Efficacy and safety of tiotropium and olodaterol in COPD: a systematic review and meta-analysis
Miravitlles et al. Respiratory Research
Efficacy and safety of tiotropium and olodaterol in COPD: a systematic review and meta-analysis
Marc Miravitlles 0 1 4
Gerard Urrutia 0 3
Alexander G. Mathioudakis 2
Julio Ancochea 5
0 Equal contributors
1 Pneumology Department, Hospital Universitari Vall d'Hebron. , P. Vall d'Hebron 119-129, ES-08035 Barcelona , Spain
2 Division of Infection, Immunity and Respiratory Medicine, University Hospital of South Manchester, The University of Manchester , Manchester , UK
3 Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau). CIBER de Epidemiología y Salud Pública (CIBERESP) , Barcelona , Spain
4 Pneumology Department, Hospital Universitari Vall d'Hebron. , P. Vall d'Hebron 119-129, ES-08035 Barcelona , Spain
5 Pneumology Department, Hospital Universitario de La Princesa, Instituto de Investigación Hospital Universitario de la Princesa (IISP) Universidad Autónoma de Madrid , Madrid , Spain
Background: Long-acting bronchodilators are the cornerstone of pharmacologic treatment of COPD. The new combination of long-acting muscarinic antagonist (LAMA) tiotropium (TIO) and long acting beta-agonists (LABA) olodaterol (OLO) has been introduced as fist line therapy for COPD. This article analyses the evidence of efficacy and safety of the TIO/OLO combination. Methods: A systematic review and metaanalysis of randomized controlled trials (RCT) with a period of treatment of at least 6 weeks, in patients with COPD confirmed by spirometry, comparing combined treatment with TIO/OLO (approved doses only), with any of the mono-components or any other active comparator administered as an inhalator. Results: A total of 10 Randomized controlled trials (RCT) were identified (N = 10,918). TIO/OLO significantly improved trough FEV1 from baseline to week 12 versus TIO, OLO and LABA/ICS (0.06 L, 0.09 L and between 0.04 and 0.05 L, respectively). TIO/OLO improved transitional dyspnea index (TDI) and St. George's Respiratory Questionnaire (SGRQ) compared with mono-components, with patients more likely to achieve clinically important improvements in TDI (risk ratio [RR]: 1.17, 95% confidence interval [CI]: [1.07, 1.28] versus TIO and RR: 1.14, 95%CI: [1. 01, 1.28] versus OLO) and in SGRQ (RR: 1.21, 95%CI: [1.12, 1.30] versus TIO and RR: 1.28, 95%CI: [1.18, 1.40] versus OLO). Patients treated with TIO/OLO showed a significant reduction in the use of rescue medication and no significant differences in frequency of general and serious adverse events were observed between TIO/OLO and mono-components. Conclusions: Treatment with TIO/OLO provided significant improvements in lung function versus monocomponents and LABA/ICS with more patients achieving significant improvements in dyspnea and health status. No differences in adverse events were observed compared with other active treatments. Clinical trial registration: PROSPERO register of systematic reviews (CRD42016040162).
Systematic review; Metanalysis; COPD; Tiotropium; Olodaterol; Tiotropium/olodaterol fixed dose combination
Long-acting bronchodilators represent the backbone of
available treatments for chronic obstructive pulmonary
disease (COPD) [
]. Both long-acting muscarinic
antagonists (LAMA) and long acting beta-agonists (LABA)
confer significant benefits to patients with COPD, which
include but are not limited to improvement in lung
function, symptoms, health status and reduction in the
exacerbations rate [
]. Fixed-dose combinations
(FDC) of a LAMA with a LABA were recently
introduced and there are increasing number of studies
supporting their efficacy and safety [
combination was included in the most recent Global
Initiative for Chronic Obstructive Lung Disease (GOLD)
strategy as a first line choice therapy for group D (high
risk and symptoms) and recommended second option in
B (low risk, high symptoms) and C (high risk, low
symptoms) groups [
], and the Spanish COPD guidelines
recommend the use of LABA/LAMA combinations as first
line therapy in patients highly symptomatic and/or at
risk for exacerbations [
The efficacy and safety of both tiotropium (TIO), the
first LAMA introduced in clinical practice, and the
LABA olodaterol (OLO) have been extensively evaluated
in trials and also in clinical practice [
3, 4, 9
FDC (5/5 μg), recently approved for the treatment of
COPD, has been thoroughly assessed for its efficacy and
safety in COPD [
Since the combination TIO/OLO is now approved for
first line therapy in COPD it is necessary to evaluate the
evidence accumulated about its efficacy and safety in
these patients. Therefore, the aim of this systematic
review was to assess the comparative efficacy, in terms of
trough forced expiratory volume in 1 s (trough FEV1),
quality of life with St. George’s Respiratory
Questionnaire (SGRQ), dyspnea (Mahler Transition Dyspnoea
Index focal score), exercise capacity, use of rescue
medication and safety outcomes of TIO/OLO in
combination, either administered in separate or same inhaler,
versus the mono-components or any other active
comparator (inhaled), in adult patients with COPD.
This systematic review methodology is based on a
protocol which was registered in PROSPERO register of
systematic reviews (CRD42016040162). The report follows
the Preferred Reporting Items for Systematic Reviews
and Meta-analyses Statement (PRISMA) guidance [
Study selection criteria
Eligible studies were randomized controlled trials (RCT)
with a period of treatment and follow up of at least
6 weeks, in patients with a history of COPD confirmed
by spirometry, comparing combined treatment with
TIO/OLO, either administered in a single or separate
inhalers, with any of the mono-components or any other
active comparator administered as an inhalator. The
RCT should report on at least one of the following
outcome measures: trough forced expiratory volume in 1 s
(trough FEV1), quality of life assessed with the St.
George’s Respiratory Questionnaire (SGRQ), symptoms
(dyspnea) assessed with the Mahler Transition Dyspnoea
Index focal score, exercise capacity, use of rescue
medication or safety outcomes, such as all and serious
adverse events. The primary objective of this meta-analysis
We searched MEDLINE and EMBASE through OVID, as
well as Cochrane CENTRAL (from inception up to May
2016), using appropriate controlled vocabulary and free
search terms (detailed search strategy containing the
keywords is provided in Additional file 1). We searched trial
registries via the World Health Organization International
Clinical Trials Platform Search Portal (ICTRP) for
ongoing or completed studies
(http://apps.who.int/trialsearch/) (accessed in December 2016).
Finally, we checked the reference lists of all trials that
were identified by the above mentioned searches.
Study selection and data extraction
All titles screening as well as full text eligibility
assessment were performed by one of the authors (AM). From
this list, the references that clearly did not meet the
eligibility criteria were excluded. Another reviewer
reassessed and validated study selection (GU). Minor
disagreements were resolved through discussion. Data from
each study was extracted by one author (AM) and
validated by a second author (GU) in detailed tabulated data
extraction forms, with a cross check against the original
papers. Variables to be extracted from each reference
were: i) study identification, ii) methods details, and iii)
outcome data (related to those data previously specified
in the study selection criteria).When required, additional
data were requested to the investigators or the sponsor.
Risk of bias and heterogeneity assessment
Risk of bias was assessed using the criteria outlined in
the Cochrane Handbook for Systematic Reviews of
] by one author (AM) and was validated
by an additional author (GU). Disagreements were
resolved by discussion.
We used the I2 statistic to measure heterogeneity
among the trials in each analysis [
]. When substantial
heterogeneity was identified (I2 ≥ 75%.), we reported this
and explored possible causes by performing
prespecified subgroup analyses.
Meta-analyses were performed only when this was
meaningful, while the rest of our findings were
presented narratively. Dichotomous data were analyzed by
calculating risk ratios (RR) and the corresponding 95%
confidence intervals (CI), continuous data by calculating
mean differences (MD) or standardized mean differences
(SMD) and 95% CI and time-to-event data by the
inverse variance method.
For data synthesis we used the fixed or random effect
models in the absence of important heterogeneity or in
the presence of moderate heterogeneity, respectively. In
case of substantial heterogeneity, which cannot be
resolved by performing the subgroup analyses, we did not
perform meta-analysis. Review Manager 5.3 software
was used for this meta-analysis.
Search strategies yielded 201 unique references, of which
five met the eligibility criteria. In addition, reports of
two more unpublished studies were identified in ICTRP
(Fig. 1: Flow diagram of study selection). We identified a
total of 10 RCT involving 10,918 participants that were
eligible for the review: ANHELTO 1 & 2 (published in
one article) [
], ENERGITO [
], MORACTO 1 & 2
], OTEMTO 1 & 2 [
], TONADO 1 & 2 [
] and VIVACITO . We identified one additional
RCT that has been completed published only as a
] (PHYSACTO), and one more trial that is
still ongoing (DYNAGITO) .
Another two RCT assessing the combined treatment
with TIO/OLO were excluded due to the short follow up
period (4 weeks) [
], or the lack of a comparison with
any of the mono-components or an active control
Description of the studies
Details on the characteristics of the included studies are
provided in Table 1 (Characteristics of the included
studies: summary) and Additional file 2: Table S1.
Six studies had a parallel group design, with a sample
size ranging from 607 and 1577 participants, whereas
the other four had a crossover design that included
between 219 and 295 participants (mean 1091; median
809). All studies except ANHELTO 1 & 2 (which were
conducted exclusively in the US) were multinational
with a wide range of participating countries. Treatment
duration was 6 weeks (4 studies), 12 weeks (4 studies)
and 24 weeks (2 studies), with an additional extension
up to 54 weeks in the later ones.
All trials (except ANHELTO 1 & 2) assessed
oncedaily TIO/OLO FDC, which was administered with the
use of a single inhaler (Respimat®). By contrast, in
ANHELTO 1&2, the combination treatment TIO + OLO
was administered using two different inhalers
(HandiHaler® and Respimat®). Regarding the dosing of TIO in the
combined treatment, ANHELTO 1 & 2 used TIO 18 μg,
whereas all the rest assessed two different FDC using
high and low doses of TIO (5 μg and 2.5 μg). OLO was
always administered at the same dose of 5 μg. For the
purposes of this review, only data from TIO/OLO FDC
arms where high dose of TIO (5 μg) were used have
been included, as the low dose (2.5 μg) is not marketed.
Nine studies had a control group with TIO (5 or
18 μg), and five a control group with OLO (5 μg). Only
one study compared the combined therapy with TIO/
OLO versus the combined therapy with salmeterol plus
fluticasone at two different dose combination (50/500 μg
or 50/250 μg) [
Overall, the inclusion criteria and populations’
characteristics of the studies were very homogeneous.
Participants were aged ≥40 years, current or ex-smokers with a
smoking history of more than 10 pack-years, mostly with
moderate to severe COPD; only TONADO 1 & 2
included participants with very severe disease (FEV1 < 30%
predicted, 10.8% of the participants). All studies required
participants to be able to inhale medication in a
competent manner from the Respimat® or HandiHaler® inhalers
as well as to perform technically acceptable pulmonary
function tests, and maintain records (paper diary) as
Risk of bias of the included studies
Risk of bias was deemed low for all domains evaluated
in all included trials (details in Additional file 3: Figure
S1 and Additional file 4: Figure S2). Risk of bias was
assessed according the criteria outlined in the Cochrane
Handbook. Where no sufficient details were provided in
the article (i.e. allocation concealment), these were
requested to the sponsor who provided further details.
Efficacy of the intervention
Trough FEV1 was reported in eight of the RCT [
]. Overall, the combined therapy proved to be
superior to the mono-components in all studies (Fig. 2:
Trough FEV1). TIO/OLO was associated with significantly
higher trough FEV1 when compared with TIO (MD 0.06
[0.04 to 0.07], I2 = 33%) (5 RCT with 3101 patients) or
OLO (MD 0.09 [0.07–0.10], I2 = 0%) (3 RCT with 2313
patients). TIO/OLO showed a statistically significant
greater improvement in trough FEV1 after 6 weeks of
treatment compared to both doses of salmeterol plus
fluticasone (with an improvement ranging between 42 and
58 mL). When treatment was administered in separate
inhalers, TIO + OLO (18/5 μg) resulted in significant
improvements over TIO (18 μg) in trough FEV1 (treatment
differences: 62 mL [P < 0.001] in ANHELTO 1; 40 mL [P
= 0.0029] in ANHELTO 2) [
TIO/OLO was associated with an improved quality
of life compared to TIO (MD -1.56 [−2.41 to −0.71],
I2 = 0%) in 4 RCT with 2697 participants [
14, 18, 19
or OLO (−1.69 [−2.77 to −0.61]) in 2 RCT with
1933 participants [
] (Fig. 3: Quality of life
SGRQ: change from baseline). More participants
receiving TIO/OLO had a clinically meaningful
difference in SGRQ compared to TIO [
14, 18, 19
1.21 [1.12 to 1.30], I2 = 0%) or OLO [
1.28 [1.18 to 1.40]) (Fig. 4: Quality of life SGRQ:
Similar results were found for TIO + OLO (18/5 μg) vs
TIO, both in the SGRQ total score change [
-1.90 [−2.80 to −1.00]) and SGRQ responders rate (RR
1.16 [1.06 to 1.27]) (Figs. 3 and 4).
Four studies measured the Mahler Transition Dyspnea
Index (TDI) [
]. TIO/OLO led to improved TDI
compared to TIO (MD 0.43 [0.22 to 0.65], I2 = 1%) and
OLO (RR 0.42 [0.16 to 0.68]) (Fig. 5: Symptoms TDI:
change from baseline). More participants receiving TIO/
OLO had a clinically meaningful difference in TDI score
(≥1.0 unit) compared to TIO (RR 1.17 [1.07 to 1.28], I2
= 75%) or OLO (RR 1.14 [1.01 to 1.28]) (Fig. 6:
Symptoms TDI: responders).
Rescue medication usage was lower with TIO + OLO
(18/5 μg) than with TIO [
]. On average, TIO +
OLO reduced the number of days using rescue
medication by 8.5 days (95% CI 4.2, 12.8) in ANHELTO 1 and
by 7.2 days (95% CI 3 to 11.49) in ANHELTO 2. In
OTEMTO 1 & 2, the use of rescue medication over 24 h
was lower in patients receiving TIO/OLO compared to
TIO after 12 weeks (P < 0.05) (post-hoc analysis). In
TONADO 1 & 2, TIO/OLO provided reductions in
adjusted weekly mean daily (24-h) rescue medication use
compared to the mono-components throughout the
52week treatment period.
MORACTO 1 & 2 trials showed a trend over
increased endurance time for TIO/OLO compared to TIO
(MD 8.06 [−13.76 to 29.87], I2 = 99%) or OLO (MD
23.67 [−21.34 to 68.69], I2 = 100%); however, these
results are limited by the significant heterogeneity between
the two included trials.
Regarding safety, no differences were observed in the
frequency of general and serious adverse events between
TIO/OLO and the mono-components. All adverse
events were reported in ANHELTO 1 & 2, OTEMTO 1
& 2, TONADO 1 & 2, VIVACITO and ENERGITO
trials. No significant differences between groups were
observed when comparing TIO/OLO versus
monocomponents (RR 0.99 [0.96 to 1.02], I2 = 0%) or versus
salmeterol fluticasone (RR 1.02 [0.85 to 1.23]) (Fig. 7: All
adverse events). Serious adverse events were assessed in
ANHELTO 1 & 2, OTEMTO 1 & 2, TONADO 1 & 2,
VIVACITO and ENERGITO trials. A similar between
group distribution was observed between participants
receiving TIO/OLO versus mono-components or placebo
(RR 0.99 [0.88 to 1.11], I2 = 49%). Also, ENERGITO trial
concluded similar number of serious adverse events
were observed between participants receiving TIO/OLO
versus fluticasone/salmeterol (RR 0.80 [0.39 to 1.65]).
The results of our analysis showed that TIO/OLO is an
effective and safe treatment for patients with COPD of a
very wide range of severity. The data obtained in the
RCT have demonstrated significant improvements in
through FEV1, SGRQ, dyspnea scores and a reduction in
the use of rescue medication compared with the
monocomponents, and a significant improvement in through
FEV1 in one study compared to LABA/ICS combination.
No safety issues were identified in the comparative
analysis with the mono-components.
Multicenter/ Double blind Baseline characteristics
✓/✓ Mean(SD) age – 51.7(9)
Male – 51.7%
Ex-smokers – 51%
Mean(SD) age - 63.6(7.6) Low
Male – 64.6%
Ex-smokers – 55.5%
Risk of Bias
Mean(SD) age – 61.7(7.7) Low
Male – 71.2%
Ex-smokers – 60.9%
Mean(SD) age – 64.7(8.4) Low
Male – 60.9%
Ex-smokers – 52.9%
Mean(SD) age - 646(8.3) Low
Male – 73.3%
Ex-smokers – 63.%
Mean(SD) age - 61.1(7.7) Low
Male - 58.9%
Ex-smokers - 37.4%
These results concur with those obtained with other
LABA/LAMA FDC, that also demonstrate to provide
better outcomes compared with mono-components [
] and with LABA/ICS [
] and support the recent
GOLD update that recommends LABA/LAMA as first
line therapy in patients classified as GOLD D (more
symptoms and increased risk of exacerbations) . In a
different approach based on clinical phenotypes, the
Spanish guideline of management of COPD in its 2017
update recommends LABA/LAMA as first line therapy
in patients classified as high risk (either FEV1 (%
predicted) < 50% or MRC ≥ 2 or >1 exacerbations or 1
hospitalization in the previous year) irrespective of the
phenotype, with the exception of the asthma-COPD
overlap (ACO) in which LABA/ICS is considered the
preferred initial option [
The current analysis was based on 10 completed
RCTs with TIO/OLO in COPD patients. Of these,
only 2 RCTs used the combination of TIO and OLO
administered with separate inhalers [
remaining 8 RCTs used TIO/OLO FDC administered
with the same inhaler (Respimat®). These studies
evaluated adult patients (≥ 40 years), predominantly men,
smokers or ex-smokers, with moderate and severe
COPD, even two of the trials included up to 10.8% of
patients with very severe COPD (FEV1 (%) < 30%). All trials
were considered of high-quality, both in terms of design
and execution, and the risk of bias in the estimation of the
effect was perceived as low.
The combination of TIO/OLO demonstrated a mean
improvement in trough FEV1 of between 60 mL to
90 mL over TIO and OLO, respectively. This
improvement is in line of the mean improvement observed with
dual bronchodilators versus LAMA alone [
Interestingly, the superiority of TIO/OLO in terms of lung
function was observed consistently in all analyzed RCTs.
The results observed in lung function were paralleled
with significant improvements in the SGRQ. The mean
differences in scores did not reach the 4 units
considered clinically relevant [
], but the probability of having
a response superior to 4 units were significantly
increased by 21% versus TIO and 28% versus OLO. Mean
differences of around 4 units have only been observed
between dual bronchodilation and placebo [
studies comparing LABA/LAMA combinations with
mono-components have shown mean differences below
that threshold, as observed in our analysis [
However it is important to highlight the increased
likelihood of achieving a clinically significant improvement in
quality of life with TIO/OLO, which may be very
relevant in more severe patients.
The current analysis has shown that TIO/OLO led to
improved TDI compared to TIO and OLO alone.
Patients on TIO/OLO had 17% higher probability to
experience an improvement >1 unit in the TDI dyspnea
score versus patients treated with TIO and 14% versus
OLO. These results are also consistent with those
reported for other LABA/LAMA FDC, where combinations
improve significantly TDI scores over monotherapies,
but mean differences do not achieve the 1 unit
]. However, all combinations increase
the probability of a patient to reach a clinically
significant improvement in dyspnea.
Rescue medication use and/or days free of rescue
medication were assessed in six trials. TIO/OLO
significantly reduced the use of rescue medication. This effect
was observed throughout the 52-week follow-up in
TONADO 1 & 2. The decrease in the use of rescue
medication is one of the proposed markers for clinical
control in COPD [
] and is associated with a decrease
risk of exacerbations [
In two RCTs, TIO/OLO showed a non-significant trend
towards an increase in exercise capacity compared to both
monotherapies. These results are similar to those obtained
with other LABA/LAMA FDC [
] and indicate that
exercise limitation in COPD is multifactorial and significant
improvements in lung function do not immediately
translate into significant increases in exercise capacity. Other
factors such as comorbidities and deconditioning may
influence the reduced exercise capacity in COPD.
Regarding safety, no differences were observed in the
frequency of general and serious adverse effects between
TIO/OLO FDC and the mono-components; thus
reassuring the excellent safety profile of this combination [
The strengths of the review are those typical of a
systematic review: exhaustive search for studies, a
reasonably high number of available studies, studies of high
methodological quality, possibility of performing a
metaanalysis, low heterogeneity and high consistency between
studies. However, as limitations we highlight that all
clinical trials were performed by the same
pharmaceutical company, common limitation when a drug is
reviewed by a meta-analysis. Another limitation is that it
was not possible to do a subgroup analysis according to
the patient’s baseline level of severity and a different
design related to variable duration of clinical trials
(between 6 and 24 weeks).
TIO/OLO is an effective and safe treatment for patients
with COPD of any degree of severity. The improvements
obtained in lung function are superior to those observed
with monotherapies or with LABA/ICS combination.
These improvements also translate with different intensity
to improvements in other patient-reported outcomes.
Additional file 1: Figure S3. Detailed search strategy. (DOCX 14 kb)
Additional file 2: Table S1. Characteristics of the included studies.
(DOCX 121 kb)
Additional file 3: Figure S1. Risk of bias graph. (JPEG 40 kb)
Additional file 4: Figure S2. Risk of bias summary. (JPEG 60 kb)
Systematic Review, Meta-Analysis and Medical writing assistance was
supported financially by Boehringer Ingelheim. Boehringer Ingelheim was given
the opportunity to check the data used in this manuscript for factual
Availability of data and materials
Data are available from the authors upon request.
All authors read and met ICMJE criteria for authorship. MM, GU had full access to
all of the data in the study and take responsibility for the integrity of the data and
the accuracy of the data analysis and wrote the manuscript. AGM and JA
contributed substantially to the study design, data analysis and interpretation and
the writing of the manuscript. All authors read and approved the final manuscript.
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1. Vogelmeier CF , Criner GJ , Martínez FJ , Anzueto A , Barnes PJ , Bourbeau J , et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report: GOLD executive summary . Arch Bronconeumol . 2017 ; 53 : 128 - 49 .
2. Kew KM , Dias S , Cates CJ . Long-acting inhaled therapy (beta-agonists, anticholinergics and steroids) for COPD: a network meta-analysis . Cochrane Database Syst Rev . 2014 ; 3 : CD010844 .
3. 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 .
4. Mathioudakis AG , Kanavidis P , Chatzimavridou-Grigoriadou V , Gialmanidis IP , Amanetopoulou SG , Christopoulou E , et al. Tiotropium HandiHaler improves the survival of patients with COPD: a systematic review and meta-analysis . J Aerosol Med Pulm Drug Deliv . 2014 ; 27 ( 1 ): 43 - 50 .
5. Schlueter M , Gonzalez-Rojas N , Baldwin M , Groenke L , Voss F , Reason T . Comparative efficacy of fixed-dose combinations of long-acting muscarinic antagonists and long-acting β2-agonists: a systematic review and network meta-analysis . Ther Adv Respir Dis . 2016 ; 10 ( 2 ): 89 - 104 .
6. Rodrigo GJ , Price D , Anzueto A , Singh D , Altman P , Bader G , et al. LABA/LAMA combinations versus LAMA monotherapy or LABA/ICS in COPD: a systematic review and meta-analysis . Int J Chron Obstruct Pulmon Dis . 2017 ; 12 : 907 - 22 .
7. Horita N , Goto A , Shibata Y , Ota E , Nakashima K , Nagai K , et al. Long-acting muscarinic antagonist (LAMA) plus long-acting beta-agonist (LABA) versus LABA plus inhaled corticosteroid (ICS) for stable chronic obstructive pulmonary disease (COPD) . Cochrane Database of Systematic Reviews 2017 , Issue 2 . Art . No.: CD012066 . DOI: https://doi.org/10.1002/14651858. CD012066. pub2 .
8. Miravitlles M , Soler-Cataluña JJ , Calle M , Molina J , Almagro P , Quintano JA , et al. Spanish COPD guidelines (GesEPOC) 2017 . Pharmacological treatment of stable chronic obstructive pulmonary disease . Arch Bronconeumol . 2017 ; 53 : 324 - 35 .
9. Ferguson GT , Feldman GJ , Hofbauer P , Hamilton A , Allen L , Korducki L , et al. Efficacy and safety of olodaterol once daily delivered via Respimat® in patients with GOLD 2-4 COPD: results from two replicate 48-week studies . Int J Chron Obstruct Pulmon Dis . 2014 ; 9 : 629 - 45 .
10. Calzetta L , Ciaprini C , Puxeddu E , Cazzola M. Olodaterol + tiotropium bromide for the treatment of COPD . Expert Rev Respir Med . 2016 : 1 - 8 .
11. Derom E , Brusselle GG , Joos GF . Efficacy of tiotropium-olodaterol fixed-dose combination in COPD . Int J Chron Obstruct Pulmon Dis . 2016 ; 11 : 3163 - 77 .
12. Moher D , Liberati A , Tetzlaff J , Altman DG , Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement . BMJ . 2009 ; 339 : b2535 .
13. Higgins JPT , Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011 ]. The Cochrane Collaboration , 2011 . Available from www. handbook.cochrane.org.
14. ZuWallack R , Allen L , Hernandez G , Ting N , Abrahams R . Efficacy and safety of combining olodaterol Respimat® and tiotropium HandiHaler® in patients with COPD: results of two randomized, double-blind, active-controlled studies . Int J Chron Obstruct Pulmon Dis . 2014 ; 9 : 1133 - 44 .
15. Beeh KM , Derom E , Echave-Sustaeta J , Grönke L , Hamilton A , Zhai D , et al. The lung function profile of once-daily tiotropium and olodaterol via Respimat® is superior to that of twice-daily salmeterol and fluticasone propionate via Accuhaler® (ENERGITO® study) . Int J Chron Obstruct Pulmon Dis . 2016 ; 11 : 193 - 205 .
16. Effect on Exercise Endurance and Lung Hyperinflation of Tiotropium + Olodaterol in COPD Patients . [Accessed December 12 , 2014 ]. ClinicalTrials. gov Identifier: NCT01533922; 2012 [updated April 30 , 2014 ]. Available from: https://clinicaltrials.gov/ct2/show/NCT01533922.
17. Effect on Exercise Endurance and Lung Hyperinflation of Tiotropium + Olodaterol in COPD Patients . [Accessed December 12 , 2014 ]. ClinicalTrials. gov Identifier: NCT01533935; 2012 [updated April 30 , 2014 ]. Available from: https://clinicaltrials.gov/ct2/show/NCT01533935.
18. Singh D , Ferguson GT , Bolitschek J , Grönke L , Hallmann C , Bennett N , et al. Tiotropium + olodaterol shows clinically meaningful improvements in quality of life . Respir Med . 2015 ; 109 ( 10 ): 1312 - 9 .
19. Singh D , Gaga M , Schmidt O , Bjermer L , Grönke L , Voß F , et al. Effects of tiotropium+olodaterol versus tiotropium or placebo by COPD disease severity and previous treatment history in the OTEMTO® studies . Respir Res . 2016 ; 17 ( 1 ): 73 .
20. Buhl R , Maltais F , Abrahams R , Bjermer L , Derom E , Ferguson G , et al. Tiotropium and olodaterol fixed-dose combination versus monocomponents in COPD (GOLD 2-4) . Eur Respir J . 2015 ; 45 ( 4 ): 969 - 79 .
21. Ferguson GT , Fležar M , Korn S , Korducki L , Grönke L , Abrahams R , et al. Efficacy of Tiotropium + Olodaterol in patients with chronic obstructive pulmonary disease by initial disease severity and treatment intensity: a post hoc analysis . Adv Ther . 2015 ; 32 ( 6 ): 523 - 36 .
22. Beeh KM , Westerman J , Kirsten AM , Hébert J , Grönke L , Hamilton A , et al. The 24-h lung-function profile of once-daily tiotropium and olodaterol fixed-dose combination in chronic obstructive pulmonary disease . Pulm Pharmacol Ther . 2015 ; 32 : 53 - 9 .
23. Bourbeau J , Lavoie KL , Sedeno M , De Sousa D , Erzen D , Hamilton A , et al. Behaviour-change intervention in a multicentre, randomised, placebocontrolled COPD study: methodological considerations and implementation . BMJ Open . 2016 ; 6 ( 4 ): e010109 .
24. Troosters T , Bourbeau J , Maltais F , Leidy N , Erzen D , De Sousa D , et al. Enhancing exercise tolerance and physical activity in COPD with combined pharmacological and non-pharmacological interventions: PHYSACTO randomised, placebocontrolled study design . BMJ Open . 2016 ; 6 ( 4 ): e010106 .
25. Comparing the Efficacy of Tiotropium + Olodaterol (5/5 μg) Fixed Dose Combination (FDC) Over Tiotropium 5 μg in Reducing Moderate to Severe Exacerbations in Patients With Severe to Very Severe Chronic Obstructive Pulmonary Disease . [Accessed December 12 , 2014 ]. ClinicalTrials.gov Identifier: NCT02296138; 2014 [updated December 11 , 2014 ]. Available from: http://clinicaltrials.gov/ct2/show/NCT02296138.
26. Aalbers R , Maleki-Yazdi MR , Hamilton A , Waitere-Wijker S , Zhao Y , Amatto VC , et al. Randomized, double-blind, dose-finding study for Tiotropium when added to Olodaterol, administered via the Respimat® inhaler in patients with chronic obstructive pulmonary disease . Adv Ther . 2015 ; 32 ( 9 ): 809 - 22 .
27. Maltais F , Gáldiz Iturri JB , Kirsten A , Singh D , Hamilton A , Tetzlaff K , et al. (P250) effects of 12 weeks of once-daily tiotropium and olodaterol fixeddose combination on exercise endurance in patients with COPD . Thorax . 2014 ; 69 ( suppl 2 ): A186 - 7 . https://doi.org/10.1136/thoraxjnl-2014- 206260 . 378 .
28. Bateman ED , Ferguson GT , Barnes N , Gallagher N , Green Y , Henley M , et al. Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study . Eur Respir J . 2013 ; 42 ( 6 ): 1484 - 94 .
29. 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 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 .
30. Singh D , Worsley S , Zhu CQ , Hardaker L , Church A . Umeclidinium/vilanterol versus fluticasone propionate/salmeterol in COPD: a randomised trial . BMC Pulm Med . 2015 ; 15 : 91 .
31. Vogelmeier C , Paggiaro PL , Dorca J , Sliwinski P , Mallet M , Kirsten AM , et al. Efficacy and safety of aclidinium/formoterol versus salmeterol/fluticasone: a phase 3 COPD study . Eur Respir J . 2016 ; 48 ( 4 ): 1030 - 9 .
32. Vogelmeier CF , Bateman ED , Pallante J , Alagappan VK , D'Andrea P , Chen H , et al. Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study . Lancet Respir Med . 2013 ; 1 ( 1 ): 51 - 60 .
33. Siler TM , Donald AC , O'Dell D , Church A , Fahy WAA . Randomized, parallelgroup study to evaluate the efficacy of umeclidinium/vilanterol 62.5/25 μg on health-related quality of life in patients with COPD . Int J Chron Obstruct Pulmon Dis . 2016 ; 11 : 971 - 9 .
34. Nibber A , Chisholm A , Soler-Cataluña JJ , Alcazar B , Price D , Miravitlles M. On behalf of the respiratory effectiveness group. Validating the concept of COPD control: a real-world cohort study from the United Kingdom . COPD . 2017 ; 14 : 504 - 12 .
35. Jenkins CR , Postma DS , Anzueto AR , Make BJ , Peterson S , Eriksson G , et al. Reliever salbutamol use as a measure of exacerbation risk in chronic obstructive pulmonary disease . BMC Pulm Med . 2015 ; 15 : 97 .
36. Maltais F , Singh S , Donald AC , Crater G , Church A , Goh AH , et al. Effects of a combination of umeclidinium/vilanterol on exercise endurance in patients with chronic obstructive pulmonary disease: two randomized, double-blind clinical trials . Ther Adv Respir Dis . 2014 ; 8 ( 6 ): 169 - 81 .
37. Buhl R , Magder S , Bothner U , Tetzlaff K , Voß F , Loaiza L , et al. Long-term general and cardiovascular safety of tiotropium/olodaterol in patients with moderate to very severe chronic obstructive pulmonary disease . Respir Med . 2017 ; 122 : 58 - 66 .