk of death in COPD. N Engl J Med 2013;369(16):1491-501.

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48. Buhling F, Lieder N, Kuhlmann UC, Waldburg N, Welte T. Tiotropium suppresses acetylcholine-induced release of chemotactic mediators in vitro. Respir Med 2007;101(11):2386-94.

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49. Sato E, Koyama S, Okubo Y, Kubo K, Sekiguchi M. Acetylcholine stimulates alveolar macrophages to release inflammatory cell chemotactic activity. Am J Physiol 1998;274(6 Pt 1):L970-L979. 50. Casarosa P, Bouyssou T, Germeyer S, Schnapp A, Gantner F, Pieper M. Preclinical evaluation of long-acting muscarinic antagonists: comparison of tiotropium and investigational drugs. J Pharmacol Exp Ther 2009;330(2):660-8. 51. Pelaia G, Vatrella A, Busceti MT, Gallelli L, Calabrese C, Terracciano R, et al. Pharmacologic rationale underlying the therapeutic effects of tiotropium/olodaterol in COPD. Ther Clin Risk Manag 2015;11:1563-72. 52. Tautermann CS, Kiechle T, Seeliger D, Diehl S, Wex E, Banholzer R, et al. Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor. J Med Chem 2013;56(21):8746-56.

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ACCEPTED MANUSCRIPT 53. Alagha K, Palot A, Sofalvi T, Pahus L, Gouitaa M, Tummino C, et al. Long-acting muscarinic receptor antagonists for the treatment of chronic airway diseases. Ther Adv Chronic Dis 2014;5(2):85-98. 54. Kruse AC, Li J, Hu J, Kobilka BK, Wess J. Novel insights into M3 muscarinic acetylcholine receptor physiology and structure. J Mol Neurosci 2014;53(3):316-23.

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55. Rabe KF, Fabbri LM, Israel E, Kogler H, Riemann K, Schmidt H, et al. Effect of ADRB2 polymorphisms on the efficacy of salmeterol and tiotropium in preventing COPD exacerbations: a prespecified substudy of the POET-COPD trial. Lancet Respir Med 2014;2(1):44-53.

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Effect of tiotropium on COPD exacerbations: A systematic review

Richard, and Antonio Anzueto

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Online Supplementary Material

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David M. G. Halpin, Claus Vogelmeier, Michael P. Pieper, Norbert Metzdorf, Frank

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ACCEPTED MANUSCRIPT Methods

Four databases (Medline [1946 to current], Biosis Previews [1926 to current], EMBASE [1947 to current], and EMBASE Alert [2014 to current]) were searched using the following

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terms: “exacerbation/s” and “tiotropium” or “Ba 679 (BR)” (manufacturer’s drug name) and “chronic obstructive pulmonary disorder” or “chronic obstructive” or “COPD.” The search included “chronic obstructive” within two terms, on either side of “disease,” and was limited to clinical trials published in the English language and covering the period from January 2000 to

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May 2014. An additional search to capture any relevant, recently published articles between the end of the search period (May 2014) and the submission date was also conducted and

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in the review are shown in Table E1.

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the results included. The definitions of exacerbation that were used in publications included

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ACCEPTED MANUSCRIPT Table E1 Summary of definitions used to describe an exacerbation event in trials comparing tiotropium with active comparator. Publication

Definition of exacerbation used (According to the 2000 Aspen Lung Conference Consensus definition): “a sustained worsening of the patient’s respiratory condition, from the stable state and beyond normal day-to-day variations, necessitating a change in regular medication in a patient with underlying COPD.”

Abrahams, et al. [2]

A complex of lower respiratory events/symptoms (increased or new onset) related to the underlying COPD, with a duration of ≥3 days, requiring a change in treatment where a complex of lower respiratory events/symptoms meant ≥2 of the following: shortness of breath; sputum production (volume); occurrence of purulent sputum; cough; wheezing; chest tightness.

Casaburi, et al. [3]

A complex of respiratory events (i.e., cough, wheezing, dyspnea, or sputum production) lasting >3 days. These were generally treated with antibiotics and/or oral steroids. Exacerbations were detected through monitoring of adverse events.

Chan, et al. [4]

A complex of lower respiratory symptoms (new onset or an increase in ≥1 of the following: cough; sputum; sputum purulence; dyspnea; wheeze; chest discomfort) lasting ≥3 days and requiring treatment with antibiotics and/or systemic steroids.

Bateman, et al. [5]

A complex of respiratory events or symptoms that lasted ≥3 days and required treatment with antibiotics and/or systemic corticosteroids or prompted the investigator to change the patient’s regular respiratory medication.

Bateman, et al. [6]

Respiratory adverse events lasting ≥3 days and requiring treatment with antibiotics and/or oral corticosteroids and/or a significant change in prescribed respiratory medication, including inhaled bronchodilators.

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Aaron, et al. [1]

Worsening for ≥2 consecutive days of ≥2 of the major symptoms (dyspnea, sputum volume, sputum purulence) or worsening of any one major symptom together with any one minor symptom (sore throat, colds [nasal discharge or congestion], fever without other cause, increased cough, increased wheeze).

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Decramer, et al. [7]

Dusser, et al. [8]

The onset of ≥1 clinical descriptor (worsening of dyspnea, cough, or sputum production; appearance of purulent sputum; fever (>38°C); appearance of new chest radiograph abnorma lity) lasting ≥2 days and requiring a new prescription or an increase in the dose of β2-agonists, antibiotics, corticosteroids, or bronchodilators.

Decramer, et al. [9]

Not described in publication.

Hanania, et al. [10]

Not described in publication.

Maleki-Yazdi, et al. [11]

Acute worsening of symptoms of COPD requiring the use of any treatment beyond study drug or rescue albuterol/salbutamol.

Niewoehner, et al. [12]

An exacerbation was defined as a complex of respiratory symptoms (increase or new onset) of >1 of the following: cough; 28

ACCEPTED MANUSCRIPT sputum; wheezing; dyspnea; chest tightness with a duration of ≥3 days requiring treatment with antibiotics or systemic steroids, hospitalization, or both. An exacerbation was defined as the presence for ≥2 days consecutively of an increase in any two major symptoms (dyspnea, sputum purulence, sputum volume) or in one major and one minor symptom (wheeze, sore throat, cough, symptoms of a common cold).

Tashkin, et al. [14]

An increase in or the new onset of >1 respiratory symptom (cough, sputum, sputum purulence, wheezing, dyspnea) lasting ≥3 days and requiring treatment with an antibiotic or a systemic corticosteroid.

Tonnel, et al. [15]

An increase in or the new onset of >1 respiratory symptom (cough, sputum, sputum purulence, wheezing, dyspnea) lasting ≥3 days and requiring treatment with an antibiotic or a systemic corticosteroid.

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Powrie, et al. [13]

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Vogelmeier, et al. [16] An increase in or new onset of >1 symptom of COPD (cough, sputum, wheezing, dyspnea, chest tightness), with ≥1 symptom lasting ≥3 days and leading the patient’s attending physician to initiate treatment with systemic glucocorticoids, antibiotics, or both (criterion for moderate exacerbation), or to hospitalize the patient (criterion for severe exacerbation). Healthcare resource utilization (i.e., those that required treatment with oral corticosteroids and/or antibiotics or required hospitalization).

Wedzicha, et al. [18]

The presence of two major symptoms (dyspnea, sputum volume, sputum purulence) for ≥2 consecutive days or a worsening of one major symptom together with an increase in any one minor symptom (sore throat, cold, fever without other cause, cough, wheeze) for ≥2 consecutive days.

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Wedzicha, et al. [17]

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Table E2 Summary of exacerbation data in trials comparing tiotropium with placebo (excluding subanalyses). Publication

Study design/patients

Exacerbation history

Interventions

Exacerbation endpoints: Findings (tiotropium vs. placebo)

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Time to first event

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• RCT, two identical 1year studies: N = 921 • Secondary endpoints: proportions of patients experiencing ≥1 COPD exacerbation, time to first event, no. of exacerbations, and exacerbation-related hospitalizations

36% vs. 42%; 14% reduction (p < 0.05)

Exacerbations: 0.76 vs. 0.95 events/patient/ year; 20% reduction (p = 0.045)

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Casaburi, et al. [3]

BEA2180 50 µg qd (n = 419), 100 µg qd (n = 415) or 200 µg qd (n = 390) vs. tiotropium 5 µg qd (n = 427) or vs. placebo (n = 429) Tiotropium 18 µg (n = 550) vs. placebo (n = 371)

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• RCT, 24 weeks: N = 2080 • Secondary endpoints: exacerbation risk, and time to first event

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Abrahams, et al. [2]

Rate/proportion of patients with ≥1 event Exacerbation yearly rates: numerically reduced (not significant)

Severe/hospitalized exacerbations Rate/proportion of Time to patients with ≥1 first event event

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Exacerbations

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Prolonged with tiotropium (p = 0.011)

0.086 vs. 0.161 events/patient/year; 47% reduction (p = 0.019) Hospitalizations: 5.5% vs. 9.4%; 41% reduction with tiotropium (p < 0.05)

Other

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Publication

Study design/patients

Exacerbation history

Interventions

Exacerbation endpoints: Findings (tiotropium vs. placebo) Exacerbations

Tiotropium 5 µg qd (n = 1989) vs. placebo (n = 2002)

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Exacerbations: 0.88 vs. 0.92 events/patient/year (p = 0.599)

Time to first event

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Tiotropium 18 µg qd (n = 608) vs. placebo (usual care minus inhaled anticholinergics) (n = 305)

Tiotropium n = 685 (35.3%); placebo = 842 (43.1%)

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• RCT, 48 wks (205.372/ NCT00387088): N = 3991 • Co-primary endpoint: time to first exacerbation

Patients were required to have experienced one exacerbation within the past 2 years (requiring treatment with antibiotics and/or oral steroids), but not within the 6 weeks before entering the study

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Bateman, et al. [5]

• RCT, 48 weeks: N = 913 (2:1 randomization) • Secondary endpoints: proportions of patients experiencing ≥1 COPD exacerbation, no. of exacerbations, and exacerbation/ hospitalization days

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Chan, et al. [4]

Rate/proportion of patients with ≥1 event 44.1% vs. 41.0% (p = 0.395)

Rate of exacerbations/patient -year significantly reduced with tiotropium (RR, 0.79; 95% CI, 0.72–0.87; p < 0.0001)

Also significant reduction in rate of exacerbations requiring hospitalization (RR, 0.81; 95% CI, 0.70– 0.93; p < 0.005)

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Severe/hospitalized exacerbations Rate/proportion of Time to patients with ≥1 first event event No difference between treatment groups Hospitalizations: 0.13 vs. 0.15 events/patient/year (p = 0.557) Hospitalizations: 8.4% vs. 8.2% (p = 1.00) Hospitalization days: 1.14 vs. 1.16 (p = 0.775)

Prolonged with tiotropium (HR, 0.69; 95% CI, 0.63–0.77; p < 0.0001)

Tiotropium n = 161 (8.3%); placebo n = 198 (10.1%)

Prolonged with tiotropium (HR, 0.73; 95% CI, 0.59–0.90; p < 0.005)

Other

No difference between treatment groups in the use of oral steroids or antibiotics for the treatment of exacerbations

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Publication

Study design/patients

Exacerbation history

Interventions

Exacerbation endpoints: Findings (tiotropium vs. placebo) Exacerbations

Prolonged with tiotropium vs. placebo (p ≤ 0.01)

Other

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32% vs. 39% (p = 0.005) No. of exacerbations: 1.07 vs. 1.49 (p = 0.025)

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Tiotropium 18 µg qd (n = 402) or salmeterol 50 µg bid (n = 405) vs. placebo (n = 400)

Prolonged with tiotropium 5 and 10 µg vs. placebo: 160 and 178 vs. 86 days (p < 0.001)

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Tiotropium 5 µg qd (n = 670) or 10 µg qd (n = 667) vs. placebo (n = 653)

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• RCT, combined analysis of two identical, 1-year studies (205.254 [NCT00168844] and 205.255 [NCT00168831]: N = 1990 • Co-primary endpoint (×4): exacerbations per patient-year; Secondary endpoints: exacerbation-related hospitalizations • RCT, combined analysis of two 6month studies (205.130 [NCT02172287] and 205.137 [NCT02173691]): N = 1207 • Endpoints: proportion of patients with ≥1 exacerbation, no. of exacerbations/ hospitalizations, time to first exacerbation event/hospitalization, no. of days in hospital

Time to first event

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Bateman, et al. [19]

Rate/proportion of patients with ≥1 event 37.2% vs. 36.9% vs. 44.1% OR vs. placebo: tiotropium 5 µg = 0.75; 95% CI, 0.60– 0.93 (p < 0.01); tiotropium 10 µg = OR: 0.74; 95% CI, 0.59–0.92 (p < 0.001)

Severe/hospitalized exacerbations Rate/proportion of Time to patients with ≥1 first event event Tiotropium 5 and 10 µg vs. placebo: 5.8%, 5.8% vs. 6.7%

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3% vs. 5% (p > 0.05) No. of hospitalizations: 0.10 vs. 0.15 (difference not significant)

No difference between treatment groups

Hospitalization days: tiotropium 0.98; placebo 1.88

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Publication

Study design/patients

Exacerbation history

Interventions

Exacerbation endpoints: Findings (tiotropium vs. placebo) Exacerbations

Other

Tiotropium reduced the no. of moderate to severe exacerbation days by 34%; p < 0.0001

Prolonged with tiotropium by ~100 days (p < 0.001)

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Tiotropium reduced the no. of exacerbations by 35% (p < 0.001)

Time to first event

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Tiotropium 18 µg qd (n = 500) vs. placebo (n = 510)

Tiotropium reduced the proportion patients with ≥1 moderate to severe exacerbations by 30% (p < 0.0001) and the no. of moderate to severe exacerbations by 36% (p < 0.0001) Tiotropium n = 255 (27.9%); placebo n = 296 (32.3%) OR: 0.81; 95% CI, 0.66–0.99) (p = 0.037)

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• RCT, 6 months (Veteran Affairs Study; 205.266 [NCT00274547]): N = 1829 • Co-primary endpoints (×2): (1) Percentage of patients with a COPD exacerbation; (2) Percentage of patients with a COPD-related hospitalization

Patients with ≥1 exacerbation in last year but not within 6 weeks prior to entry

Tiotropium 18 µg qd (n = 914) vs. placebo (n = 915)

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• RCT, 1 year (MISTRAL): N = 1010 • Endpoints: proportion of patients with ≥1 COPD exacerbation, time to first event, rate/proportion of patients with exacerbations, exacerbation days

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Dusser, et al. [8]

Rate/proportion of patients with ≥1 event 17% reduction with tiotropium (p < 0.01)

Severe/hospitalized exacerbations Rate/proportion of Time to patients with ≥1 first event event

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Prolonged with tiotropium (HR, 0.83; 95% CI, 0.70–0.98; p = 0.028)

Tiotropium n = 64 (7.0%); placebo n = 87 (9.5%); OR: 0.72; 95% CI, 0.51–1.01) (p = 0.056)

Prolonged with tiotropium (HR, 0.73; 95% CI, 0.53–1.01; p = 0.055)

Tiotropium reduced healthcare utilization for exacerbations (hospitalizations [p = 0.047], unscheduled clinic visits [p = 0.019] and days of antibiotic treatment [p = 0.015])

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Publication

Study design/patients

Exacerbation history

Interventions

Exacerbation endpoints: Findings (tiotropium vs. placebo) Exacerbations

Tonnel, et al. [15]

• RCT; 9 months (TIPHON study): N = 555

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Time to first event

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Prolonged with tiotropium (236 vs. 157 days; p = 0.09)

Tiotropium 18 µg qd (n = 2987) vs. placebo (n = 3006)

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Exacerbations: 1.17 vs. 2.46 exacerbations/year (p = 0.001; 52% reduction)

Tiotropium n = 2001 (67.0%); placebo n = 2049 (68.2%)

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• RCT; 4 yrs (UPLIFT trial; 205.235 [NCT00144339]): N = 5993 • Secondary endpoints: proportions of patients experiencing ≥1 COPD exacerbation, time to first event, and exacerbation/ hospitalization days

Tiotropium 18 µg qd (n = 69) vs. placebo (n = 73)

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Tashkin, et al. [14]

• RCT, 1 year: N = 142 • Secondary endpoints: proportions of patients experiencing ≥1 COPD exacerbation, exacerbation frequency

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Powrie, et al. [13]

Rate/proportion of patients with ≥1 event 43% vs. 64% (p = 0.01)

Severe/hospitalized exacerbations Rate/proportion of Time to patients with ≥1 first event event Two vs. three patients hospitalized (p = 0.657)

Tiotropium 18 µg qd (n = 266) vs. placebo (n = 288)

No. of exacerbation events: 0.73 vs. 0.85 patient/year (HR [95% CI]: 0.86 [0.81–0.91]; p < 0.001); 14% reduction Tiotropium 38.0%; placebo 45.1% (p = 0.10)

No. of exacerbations: 1.05 vs. 1.83; 43% reduction (p = 0.03)

N numbers refer to the randomized population. 34

Median no. months (95% CI) 16.7 months (14.9–17.9) vs. 12.5 months (11.5–13.8); HR, 0.86; 95% CI, 0.81–0.91; p < 0.05 Prolonged with tiotropium (201 vs. 181 days) (p = 0.0081)

Tiotropum n = 759 (25.4%); placebo n = 811 (27.0%) No. of hospitalization events: 0.15 vs. 0.16 patient/year (RR, 0.94; 95% CI, 0.82–1.07; p = 0.34)

HR, 0.86; 95% CI, 0.78–0.95; p < 0.05

Other

Exacerbation days: 17.3±33.6 (median 0) vs. 34.5±47.5 (median 21.7) days/year-1 (p = 0.002) No. of exacerbations in patients treated with antibiotics or steroids: 0.98 vs. 1.73 (p = 0.007) Exacerbation days/patent/year: 12.11±0.32 vs. 13.64±0.35 (p = 0.86) Hospitalization days/patient/year: 3.17±0.17 vs. 3.13±0.17 (p = 0.86)

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MISTRAL: Mesure de l’Influence de Spiriva® sur les Troubles Respiratoires Aigus à Long terme; NCT: National Clinical Trial; OR: odds ratio; qd: once daily; RCT: randomized controlled trial; RR: relative risk; TIPHON: Tiotropium: Influence sur la Perception de l’amelioration des activites Habituelles Objectivee par une echelle Numerique; UPLIFT®: Understanding Potential Long-term Impacts on Function with Tiotropium.

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Table E3 Summary of exacerbation data in trials comparing tiotropium versus active comparator (excluding subanalyses). Publication

Study design/ patients

Exacerbation history

Interventions

Exacerbation endpoints: Findings

Time to first event 130 vs. 128 vs. 217 days (median); no difference between treatment groups

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Tiotropium + placebo (n = 156) vs. tiotropium + salmeterol (n = 148) vs. tiotropium + salmeterol + fluticasone (n = 145)

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Eligible patients had to have ≥1 exacerbations requiring treatment with corticosteroids/ antibiotics within 12 months of randomization

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Tiotropium + salmeterol vs. tiotropium + placebo (RR, 1.09; 95% CI, 0.84–1.40; p = 0.51)

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• RCT, 12 months: N = 449 • Primary endpoint: proportion of patients with an exacerbation requiring systemic steroids or antibiotics • Secondary endpoints included exacerbations/ patient/year, time to first exacerbation, and hospitalizations due to COPD exacerbation

Tiotropium + salmeterol + fluticasone vs. tiotropium + placebo (RR 0.85; 95% CI, 0.65–1.11; p = 0.24)

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Aaron, et al. [1]

Rate/proportion of patients with ≥1 event Mean no. exacerbations/patientyear: 1.61 (tiotropium + placebo) vs. 1.75 (tiotropium + salmeterol) vs. 1.37 (tiotropium + salmeterol + fluticasone)

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Severe/hospitalized exacerbations Rate/proportion of Time to patients with first ≥1 event event Tiotropium + salmeterol (n = 38) vs. tiotropium + placebo (n = 49) (RR, 0.83; 95% CI, 0.54–1.27; NS)

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Exacerbations

Tiotropium + placebo vs. tiotropium + salmeterol (unadj. HR, 1.02; 95% CI, 0.77–1.37; p = 0.87) Tiotropium + placebo vs. tiotropium + fluticasone– salmeterol (unadjusted HR, 1.25; 95% CI, 0.93–1.67; b p = 0.15)

Tiotropium + salmeterol + fluticasone (n = 26) vs. tiotropium + placebo (n = 49) (RR 0.53; 95% CI, 0.33–0.86; p = 0.01)

Other

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Publication

Study design/ patients

Exacerbation history

Interventions

Exacerbation endpoints: Findings Exacerbations

Background of tiotropium 18 µg qd + fluticasone/ salmeterol 250/50 bid (n = 173) vs. tiotropium 18 µg qd + placebo bid (n = 169)

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Time to first event

Prolonged with tiotropium vs. indacaterol (HR, 0.83; 95% CI, 0.75–0.93; a p = 0.0012)

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• RCT, 24 wks (Study: ADC111114; NCT00784550): N = 342 • Secondary endpoints: rate/no. of exacerbations

Indacaterol 150 µg (n = 1723) vs. tiotropium 18 µg qd (n = 1721)

No. of exacerbations: 26 vs. 30 Mean rate of exacerbations: 0.14 vs. 0.17; p = 0.531

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Hanania, et al. [10]

Patients ≥1 moderate or severe exacerbations in previous 12 months were eligible for inclusion

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• RCT, 52 weeks (INVIGORATE; NCT00845728): N = 3444 • Secondary endpoints: rate of exacerbations and time to first event/hospitalization

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Decramer, et al. [7]

Rate/proportion of patients with ≥1 event 0.90 vs. 0.73 events/patient-year RR 1.24; 95% CI 1.12–1.37; p < 0.0001

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Severe/hospitalized exacerbations Rate/proportion of Time to patients with first ≥1 event event Increased with tiotropium vs. indacaterol (HR, 0.84; 95% CI, 0.65– a 1.09; p = 0.19)

Other

Rate of exacerbations requiring OCS and/or antibiotics or hospital admissions or ER visits was higher with indacaterol vs. tiotropium Exacerbations treated with OCS: 65% vs. 87% Exacerbations treated with antibiotics: 88% vs. 57% antibiotics Rate of exacerbations by HCU could not be calculated due to the low number of events in each group 92% vs. 73% exacerbations did not result in an urgent care, ER visit or hospital stay

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Exacerbation endpoints: Findings Exacerbations

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Time to first event Prolonged with tiotropium (187 vs. 145 days; HR, 0.83; 95% CI, 0.77–0.90; c p < 0.001)

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Tiotropium 18 µg qd + placebo bid (n = 3707) vs. salmeterol 50 µg bid + placebo qd (n = 3669)

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Patients who had a documented history of ≥1 exacerbation in previous year that required treatment or hospitalization were eligible for inclusion

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• RCT, 1 year (POET® COPD ): N = 7376 • Primary endpoint: time to first COPD exacerbation; secondary endpoints: time to event and number of event

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Vogelmeier, et al. [16]

Rate/proportion of patients with ≥1 event Annual rate 0.64 vs. 0.72 (11% reduction [RR, 0.89; 95% CI, 0.83–0.96; p = 0.002])

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Severe/hospitalized exacerbations Rate/proportion of Time to patients with first ≥1 event event Annual rate of Prolonged severe with exacerbations: tiotropium 0.09 vs. 0.13 (RR, (HR, 0.72; 0.73; 95% CI, 0.66– 95% CI, 0.82; p < 0.001) 0.61–0.85; p < 0.001)

Other

44% patients with an exacerbation had moderate COPD at the trial onset (GOLD stage 2) Tiotropium reduced exacerbations leading to treatment with both systemic glucocorticoids and antibiotics by 20% (0.23 vs. 0.28; RR, 0.80; 95% CI, 0.73–0.88; p < 0.001)

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Publication

Study design/ patients

Exacerbation history

Interventions

Exacerbation endpoints: Findings Exacerbations

Wedzicha, et al. [18]

• RCT; 64 weeks (SPARK; NCT01120691): N = 2224 • Primary endpoints: rate of moderate to severe exacerbations; secondary endpoints: superiority of QVA149 vs. tiotropium for rate of moderate to severe exacerbations; rate of mild exacerbations

Patients at risk of exacerbations were enrolled, including those with a documented history of ≥1 exacerbation in the past year that required treatment with systemic corticosteroids or antibiotics or both

QVA149 (FDC of indacaterol 110 µg and glycopyrronium 50 µg; n = 741) vs. glycopyrronium 50 µg (n = 741) vs. tiotropium 18 µg (n = 742)

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Tiotropium 18 µg qd (n = 665) vs. salmeterol + fluticasone 50/500 µg bid (n = 658)

Time to first event

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Patients with a clinical history of exacerbations were eligible for inclusion

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Moderate or severe exacerbations:

Severe exacerbations:

QVA149 vs. glycopyrronium (RR, 0.88; 95% CI, 0.77– 0.99; p = 0.038)

QVA149 vs. glycopyrronium (RR, 0.81; 95% CI, 0.60–1.10; p = 0.18)

QVA149 vs. tiotropium (RR, 0.90; 95% CI, 0.79–1.02; p = 0.096)

QVA149 vs. tiotropium (RR, 1.16; 95% CI, 0.84– 1.61; p = 0.36)

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Wedzicha, et al. [17]

Rate/proportion of patients with ≥1 event Proportion of patients with ≥1 exacerbation requiring therapeutic intervention: 59% vs. 62%. Exacerbation rate (modeled): 1.32 vs. 1.28 (RR, 0.97; 95% CI, 0.84– 1.12; p = 0.656)

Severe/hospitalized exacerbations Rate/proportion of Time to patients with first ≥1 event event Rate of hospitalizations:13% vs. 16% (p = 0.085)

Glycopyrronium vs. tiotropium (RR, 1.03; 95% CI, 0.91–1.16; p = 0.68)

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Glycopyrronium vs. tiotropium (RR, 1.43; 95% CI, 1.05– 1.97; p = 0.025)

Other

Exacerbations treated with antibiotics: 0.82/year vs. 0.97/year (p = 0.028). Exacerbations treated with systemic corticosteroids: 0.85 vs. 0.69/year (p = 0.039)

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Interventions

Exacerbation endpoints: Findings Exacerbations

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Time to first event

Increased risk of exacerbation with tiotropium (HR, 2.0; 95% CI, 1.0– 3.3; p = a 0.044)

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Umeclidinium/ vilanterol 62.5/25 µg qd (n = 454) vs. tiotropium 18 µg qd (n = 451)

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• RCT, 24-wk (NCT01777334) N = 905 • Secondary endpoint: time to first COPD exacerbation

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MalekiYazdi, et al. [11]

Rate/proportion of patients with ≥1 event

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Severe/hospitalized exacerbations Rate/proportion of Time to patients with first ≥1 event event

Other

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Study design/ patients

Exacerbation history

Interventions

Exacerbation endpoints: Findings Exacerbations

No significant difference in risk of exacerbation between tiotropium and umeclidinium 62.5 µg + vilanterol 25 µg Study 1: HR, 0.83; 95% CI, 0.38–2.0; a p = 0.71 Study 2: HR, 0.53; 95% CI, 0.28–1.0; a p = 0.06

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Study 2: Umeclidinium 125 µg + vilanterol 25 µg (n = 215) vs. umeclidinium 62·5 µg + vilanterol 25 µg (n = 217) vs. tiotropium 18 µg (n = 215) vs. umeclidinium 125 µg (n = 222)

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Study 1: Umeclidinium 125 µg + vilanterol 25 µg (n = 214) vs. umeclidinium 62.5 µg + vilanterol 25 µg (n = 212) vs. tiotropium 18 µg (n = 208) vs. vilanterol 25 µg (n = 209)

Time to first event

Other

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• RCT × 2, 24 weeks • Study 1: NCT01316900 (N = 843) Study 2: NCT01316913 (N = 869) • Additional secondary endpoint: time to first COPD exacerbation

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Decramer, et al. [9]

Rate/proportion of patients with ≥1 event

Severe/hospitalized exacerbations Rate/proportion of Time to patients with first ≥1 event event

N numbers refer to the randomized population. bid: twice daily; ER: emergency room; FDC: fixed-dose combination; HCU: healthcare utilization; INSPIRE: Investigating New Standards for Prophylaxis in Reduction of Exacerbations; INVIGORATE: Comparison of Indacaterol and Tiotropium on Lung Function and Related Outcomes in ® Patients With COPD; NS: not significant; OCS: oral corticosteroid; POET-COPD : Prevention of Exacerbations with Tiotropium in COPD; qd: once daily; RCT: randomized controlled trial; RR: rate ratio; SPARK: Effect of QVA149 Vs. NVA237 and Tiotropium on COPD Exacerbations. a The reciprocal HR and 95% CIs for tiotropium vs. active comparator were derived and not statistically reported in the original publications where b values for active comparator vs. tiotropium were given. Reciprocal HR and 95% for tiotropium versus tiotropium plus fluticasone-salmeterol were derived and not as reported in the Aaron et al, 2007 [21] (the reported unadjusted of HR [95% CI], 0.80 [0.60–1.08] are inconsistent with the results presented in the text and are therefore a likely error in the original publication [21]). c Data shown are time to the first quartile. 41

ACCEPTED MANUSCRIPT References

1. Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for

2007;146(8):545-55. 2.

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treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med

Abrahams R, Moroni-Zentgraf P, Ramsdell J, Schmidt H, Joseph E, Karpel J. Safety and

with COPD. Respir Med 2013;107(6):854-62.

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efficacy of the once-daily anticholinergic BEA2180 compared with tiotropium in patients

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3. Casaburi R, Mahler DA, Jones PW, Wanner A, San PG, ZuWallack RL, et al. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J 2002;19(2):217-24.

4. Chan CK, Maltais F, Sigouin C, Haddon JM, Ford GT. A randomized controlled trial to

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assess the efficacy of tiotropium in Canadian patients with chronic obstructive pulmonary disease. Can Respir J 2007;14(8):465-72.

5. Bateman ED, Tashkin D, Siafakas N, Dahl R, Towse L, Massey D, et al. A one-year trial

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of tiotropium Respimat plus usual therapy in COPD patients. Respir Med

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2010;104(10):1460-72.

6. Bateman ED, Rennard S, Barnes PJ, Dicpinigaitis PV, Gosens R, Gross NJ, et al. Alternative mechanisms for tiotropium. Pulm Pharmacol Ther 2009;22(6):533-42. 7. Decramer ML, Chapman KR, Dahl R, Frith P, Devouassoux G, Fritscher C, et al. Oncedaily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallel-group study. Lancet Respir Med 2013;1(7):524-33.

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ACCEPTED MANUSCRIPT 8. Dusser D, Bravo ML, Iacono P. The effect of tiotropium on exacerbations and airflow in patients with COPD. Eur Respir J 2006;27(3):547-55. 9. Decramer M, Anzueto A, Kerwin E, Kaelin T, Richard N, Crater G, et al. Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium

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monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials. Lancet Respir Med 2014;2(6):472-86.

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10. Hanania NA, Crater GD, Morris AN, Emmett AH, O'Dell DM, Niewoehner DE. Benefits of

Respir Med 2012;106(1):91-101.

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adding fluticasone propionate/salmeterol to tiotropium in moderate to severe COPD.

11. Maleki-Yazdi MR, Kaelin T, Richard N, Zvarich M, Church A. Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in chronic obstructive pulmonary disease: Results of a 24-week, randomized, controlled trial. Respir Med

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2014;108(12):1752-60.

12. Niewoehner DE, Rice K, Cote C, Paulson D, Cooper JA, Jr., Korducki L, et al. Prevention

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of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial. Ann Intern Med

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2005;143(5):317-26.

13. Powrie DJ, Wilkinson TM, Donaldson GC, Jones P, Scrine K, Viel K, et al. Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD. Eur Respir J 2007;30(3):472-8. 14. Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008;359(15):1543-54.

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ACCEPTED MANUSCRIPT 15. Tonnel AB, Perez T, Grosbois JM, Verkindre C, Bravo ML, Brun M. Effect of tiotropium on health-related quality of life as a primary efficacy endpoint in COPD. Int J Chron Obstruct Pulmon Dis 2008;3(2):301-10. 16. Vogelmeier C, Hederer B, Glaab T, Schmidt H, Rutten-van Molken MP, Beeh KM, et al.

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Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med 2011;364(12):1093-103.

17. Wedzicha JA, Calverley PM, Seemungal TA, Hagan G, Ansari Z, Stockley RA. The

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prevention of chronic obstructive pulmonary disease exacerbations by

salmeterol/fluticasone propionate or tiotropium bromide. Am J Respir Crit Care Med

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2008;177(1):19-26.

18. Wedzicha JA, Decramer M, Ficker JH, Niewoehner DE, Sandstrom T, Taylor AF, et al. Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a

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randomised, double-blind, parallel-group study. Lancet Respir Med 2013;1(3):199-209. 19. Bateman E, Singh D, Smith D, Disse B, Towse L, Massey D, et al. Efficacy and safety of

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tiotropium Respimat SMI in COPD in two 1-year randomized studies. Int J Chron Obstruct Pulmon Dis 2010;5:197-208.

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20. Brusasco V, Hodder R, Miravitlles M, Korducki L, Towse L, Kesten S. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax 2003;58(5):399-404.

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Highlights [3–5 bullet points; maximum 85 characters, including spaces, per bullet point] Systematic review of exacerbation data from randomized trials of tiotropium.

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Fewer exacerbations and longer time to first event with tiotropium than placebo.

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Tiotropium more effective at preventing exacerbations than LABA therapy.

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Tiotropium exacerbation efficacy similar to LAMA or LAMA/LABA combinations.

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ACCEPTED MANUSCRIPT Conflicts of interest DMGH has received personal fees and non-financial support from AstraZeneca, Boehringer Ingelheim and Novartis, and personal fees from GlaxoSmithKline and Pfizer. CV has received personal fees from Almirall, AstraZeneca, Boehringer

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Ingelheim, Chiesi, Cytos, GlaxoSmithKline, Janssen, Mundipharma, Novartis and Takeda, and grants and personal fees from Grifols. MPP and NM are employees of Boehringer Ingelheim. FR was an employee of Boehringer Ingelheim at the time of

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manuscript submission. AA has received personal fees from AstraZeneca, Bayer-

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Schering Pharma, Boehringer Ingelheim, Dey Pharma, GlaxoSmithKline and Pfizer.