Miravitlles et al. Respiratory Research (2022) 23:347 https://doi.org/10.1186/s12931-022-02268-3 RESEARCH Open Access Exercise capacity and physical activity in COPD patients treated with a LAMA/ LABA combination: a systematic review and meta‑analysis Marc Miravitlles1*, Juan Luís García‑Rivero2, Xavier Ribera3, Jordi Galera4, Alejandra García5, Rosa Palomino5 and Xavier Pomares6 Abstract Background: Persistent airflow limitation and dyspnoea may reduce chronic obstructive pulmonary disease (COPD) patients exercise capacity and physical activity, undermining their physical status and quality of life. Long-acting muscarinic antagonists and long-acting beta-2 agonists (LAMA/LABA) combinations are amongst moderate-to-severe COPD recommended treatments. This article analyses LAMA/LABA combinations effect on COPD patients exercise capacity and physical activity outcomes. Methods: A systematic review and meta-analysis of double-blind randomized controlled trials comparing LAMA/ LABA combinations against monotherapy or placebo was conducted. Results: Seventeen articles were identified (N = 4041 patients). In endurance shuttle walk test and constant work rate cycle ergometry, LAMA/LABA combinations obtained better results than placebo, but not monotherapy, whereas in 6-min walking test, results favoured LAMA/LABA over monotherapy (four studies), but not over placebo (one study). Moreover, LAMA/LABA combinations obtained better results than placebo in number of steps per day, reduction in percentage of inactive patients and daily activity-related energy expenditure, and better than monotherapy when measuring time spent on ≥ 1.0–1.5, ≥ 2.0 and ≥ 3.0 metabolic equivalents of task activities. Conclusions: LAMA/LABA combinations in COPD patients provided better results than monotherapy or placebo in most exercise capacity and physical activity outcomes. Keywords: Bronchodilators, COPD, Exercise capacity, LABA, LAMA, Physical activity Background or physical activity, which can undermine their physi- Patients with chronic obstructive pulmonary dis- cal status and quality of life [1, 2]. Physical inactivity is ease (COPD) present persistent airflow limitation and the most important predictor of all-cause mortality in dyspnoea that result in reduced exercise capacity and/ COPD and inactivity by itself induces a higher physi- cal deterioration creating a vicious circle that results in isolation and increased mortality [3, 4]. A study carried *Correspondence: marcm@separ.es out in Latin America showed that low levels of physical 1 Pneumology Department, Hospital Universitari Vall d’HebronVall d’Hebron activity are especially important in women and older Institut de Recerca, Vall d’Hebron Barcelona Hospital Campus, Pg. Vall patients, and it is related with worse functional and d’Hebron 119‑129, 08035 Barcelona, Spain clinical factors [4]. Therefore, the Global Initiative for Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. The Creative Commons Public Domain Dedication waiver (http://​creat​iveco​ mmons.​org/​publi​cdoma​in/​zero/1.​0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Miravitlles et al. Respiratory Research (2022) 23:347 Page 2 of 20 Chronic Obstructive Lung Disease (GOLD) recom- Search strategy mends regular physical activity for COPD patients [1]. A search strategy was designed for MEDLINE (through The documented reduction in daily activity in COPD PubMed), CENTRAL and EMBASE using appropriate patients results from the respiratory and non-respir- controlled terms related to COPD, LAMA, LABA, exer- atory clinical conditions of each patient. Particularly, cise capacity, physical activity and lung function in arti- the limitation on exercise capacity is mainly due to cles published between the 1st January 2012 and the 31st dynamic pulmonary hyperinflation, although other fac- December 2021 as the first LAMA/LABA combination tors also contribute, such as comorbidities or an imbal- inhaler was approved in 2013 and prior 2012 there was ance between respiratory and locomotive muscles due no evidence about double bronchodilators (Additional to limited energy supply [5]. Moreover, it has been file 2: Table A1). There were no limitations regarding lan- shown that the exercise capacity and the limitation in guage. Additionally, references to selected articles were daily activities are closely related to life expectancy also reviewed to identify other articles that met the inclu- and, therefore, pulmonary and systemic manifestations sion and exclusion criteria. would be improved by improving exercise capacity and physical activity [6]. Study selection and data extraction The recommended treatment for patients with mod- The titles and abstracts resulting from the search were erate-to-severe COPD and for symptomatic patients evaluated by two reviewers. The studies that didn’t meet or those with exercise limitation, is inhaled long-acting inclusion and exclusion criteria were ruled out, collect- beta-2 agonists (LABA) and/or long-acting muscarinic ing the reasons for exclusion. The articles selected were antagonists (LAMA) [1, 6, 7]. Bronchodilators increase read independently in full by the same two reviewers, lung emptying by reducing airway resistance, enabling who recorded the reasons for non-selection. In the event COPD patients to achieve better alveolar ventilation with of discrepancies between the reviewers, the criterion of a a lower operating pulmonary volume, both at rest and third reviewer was used. during exercise. As a result, patients using bronchodila- Data from the selected articles were tabulated by one tors are able to exercise for longer before reaching the reviewer and validated by a second reviewer in a detailed critical limit of their inspiratory reserve [8]. extraction form. From each article we extracted the study Due to the relevance of exercise capacity and physical characteristics (type of study, design, countries), patient activity on the quality of life of COPD patients, we have characteristics (mean age, sex, disease severity), and conducted a systematic literature review (SLR) and meta- interventions and comparators (LAMA/LABA, LAMA, analysis of randomized clinical trials aimed to evaluate LABA or placebo inhalers used, dose, treatment dura- the effect of the combination of LAMA/LABA bron- tion), and the results of variables related to the exercise chodilators compared with placebo or LAMA or LABA capacity and physical activity. monotherapy on the exercise capacity and physical activ- ity outcomes of COPD patients. Assessed outcomes The identified outcome variables are defined as: Methods • 6-min walking test (6MWT), measuring the distance This SLR was carried out according to the Preferred walked in 6 min in meters. Reporting Items for Systematic Reviews and Meta-anal- • Endurance Shuttle Walk Test (ESWT) measured in yses Statement (PRISMA) and the QUORUM State- seconds (one study measured it in mean percentage ment [9]. The protocol was registered with PROSPERO change from baseline). (CRD42020191639). • Constant Work Rate Cycle Ergometry (CWRCE) measured in seconds. • Steps per day (steps/day), examined by accelerometer Inclusion and exclusion criteria and evaluated as average number of steps per day. We included randomized clinical trials in patients • Energy expenditure of ≥ 1.0–1.5, ≥ 2.0, ≥ 3.0 Meta- aged ≥ 40 years diagnosed with COPD, with a post-bron- bolic Equivalent of Task (METs), consisting on the chodilator forced expiratory volume at 1 s ­(FEV1)/forced average daily duration (in minutes) of ≥ 1.0–1.5, ≥ 2.0 vital capacity (FVC) < 0.7 and treated with a combination and ≥ 3.0 METs. Periods of sedentary time were cat- of LAMA/LABA inhaled bronchodilators compared with egorized as an energy expenditure of 1.0–1.5 METs, placebo or monotherapy with LAMA or LABA. To be whereas periods of physical activity performed at included, the trials had to evaluate at least one variable more than light (i.e., moderate, or vigorous) and related to exercise capacity or physical activity. Miravitlles et al. Respiratory Research (2022) 23:347 Page 3 of 20 more than moderate (i.e., vigorous) intensities were be significant heterogeneity. In those comparisons with categorized as ≥ 2.0 METs and ≥ 3.0 METs, respec- no statistical evidence of heterogeneity, a fixed effects tively. model was used; otherwise, a random effects model was • Energy expenditure related to activity, measured in employed. kilocalories per day. A sensitivity analysis stratified by study design (paral- • Walking time per day, measured in minutes per day. lel and cross-over) was performed for results that showed • Walking intensity, average daily walking intensity heterogeneity ­(I2 > 0%). measured in meters per square second. The analysis considered the results of two treatment • Percentage of inactive patients, where inactive arms compared in each study. For studies with more than patient was defined as patient who walked less than 2 treatment arms, comparisons were made separately, 6,000 steps per day. dividing the sample size of the study by the number of • Daily PROactive Physical Activity COPD question- comparisons to avoid overestimation of results. The anal- naire (D-PPAC) punctuation (questionnaire punctua- ysis was made using Review Manager 5.4. tion) is a daily recall, electronic, patient-reported out- come (PRO) tool, it was filled out by patients every Results evening for a period of time (usually a week). This The search strategies yielded 1590 articles, of which 17, seven-item PRO measure consists of two physical including 4,041 patients, met the inclusion criteria, 2964 activity experience domains: amount and difficulty of the patients were treated with the LAMA/LABA com- [10]. bination, 1901 treated with placebo, 1070 treated with LAMA and 755 treated with LABA (Fig. 1) [12–28]. The reference search yielded no further articles. Assessment of risk of bias The risk of bias assessment was carried out according to Description of the studies the Cochrane Manual for Systematic Reviews and Meta- All included studies were randomized, controlled, dou- Analysis of Interventions criteria [11] and evaluated the ble-blind trials. Five studies had a parallel design, includ- generation of the randomization sequence, concealment ing between 80 and 404 participants and the remaining of the assignment, blinding of patients and researchers, twelve were crossover trials, including 17–657 partici- blinding of the results of the variables to be evaluated, pants (mean 238, median 184). The duration of treatment data on incomplete results, bias of scientific informa- was 52 weeks (1 study), 12 weeks (7 studies), 8 weeks (1 tion, and other biases. The risk of bias was assessed by study), 6 weeks (4 studies), 4 weeks (1 study), 3 weeks (1 one reviewer and validated by a second on a detailed study) and 2 weeks (1 study) (Table 1). form. Review Manager 5.4 was used for the risk of bias The combinations of bronchodilators most commonly assessment. used as an intervention were tiotropium/olodaterol 5 µg/5 µg (7 studies), tiotropium/olodaterol 2.5 µg/5 µg Data analysis (3 studies) and umeclidinium/vilanterol 62.5 µg/25 µg The analysis was based on the change from baseline in (3 studies). Comparators were placebo in 13 studies and the above-mentioned outcome variables and assessed monotherapy in 10 studies, using tiotropium 5 µg in 5 using dichotomous and continuous outcomes. Dichoto- studies, olodaterol 5 µg in 1 study, umeclidinium 62.5 µg mous data were analysed by calculating the estimate for in 3 studies, umeclidinium 125 µg in 2 studies and the odds ratio (OR) and their corresponding 95% con- vilanterol 25 µg in 2 studies. In two studies more than fidence intervals (CI). Continuous data were analysed one monotherapy was used as a comparator. by calculating weighted mean differences (WMD) and standardized mean differences (SMD), both with the cor- Risk of bias responding 95% CI. The risk of bias was considered low for all domains evalu- When useful, forest plots were created, in order to ated except for blinding of the results and concealment of graphically assess the variability of sample estimates and assignment domains, where the risk of bias was unclear the weight of sample sizes in the calculation of estimates for the majority of studies analysed (Additional file 1: Fig. (weighted averages). In addition, to facilitate interpreta- A1). tion of the results from studies that were not included in the forest plots, the mean and standard deviation were Effectiveness of the intervention shown. A significance level of α = 0.05 was considered. Table 2 shows a summary of meta-analysis comparisons For data synthesis among studies, statistical heteroge- for those variables of interest that estimated change from neity was evaluated using I­2, with I­2 > 50% considered to baseline. Miravitlles et al. Respiratory Research (2022) 23:347 Page 4 of 20 Fig. 1 PRISMA flowchart. COPD chronic obstructive pulmonary disease, LABA long-acting beta-2 agonists, LAMA long-acting muscarinic antagonists, PRISMA Preferred Reporting Items for Systematic Reviews and Meta-analyses Statement Effectiveness of the intervention in exercise capacity In Canto et al. [23] LAMA/LABA combination was The LAMA/LABA combination was associated with compared to monotherapy, measuring the increase, significantly better physical endurance than placebo, in percentage, of the tolerance limit in constant work when evaluated by both ESWT and CWRCE (Fig. 2a, rate test. This comparison showed the superiority of b). Compared with monotherapy, LAMA/LABA com- LAMA/LABA combination against monotherapy with binations showed favourable results, although, these statistically significant differences (Table 2). By com- results just failed to be statistically significant, both paring LAMA/LABA against placebo, two studies when evaluated by ESWT (SMD: 0.16; 95%CI: − 0.00 estimated CWRCE after treatment (these studies were to 0.33) and by CWRCE (SMD: 0.06; 95%CI: − 0.00 to not designed to evaluate the change from baseline). In 0.13) (Fig. 2a, b). both studies a mean increase in exercise capacity was In the study by Maltais et al. a subgroup of patient observed with LAMA/LABA versus placebo in COPD of the TORRACTO study in which both CWRCE and (55 s [95% CI: 20–90, p = 0.013] [26] y 113 s [95% CI: ESTW were evaluated, results were consistent with 6–220, p = 0.037] [27]. previous publications and show significant superiority Regarding 6MWT, the mean difference of 11.87 mts. of LAMA/LABA combination vs. placebo in CWCRE observed between LABA/LAMA and placebo in a sin- (difference: 118.3 [95% CI: 45.9 to 190.8]; p = 0.0015), gle study (n = 125) did not reach statistical significance although these differences were not statistically signifi- (Table 2); however, the meta-analysis of results of the cant in ESWT (difference: 76.3 [95% CI: − 2.8 to 155.4]; 4 studies comparing LAMA/LABA with monotherapies p = 0.0585) [22]. Table 1 Characteristics of studies included Abbreviated reference and Study type, number of Duration Inclusion criteria Intervention Comparator Outcomes selected for Main results countries arms and randomized analysis patients Miravitlles et al. Respiratory Research Troosters et al. 2018 [12] Parallel, 4 arms, 304 patients 12 weeks 40–75 years, smoking his‑ Tiotropium 5 μg/Olodaterol Tiotropium 5 μg or placebo ESWT, 6MWT, steps/day, Arithmetic mean (SE) change Australia, Austria, Belgium, tory > 10 pack-years, FEV1 5 μg, or Tiotropium 5 μg/ walking intensity, walking from baseline, ESWT: Canada, Denmark, Germany, post-bronchodilator 30% to Olodaterol 5 μg with train‑ time/day - Tiotropium 5 μg/Olodaterol New Zealand, Poland, 80% predicted, and FEV1/ ing program 5 μg: 91.0 (28.0) Portugal, United Kingdom, FVC < 70% - Placebo: 31.0 (30.0) United States Adjusted mean (SE) change (2022) 23:347 from baseline, 6MWT: - Tiotropium 5 μg/Olodaterol 5 μg: 25.76 (7.17) - Tiotropium 5 μg: 6.87 (7.75) - Placebo: 13.89 (8.09) Adjusted mean (SE) change from baseline, steps/day: - Tiotropium 5 μg/Olodaterol 5 μg: 1394.24 (310.22) - Tiotropium 5 μg: 153.19 (317.98) - Placebo: 1098.07 (325.08) Walking intensity and walking time/day results showed in results section O’Donnell et al. 2017 [13] Crossover 5 arms, 586 6 weeks Smoking history > 10 pack- Tiotropium 2.5 g/Olodaterol Tiotropium 5 μg, olodaterol CWRCE Adjusted arithmetic mean (SE) United States, Argentina, patients years, post-bronchodilator 5 μg, or Tiotropium 5 μg/ 5 µg and placebo of EET during CWRCE: Australia, Austria, Belgium, FEV1/FVC < 0.7; post-bron‑ Olodaterol 5 μg - At Beginning: Canada, Chile, Germany, chodilator FEV1 ≥ 30% - All treatments: 511.6 (SD: Italy, Netherlands, New and < 80% of predicted 269.4) Zealand, Russia, Sweden - At 6 weeks: - Placebo: 470.6 (12.6) - Olodaterol 5 μg: 521.1 (12.6) - Tiotropium 5 μg: 536.2 (12.6) - Tiotropium 2.5 g/Olodaterol 5 μg: 552.1 (12.5) - Tiotropium 5 μg/Olodaterol 5 μg: 554.5 (12.5) Page 5 of 20 Table 1 (continued) Abbreviated reference and Study type, number of Duration Inclusion criteria Intervention Comparator Outcomes selected for Main results Miravitlles et al. Respiratory Research countries arms and randomized analysis patients Ichinose et al. 2018 [14] Crossover 2 arms, 6 weeks Japanese Tiotropium 5 μg/Olodaterol Tiotropium 5 μg 6MWT, steps/day, duration Adjusted mean (SD), 6MWT: Japan 184 patients patients ≥ 40 years, with 5 μg of activity - At Beginning: history of smoking > 10 - All treatments: 293.8 (93.3) pack-years, with COPD and - At 6 weeks: (2022) 23:347 stable airway obstruc‑ - Tiotropium 5 μg/Olodaterol tion, post-bronchodilator 5 μg: 311.5 (n.a) FEV1 < 80% of predicted; - Tiotropium 5 μg: 307.4 (n.a) post-bronchodilator Adjusted mean (95%CI) treat‑ FEV1/FVC < 0.7 at visit 1; ment difference at 6 weeks, mMRC ≥ 1; 6MWD < 400 m; 6MWT: 4.2 (-6.2–14.5) and a score ≥ 4 on Borg’s Adjusted mean, steps/day: modified scale following the - At Beginning: 6MWD test on visit 2 - All treatments: 3723.0 - At 6 weeks: - Tiotropium 5 μg/Olodaterol 5 μg: 3871.1 - Tiotropium 5 μg: 3793.6 Adjusted mean (95%CI) treat‑ ment difference at 6 weeks, steps/day: 77.5 (-92.7–247.7) Adjusted mean (SD), ≥ 2 METs: - At Beginning: - All treatments: 181.4 (82.0) - At 6 weeks: - Tiotropium 5 μg/Olodaterol 5 μg: 191.5 (n.a) - Tiotropium 5 μg: 186.5 (n.a) Adjusted mean (95%CI) treatment difference at 6 weeks, ≥ 2 METs: 5.0 (0.39–9.69) Page 6 of 20 Table 1 (continued) Abbreviated reference and Study type, number of Duration Inclusion criteria Intervention Comparator Outcomes selected for Main results countries arms and randomized analysis patients Watz et al. 2017 [15] Parallel 8 weeks ≥ 40 years, history of smok‑ Aclidinium 800 μg/Formo‑ Placebo CWRCE, % inactive patients, Least square mean (95%CI) Canada, Germany, Hungary, 2 arms, terol 24 μg steps/day, duration of change from baseline, CWRCE: Miravitlles et al. Respiratory Research ing, (FRC) ≥ 120% of pre‑ Spain 267 patients dicted, post-bronchodilator activity, energy expenditure, - Aclidinium 800 μg/Formo‑ FEV1 ≥ 40% and < 80% of D-PPAC terol 24 μg: 45.5 (13.7–77.3) predicted, FEV1/FVC < 70%, - Placebo: -13.40 (n.a) and score ≥ 2 on mMRC Treatment difference of % dyspnoea scale inactive patients: OR:0.27; 95%CI: 0.14–0.51 Least squares mean (SE) (2022) 23:347 change from baseline, steps/ day: - Aclidinium 800 μg/Formo‑ terol 24 μg: 621.0 (167.0) - Placebo: -110.0 (167.0) Least squares mean (95%CI) change from baseline, ≥ 3 METs: - Aclidinium 800 μg/Formo‑ terol 24 μg: 8.5 (4.3–12.8) - Placebo: -1.2 (-5.40–3.10) Adjusted mean (95%CI) treatment difference at 4 weeks, ≥ 3 METs: 9.7 (3.8–15.5) Least squares mean (95%CI) change from baseline, energy expenditure: - Aclidinium 800 μg/Formo‑ terol 24 μg: 36.5 (16.8–56.1) - Placebo: − 4.4 (− 24.1 to 15.2) Adjusted mean (CI-95%) treat‑ ment difference at 4 weeks, energy expenditure: 40.9 (13.9–67.9) D-PPAC results showed in results section Page 7 of 20 Table 1 (continued) Abbreviated reference and Study type, number of Duration Inclusion criteria Intervention Comparator Outcomes selected for Main results countries arms and randomized analysis patients Minakata et al. 2019 [16] Crossover 6 weeks ≥ 40 years, diagnosed with Tiotropium 5 μg/Olodaterol Tiotropium 5 μg MET(s) Adjusted mean (SD), ≥ 1.0–1.5 Japan 2 arms, COPD and GOLD grade II–IV 5 μg METs: 182 patients - At Beginning: - All treatments: 408.4 (90.0) Miravitlles et al. Respiratory Research - At 6 weeks: - Tiotropium 5 μg/Olodaterol 5 μg: 407.9 (n.a) - Tiotropium 5 μg: 416.6 (n.a) Adjusted mean (95%CI) treatment difference at (2022) 23:347 6 weeks, ≥ 1.0–1.5 METs: -8.64 (-16.88–-0.40) Adjusted mean (SD), ≥ 2 METs: - At Beginning: - All treatments: 177.30 (64.4) - At 6 weeks: - Tiotropium 5 μg/Olodaterol 5 μg: 179.1 (n.a) - Tiotropium 5 μg: 172.5 (n.a) Adjusted mean (95%CI) treatment difference at 6 weeks, ≥ 2 METs: 6.51 (1.17–11.85) Adjusted mean (SD), ≥ 3 METs: - At Beginning: - All treatments: 42.2 (24.7) - At 6 weeks: - Tiotropium 5 μg/Olodaterol 5 μg: 46.1 (n.a) - Tiotropium 5 μg: 43.5 (n.a) Adjusted mean (95%CI) treatment difference at 6 weeks, ≥ 3 METs: 2.6 (0.7–4.49) Singh et al. 2018 [17] Crossover 4 arms, 12 weeks ≥ 40 years, with history of Umeclidinium 62.5 μg/ Umeclidinium 62.5 μg, ESWT Least squares mean (SE) United States, Bulgaria, 657 patients smoking > 10 pack-years, Vilanterol 25 μg Vilanterol 25 μg, and change from baseline, ESWT: Estonia, Germany, Russia, FRC at rest > 120% of - Umeclidinium 62.5 μg/ United Kingdom, Canada, predicted, FEV1/FVC post- Vilanterol 25 μg: 27.3 (4.4) Czech Republic, Denmark, bronchodilator < 70% and - Umeclidinium 62.5 μg: 20.4 South Africa, Ukraine FEV1 ≥ 35% and ≤ 70% of (7.7) predicted - Vilanterol 25 μg: 12.6 (6.3) Page 8 of 20 Table 1 (continued) Abbreviated reference and Study type, number of Duration Inclusion criteria Intervention Comparator Outcomes selected for Main results countries arms and randomized analysis patients Riley et al. 2018 [18] Crossover 12 weeks ≥ 40 years, history of Umeclidinium 62.5 μg/ Placebo ESWT Least squares mean (SE) United States 2 arms, smoking ≥ 10 packages/ Vilanterol 25 μg change from baseline, ESWT 198 patients year; FEV1/FVC < 0.70 and - Umeclidinium 62.5 μg/ FEV1 post-bronchodilation Vilanterol 25 μg: -2.1 (9.29) 30–70% of predicted; FRC - Placebo: − 5.4 (9.68) at rest ≥ 120% of predicted; score ≥ 2 on mMRC dysp‑ Miravitlles et al. Respiratory Research noea scale O’Donnell et al. 2018 [19] Crossover 4 weeks > 40 years, with smoking Umeclidinium 125 μg/ Umeclidinium 125 μg CWRCE Mean (SD), CWRCR (min): Canada 2 arms, history > 20 pack-years, post- Vilanterol 25 μg - At Beginning: 17 patients bronchodilator FEV1 ≥ 50 - Umeclidinium 125 μg/ and < 80% over predicted, Vilanterol 25 μg: 7.19 (4.13) FEV1/FVC < 0.7, and activity- - Umeclidinium 125 μg: 6.83 (4.67) (2022) 23:347 related dyspnoea (BDI ≤ 9 or mMRC dyspnoea scale ≥ 2) - At 4 weeks: - Umeclidinium 125 μg/ Vilanterol 25 μg: 7.49 (4.99) - Umeclidinium 125 μg: 7.82 (6.15) Maltais et al. 2018 [20] Parallel 12 weeks 40–75 years, with history of Tiotropium 2.5 μg/Olo‑ Placebo CWRCE, ESWT Adjusted arithmetic mean United States, Argentina, 3 arms, smoking > 10 pack-years; daterol 5 μg, or Tiotropium (SD) of EET during CWRCE: Canada, Finland, France, 404 patients post-bronchodilator FEV1/ 5 μg/Olodaterol 5 μg - At Beginning: Germany, Hungary, Italy, FVC < 70% and post- - Tiotropium 2.5 μg/Olodaterol Spain, United Kingdom bronchodilator FEV1 < 80% 5 μg: 490.7 (272.4) and ≥ 30% above predicted - Tiotropium 5 μg/Olodaterol 5 μg: 527.5 (279.2) - Placebo: 502.7 (258.6) - At 12 weeks: - Tiotropium 2.5 μg/Olodaterol 5: 616.35 (SE: 23.41) - Tiotropium 5 μg/Olodaterol 5 μg: 628.32 (SE: 22.94) - Placebo: 549.42 (SE:24.36) Adjusted arithmetic mean (SD) of EET during CWRCE: - At Beginning: - Tiotropium 2.5 μg/Olodaterol 5: 366.7 (206.0) - Tiotropium 5 μg/Olodaterol 5 μg: 373.7 (217.1) - Placebo: 346.3 (186.5) - At 12 weeks: - Tiotropium 2.5 μg/Olodaterol 5: 473.43 (SE: 31.47) - Tiotropium 5 μg/Olodaterol 5 μg: 465.48 (SE: 30.40) - Placebo: 379.95 (SE:33.06) Page 9 of 20 Table 1 (continued) Abbreviated reference and Study type, number of Duration Inclusion criteria Intervention Comparator Outcomes selected for Main results countries arms and randomized analysis patients Maltais et al. 2014 [28] Crossover 12 weeks ≥ 40 years, with history of Umeclidinium 62.5 μg/ placebo ESWT Adjusted arithmetic mean (SE) United States, Bulgaria, 6 arms, smoking ≥ 10 pack-years, Vilanterol 25 μg or Umecli‑ of EET during ESWT, change Estonia, Germany, Russia, 655 patients post-bronchodilator FEV1/ dinium 125 μg/ Vilanterol from baseline: Miravitlles et al. Respiratory Research United Kingdom, Canada, FVC < 70% and FEV1 ≥ 35% 25 μg - Umeclidinium 62.5 μg/ Czech Republic, Denmark, and ≤ 70% of predicted; Vilanterol 25 μg: 62.9 (10.8) South Africa, Ukraine score ≥ 2 on mMRC - Umeclidinium 125 μg/ dyspnoea scale on visit 1 Vilanterol 25 μg: 66.7 (10.99) and FRC at rest ≥ 120% of - Placebo: 19.2 (10.39) predicted (2022) 23:347 Watz et al. 2016 [21] Crossover 3 weeks ≥ 40 years, with history of Indacaterol 110 μg/ Glyco‑ Placebo Energy expenditure, steps/ Least squares mean change Germany 2 arms, smoking ≥ 10 pack-years, pyrronium 50 μg day, duration of activity from baseline, energy 194 patients post-bronchodilator FEV1 expenditure: between 40 and 80% of pre‑ - Indacaterol 110 μg/Glycopyr‑ dicted and FEV1/FVC < 0.70 ronium 50 μg: 5.10 at visit 2 - Placebo: − 31.60 Least squares mean (95%CI) treatment difference, change from baseline, energy expenditure: 36.7 (1.7–71.7) Mean (SD) change from baseline, steps/day: - Indacaterol 110 μg/Glycopyr‑ ronium 50 μg: 31.0 (1662.4) - Placebo: − 321.0 (1647.6) Mean (SD) treatment differ‑ ence, change from baseline, steps/day: 358.0 (2458.0) Least squares mean (95%CI) change from baseline, ≥ 3 METs: - Indacaterol 110 μg/Glycopyr‑ ronium 50 μg: − 6.9 (− 13.4 to − 0.40) - Placebo: − 11.3 (− 17.9 to − 4.60) Least squares mean (95%CI) treatment difference, change from baseline, ≥ 3 METs: 4.4 (-3.30–12.1) Page 10 of 20 Table 1 (continued) Miravitlles et al. Respiratory Research Abbreviated reference and Study type, number of Duration Inclusion criteria Intervention Comparator Outcomes selected for Main results countries arms and randomized analysis patients Maltais et al. 2020 [22] Parallel 12 weeks 40–75 years, post-broncho‑ Tiotropium 2.5 μg/Olo‑ Placebo CWRCE, ESWT Arithmetic mean CWRCE (SE) United States, Argentina, 3 arms, dilator FEV1 between ≥ 30% daterol 5 μg, or Tiotropium at week 6: Canada, Finland, France, 151 patients and < 80% than predicted, 5 μg/Olodaterol 5 μg - Placebo: 425.2 (25.3) (2022) 23:347 Germany, Hungary, Italy, and post-bronchodilator - Tiotropium 5 μg/Olodaterol Spain, United Kingdom FEV1/FVC < 70% 5 μg: 507.0 (27.0) Arithmetic mean ESWT (SE) at 6 weeks6: - Placebo: 375.6 (34.0) - Tiotropium 5 μg/Olodaterol 5 μg: 457.2 (30.3) Canto et al. 2012 [23] Crossover 2 weeks Patients with stable COPD Formoterol 24 μg /Tiotro‑ Placebo/Formoterol 12 μg Tolerance limit in constant Percentage of mean (SD) Brazil 2 arms, who met GOLD criteria, with pium 18 μg work rate test change from baseline: 41 patients a history of smoking > 20 - Formoterol 24 μg /Tiotro‑ pack-years pium 18 μg: 84.5 (8.2) - Placebo/Formoterol 12 μg: 40.7 (7.6) Jayaram et al. 2013 [24] Crossover 6 weeks Age: 18–80 years, Formoterol 24 μg /Tiotro‑ Placebo /Tiotropium 5 μg 6MWT Mean (95%CI) change from Australia, New Zealand 2 arms, smoking history ≥ 10 pack- pium 18 μg baseline, 6MWT: 38 patients years, - Formoterol 24 μg /Tiotro‑ COPD defined by ATS/ERS pium 18 μg: 25.5 (4.4–46.5) criteria - Placebo /Tiotropium 5 μg: − 7.6 (− 23.1 to 7.8) Mean (CI-95%) treatment dif‑ ference at 6 weeks, ≥ 2 METs: 36.3 (2.4–70.1) Page 11 of 20 Table 1 (continued) Abbreviated reference and Study type, number of Duration Inclusion criteria Intervention Comparator Outcomes selected for Main results countries arms and randomized analysis patients Takahashi et al. 2020 [25] Parallel, 2 arms, 80 patients 12 weeks 40 to 85 years, untreated, Tiotropium 5 μg/Olodaterol Tiotropium 5 μg 6MWT, steps/day, MET(s) Mean (SD), 6MWT: Japan with smoking history ≥ 10 5 μg - At Beginning: packages/year, post- - Tiotropium 5 μg/Olodaterol bronchodilator FEV1 < 80% 5 μg: 470.3 (77.6) predicted, and FEV1/ - Tiotropium 5 μg: 438.8 (88.1) FVC < 70% - At 12 weeks: - Tiotropium 5 μg/Olodaterol 5 μg: 475.7 (68.7) Miravitlles et al. Respiratory Research - Tiotropium 5 μg: 445.7 (80.6) Mean (SE) change from base‑ line, steps/day: - Tiotropium 5 μg/Olodaterol 5 μg: 168.1 (392.5) - Tiotropium 5 μg: 37.6 (192.4) Mean (CI-95%) treatment dif‑ (2022) 23:347 ference at 6 weeks, steps/day: 130.5 (− 750.0 to 1011.1) Mean (SD), ≥ 1.0–1.5 METs: - At Beginning: - Tiotropium 5 μg/Olodaterol 5 μg: 299.6 (92.4) - Tiotropium 5 μg: 287.0 (97.1) - Change from baseline: - Tiotropium 5 μg/Olodaterol 5 μg: -38.7 (n.a) - Tiotropium 5 μg: − 4.6 (n.a) Mean (95%CI) treatment dif‑ ference at 12 weeks, ≥ 1.0–1.5 METs: -34.1 (-70.4–2.2) Mean (SD), ≥ 2 METs: - At Beginning: - Tiotropium 5 μg/Olodaterol 5 μg: 138.5 (63.3) - Tiotropium 5 μg: 141.2 (68.5) - Change from baseline: - Tiotropium 5 μg/Olodaterol 5 μg: 10.8 (n.a) - Tiotropium 5 μg: 8.3 (n.a) Mean (95%CI) treatment dif‑ ference at 12 weeks, ≥ 2 METs: 2.5 (− 19.0 to 24.0) Mean (SD), ≥ 3 METs: - At Beginning: - Tiotropium 5 μg/Olodaterol 5 μg: 41.0 (29.0) - Tiotropium 5 μg: 36.1 (24.2) - Change from baseline: - Tiotropium 5 μg/Olodaterol 5 μg: 5.2 (n.a) - Tiotropium 5 μg: 2.5 (n.a) Mean (95%CI) treatment dif‑ ference at 12 weeks, ≥ 3 METs: 2.7 (-7.4–12.8) Page 12 of 20 Miravitlles et al. Respiratory Research Table 1 (continued) Abbreviated reference and Study type, number of Duration Inclusion criteria Intervention Comparator Outcomes selected for Main results (2022) 23:347 countries arms and randomized analysis patients Stringer et al. 2021 [26] Crossover 52 weeks Between 40 and 80 year Formoterol/Glycopyrronium Placebo CWRCE Mean (95% CI) treatment dif‑ United States 2 arms, 60 patients with a clinical diagnosis of (5/7.2 μg) ference, CWRCE: 55 s (20–90) COPD (postalbuterol FEV1/ FVC ratio < 0.70) and stable, without change in medica‑ tions or exacerbation within the prior 4wk Current or ex-smokers with > 10 pack-years smok‑ ing history Tufvesson et al. 2021 [27] Crossover n.a FEV1 of 40– 80% of pre‑ Indacaterol/Glycopyrronium Placebo CWRCE Mean (95% CI) treatment dif‑ Sweden 2 arms, 23 patients dicted normal (%pred) and (110/50 μg) ference, CWRCE: 113 s (6–220) a ratio of FEV1 to forced vital capacity (FVC) of ⩽0.7 Page 13 of 20 Miravitlles et al. Respiratory Research (2022) 23:347 Page 14 of 20 Table 2 Summary of meta-analysis comparisons and main results in weighted mean differences (WMD) and standardised mean differences (SMD) LAMA/LABA comparator Characteristics Weighted results Standardized results Number N MD 95% CI MD 95% CI of CT ESWT Placebo* 4 1730 31.75 s 16.03 s to 47.47 s 0.21 0.12 to 0.31 Monotherapy 1 689 11.36% − 0.03% to 22.74% 0.16 − 0.00 to 0.33 CWRCE Placebo* 3 2466 72.45 s 46.77 s to 98.13 s 0.22 0.14 to 0.30 Monotherapy 2 3398 24.23 s − 0.86 s to 49.32 s 0.06 − 0.00 to 0.13 Tlim CWRT​ Monotherapy* 1 38 43.80% 38.77% to 48.83% 5.42 3.99 to 6.86 6MWT Placebo 1 125 11.87 m − 9.32 m to 33.06 m 0.20 − 0.16 to 0.55 Monotherapy* 4 634 9.77 m 1.22 m to 18.31 m 0.17 0.02 to 0.33 Steps/day Placebo* 3 710 471.89 steps/day 206.08 steps/day to 737.71 steps/ 0.26 0.11 to 0.41 day Monotherapy** 3 521 398.48 steps/day − 264.40 steps/day to 1061.36 0.18 0.01 to 0.36 steps/day ≥ 1.0–1.5 METs Monotherapy* 2 315 − 9.93 min − 17.91 min to − 1.95 min − 0.30 − 0.53 to − 0.08 ≥ 2.0 METs Monotherapy* 3 645 5.59 min 2.13 min to 9.05 min 0.24 0.08 to 0.39 ≥ 3.0 METs Placebo*** 2 612 7.73 min 3.07 min to 12.39 min 0.24 − 0.05 to 0.53 Monotherapy* 2 315 2.60 min 0.74 min to 4.46 min 0.29 0.07 to 0.51 Energy expenditure Placebo* 2 612 39.33 kcal/day 17.95 kcal/day to 60.71 kcal/day 0.28 0.12 to 0.44 * Statistically significant differences, both in WMD and SMD. **Statistically significant differences in SMD. ***Statistically significant differences in WMD CI confidence interval, CT clinical trial, CWRCE constant work rate cycle ergometry, ESWT endurance shuttle walk test, kcal kilocalories, LABA long-acting beta-2 agonists, LAMA long-acting muscarinic antagonists, m meters, MD mean difference, MET metabolic equivalent of task, min minutes, N number of patients, s seconds, SMD standardized mean difference, Tlim CWRT​tolerance limit in constant work rate test, WMD weighted mean difference, 6MWT 6-min walking test (n = 634) showed significant differences in 6MWT in intensity with SMBM plus placebo compared with base- favour of LAMA/LABA combination (Table 2; Fig. 2c). line (1.97 vs. 1.90 m/s2, p = 0.006) and with SMBM + tio- tropium/olodaterol (1.99 vs. 1.91 m/s2; p < 0.05) [12]. Effectiveness of the intervention in physical activity In Watz et al. [15] the D-PPAC questionnaire total When measured in steps per day, LAMA/LABA combi- score (LSM [95% CI]: 2.7 [1.3–4.1]; p = 0.0002), amount nations were significantly superior to both placebo and (3.4 [1.4–5.4]; p = 0.0008), and difficulty (2.3 [0.3–4.4]; monotherapy (Fig. 3a). Regarding daily duration activity, p = 0.0258) domains improved significantly in the patients treated with LAMA/LABA combination reduced LAMA/LABA combination group versus placebo at week the duration of ≥ 1.0–1.5 METs activity than patients 4. At week 8, LAMA/LABA combination maintained the treated with monotherapy. On the other hand, for mod- improvements seen after 4 weeks; however, the differ- erate physical activity, the results favoured LAMA/LABA ences versus placebo were not statistically significant for therapy by increasing the duration of ≥ 2.0 METs activi- either total score (1.2 [− 0.5 to 3.0]; p = 0.1710), amount ties. For vigorous physical activity (≥ 3.0 METs), LAMA/ (0.7 [− 2.1 to 3.4]; p = 0.6303) or difficulty (2.1 [− 0.4 to LABA therapy was superior to both monotherapy and 4.5]; p = 0.0933) domains. In Troosters et al. [12] similar placebo, although the latter results were not statistically results were observed for LAMA/LABA combination significant when standardized under a random effects and LAMA monotherapy vs. baseline at week 9 for dif- model (Fig. 3b). Daily activity-related energy expendi- ficulty and amount domain, and at week 12 for difficulty ture was higher in the LAMA/LABA group than in the domain. No statistically improvements were shown when placebo group (Fig. 3c). Finally, more inactive patients comparing LAMA/LABA vs. placebo, although numeri- (< 6000 steps/day) were observed in the placebo group cally the combination showed better results in both than in the LAMA/LABA combination group (OR [95% domains at week 9 and 12 [12]. CI]: 0.27 [0.14–0.51]; 1 study, N = 267) [15]. In Troosters et al. [12] walking intensity and walking time per day were Sensitivity analysis also evaluated at week 12, results for average daily walk- Sensitivity analysis, stratified by study design in cases where ing time mirrored those of steps per day and there was heterogeneity was present, confirmed the LAMA/LABA a small but significant increase in average daily walking combinations favorable results compared to monotherapy Miravitlles et al. Respiratory Research (2022) 23:347 Page 15 of 20 Fig. 2 ESWT, CWRCE and 6MWT; Mean change from baseline, LAMA/LABA vs placebo and LAMA/LABA vs monotherapy. Fixed effects analysis model. Aclid aclidinium, CI confidence interval, CWRCE constant work rate cycle ergometry, EET exercise endurance time, ESWT endurance shuttle walk test, Formo formoterol, IV inverse variance, LABA long-acting beta-2 agonists, LAMA long-acting muscarinic antagonists, Olo olodaterol, Plcb placebo, SE standard error, Std. standardized, Tio Tiotropium, Ume umeclidinium, Vila vilanterol, 6MWT 6-min walking test, µm microgram in 6MWT and steps per day. For vigorous physical activity differences were not significant. Patients included in the (≥ 3.0 METs), LAMA/LABA therapy was superior to both Watz et al. 2016 [21] study appeared to have high durations monotherapies with a significant heterogeneity (I2 = 69%); of physical activity on entry (mean baseline values of 125 due to the limited number of studies included in this anal- and 130 min per day), which were about 30% higher than ysis (n = 2), the sensitivity analysis was explained based in previous studies with similar COPD populations. This on individual studies results. In Watz H et al. 2016 [21] would suggest that the patients had limited opportunities LAMA/LABA combination was significantly better com- to increase the duration of physical activity in their day-to- pared to monotherapy; whereas in Watz et al. 2017 [15] day lifestyle. Miravitlles et al. Respiratory Research (2022) 23:347 Page 16 of 20 Fig. 3 Steps/day, duration of activity and energy expenditure; mean change from baseline, LAMA/LABA vs placebo and vs monotherapy. Random effects analysis model (against placebo, ≥ 3.0 METs); fixed effects analysis model for other comparisons. Aclid aclidinium, CI confidence interval, Formo formoterol, Glicopi glycopyrronium, Inda indacaterol, IV inverse variance, kcal kilocalories, LABA long-acting beta-2 agonists, LAMA long-acting muscarinic antagonists, MET metabolic equivalent task, Olo olodaterol, Plcb placebo, SE standard error, Std. standardized, Tio Tiotropium, µm microgram Discussion LAMA/LABA combinations, but the differences did not The results of this systematic review of RCTs indicate that reach statistical significance. exercise capacity and physical activity outcomes favoured The latest American Thoracic Society (ATS) guidelines LAMA/LABA combinations over placebo for ESTW, on pharmacologic management of COPD recommend CWRE and steps per day; and over LAMA or LABA treating COPD patients who complain of dyspnoea or monotherapies for ­Tlim in CWRE, 6MWT and steps per exercise intolerance with LAMA/LABA combination day, where the differences were statistically significant. over LAMA or LABA monotherapies [29], as the combi- For LAMA/LABA versus placebo in 6MWT and ver- nation of the two mechanisms of action effectively reduce sus monotherapy in ESTW and CWRE results favoured the dynamic hyperinflation process characteristic in Miravitlles et al. Respiratory Research (2022) 23:347 Page 17 of 20 COPD patients, that usually limits their ability to exercise were not significant when comparing LAMA/LABA ver- [6, 7, 30]. Several studies on COPD patients have asso- sus monotherapy in ESWT or CWRCE tests, probably ciated low levels of physical activity and sedentary time because there could be a threshold for bronchodilation with an increased frequency of exacerbations, hospitali- to immediately translate into better exercise tolerance. zations, worse quality of life, and also an increased risk It may be unrealistic to expect the same exercise ben- of death as a result of progressive ventilatory limitation, efit when adding a second bronchodilator to an existing cardiac impairment, peripheral muscle, and psychologi- one than when adding a bronchodilator to placebo [13]. cal factors [3, 31, 32]. Increasing physical activity and its These results agree with recent meta-analysis, which also intensity in those patients may improve quality of life and concluded that LAMA/LABA combinations were more reduce the loss of pulmonary function [33, 34]. effective than LABA or LAMA monotherapy in terms Moreover, increasing the duration of low-intensity of exercise capacity and symptoms [6, 42]. The meta- activity, instead of high-intensity activity, contributes to analysis by Di Marco et al. [6] showed weighted mean a lower risk of hospitalization in patients with moderate increase in endurance time of 78.4 s with LAMA/LABA, to severe COPD, which can be achieved with combined 72.6 s with LAMA monotherapy and 51 s with LABA LAMA/LABA therapies [16, 25]. However, reaching bet- monotherapy compared to placebo, and improvements ter exercise capacity is no guarantee of physical activity in BORG scale score of -0.25 units with LAMA/LABA improvements [12, 35]. Regarding this topic, in this meta- versus − 0.51 and − 0.45 with LABA and LAMA mon- analysis, LAMA/LABA therapy significantly reduced the otherapies respectively. The relative effect results of the duration of 1.0–1.5 METs (sedentary time) and increased meta-analysis by Calzetta et al. [42] also pointed LABA/ the durations of ≥ 2.0 METs (standing position or walk- LAMA as the combination significantly (P < 0.05) more ing less than 55 m/min), and ≥ 3.0 MET (walking faster effective than the LABA or LAMA alone and placebo than 55 m/min). In general, our results provide proof of in terms of improvement in endurance time (+ 43, + 22 a significant reduction in sedentary time in patients with and + 60 s, respectively) and increase in inspiratory COPD who are administered LAMA/LABA compared to capacity as measure of reduction in lung hyperinflation monotherapy. (+ 107 ml, + 87 ml and + 229 ml, respectively), although The results observed in sedentary time were paralleled these improvements were slightly lower than the ones with significant improvements in daily walking time and observed by Di Marco et al. [6] as Calzzeta et al. point in the intensity of walking in the D-PPAC questionnaire out [42]. The results of both meta-analyses are in line score where superiority of LAMA/LABA combinations with our results, as in our analysis differences between over placebo was observed, as it was already noticed in LAMA/LABA versus placebo or monotherapy were also the PHYSACTO and ACTIVATE studies. In the PHYS- significant (LAMA/LABA vs placebo + 31.75–72.45 s, vs. ACTO study, significant differences in the questionnaire monotherapy + 11.36% and + 24.23 s). score between tiotropium monotherapy and the tiotro- Besides pharmacological treatment, the ATS, the Euro- pium/olodaterol combination were found [12], and in the pean Respiratory Society (ERS) and the Spanish guide- ACTIVATE study between placebo and aclidinium/for- lines for COPD agree on using non-pharmacological moterol combination [15], indicating that LAMA/LABA treatment as part of the comprehensive COPD patient combination improves the amount and level of intensity care as increasing physical activity and reducing discom- of physical activity in COPD patients. fort during physical activity requires a more integrated In some observational studies [36–41] the use of tiotro- approach than only providing adequate bronchodilation pium/olodaterol showed improvements in patient self- and it should consider all aspects of the disease, including reported physical condition. Therapeutic success in the mental, physical and emotional health [43–47]. Besides, physical functioning score varied from 48.9% to 67.8%, as hyperinflation is the main driver of the reduced physi- with improved patient general condition as indicated by cal activity in COPD patients, by combining effective an improvement in Physician’s Global Evaluation scores bronchodilators with pulmonary rehabilitation pul- between visits in these studies [36–41] and increased monary function will be optimized and gas trapping absolute physical functioning scores [36]. These results reduced, increasing patient’s exercise capacity [48–50]. are consistent with those obtained in our meta-analy- Pulmonary rehabilitation includes exercise training, edu- sis, where tiotropium/olodaterol was the most frequent cation and behavior change, aimed to improve the physi- LAMA/LABA analysed versus monotherapy, used in five cal and psychological condition of COPD patients and to different studies [13, 14, 16, 25]. Also, tiotropium/olo- promote the long-term adherence to health-enhancing daterol was compared to placebo in the study by Maltais behaviours [47]. Before any actions are undertaken it et al. [20]. In general, LAMA/LABA combinations were is important to assess the initial level of physical activ- superior to LAMA or LABA monotherapies. Differences ity in daily life as physical activity can be improved with Miravitlles et al. Respiratory Research (2022) 23:347 Page 18 of 20 the appropriate strategies in most COPD patients, and Abbreviations 6MWT: 6-Minute walking test; ATS: American Thoracic Society; CI: Confidence during all this process counselling or psychological pro- intervals; COPD: Chronic obstructive pulmonary disease; CWRCE: Constant grammes help supporting the change in behaviour that Work Rate Cycle Ergometry; D-PPAC: Daily PROactive Physical Activity COPD is needed for patients to be more active. Accordingly, the questionnaire; ERS: European Respiratory Society; ESWT: Endurance Shuttle Walk Test; FEV1: Forced expiratory volume at 1 s; FVC: Forced vital capacity; implementation of physical performance or muscle func- GOLD: Global Initiative for Chronic Obstructive Lung Disease; LABA: Long- tion/mass tests that correlate with objectively measured acting beta-2 agonists; LAMA: Long-acting muscarinic antagonists; METs: physical activity in clinical practice can be a good imple- Metabolic equivalent of task; OR: Odds ratio; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-analyses Statement; PRO: Patient- mentation to assess COPD patients’ level of daily physical reported outcome; SLR: Systematic literature review; SMD: Standardized mean activity, to identify those with severely reduced levels of differences; Tlim: Tolerance limit; WMD: Weighted mean differences. physical activity (such the 6MWT, or the 30-s chair stand test), and establish an exercise plan taking into account Supplementary Information personal needs, preferences and personal goals to go The online version contains supplementary material available at https://​doi.​ along with the pharmacological treatment [47, 51, 52]. org/​10.​1186/​s12931-​022-​02268-3. The ESWT, CWRCE and 6MWT are the commonest test Additional file 1: Fig A1. Bias risk assessment. used to assess COPD patients’ level of physical activity; these are reliable tests to which patients respond and are Additional file 2: Table A1. Search strategy in MEDLINE (through Pub‑ Med), CENTRAL and EMBASE. familiarized with, they can be used in a multicentre trial setting, as they have good reproducibility and repeatabil- Acknowledgements ity, and have an important intra class (IC) correlation and Not applicable. are significant predictors of mortality in COPD [14, 22, 53]. Particularly, ESWT has been reported to be more Author contributions All authors made a significant contribution to the work reported, whether that sensitive than other tests to therapeutic intervention in a is in the conception, study design, execution, acquisition of data, analysis and systematic review, where protocol variations significantly interpretation, or in all these areas; took part in drafting, revising or critically affected performance in several studies [53]. reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to This SRL and meta-analysis has some limitations, the be accountable for all aspects of the work. All authors read and approved the main one is the existing differences between the studies final manuscript. on variables used to measure physical activity which, in Funding some cases, makes comparison difficult. Furthermore, it This systematic review and meta-analysis has been funded by Boehringer should be taken into account that in some analyses dif- Ingelheim Spain. The authors did not receive compensation related to the ferent LAMA/LABA combinations were compared with development of the manuscript. AG, VC and RP are employees of Pharmalex Spain, an independent contracting health economic organization which different LAMA or LABA monotherapies, and also out- received consultancy fees from Boehringer Ingelheim Spain. comes evaluation times were different between studies, ranging from 3 to 12 weeks. Another limitation is that Availability of data and materials This manuscript is an SLR and the data used are the ones available at the statistical heterogeneity was high in some comparison, included publications, thus this sections is not applicable. limiting the validity and the generalizability of these results. Despite these limitations, the use of LAMA/ Declarations LABA consistently improves exercise capacity and physi- cal activity compared with placebo or monotherapy in Ethics approval and consent to participate Not applicable. most outcomes and combinations analysed. On the other hand, our study has the following strengths: a reason- Consent for publication able number of studies and patients available and their Not applicable. rigorous methodological quality, as none of the studies Competing interests included showed high risk of bias in any item. Marc Miravitlles has received speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Menarini, Rovi, Bial, Sandoz, Zambon, CSL Behring, Grifols and Novartis, consulting fees from AstraZeneca, Atriva Therapeutics, Conclusion Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Bial, Gebro Pharma, CSL In conclusion, our review showed that LAMA/LABA Behring, Laboratorios Esteve, Ferrer, Mereo Biopharma, Verona Pharma, Spin Therapeutics, ONO Pharma, pH Pharma, Palobiofarma SL, Takeda, Novartis, combination therapy was superior to placebo and mon- Sanofi and Grifols and research grants from Grifols. Juan Luis García-Rivero has otherapy in terms of evaluating exercise capacity and received speaker fees from Novartis, GSK, Boehringer-Ingelheim, Astra-Zeneca, physical activity in patients with COPD in almost every Chiesi, ALK, Teva, Menarini, Viso and Sanofi; and consulting fees from Novartis, GSK, Astra-Zeneca, Teva, Boehringer-Ingelheim, ALK, Viso, Gebro and Sanofi. comparison. Enhancing physical activity and exercise Xavier Pomares has received speaker fees from Boehringer Ingelheim, GlaxoS‑ capacity in COPD patients might lead to improve their mithKline, Chiesi, Rovi, Novartis, Vertex and Actelion. quality of life and minimize the burden of the disease. Miravitlles et al. Respiratory Research (2022) 23:347 Page 19 of 20 Author details 17. Singh S, Maltais F, Tombs L, Fahy WA, Vahdati-Bolouri M, Locantore N, et al. 1 Pneumology Department, Hospital Universitari Vall d’HebronVall d’Hebron Relationship between exercise endurance and static hyperinflation in a Institut de Recerca, Vall d’Hebron Barcelona Hospital Campus, Pg. Vall post hoc analysis of two clinical trials in patients with COPD. Int J Chron d’Hebron 119‑129, 08035 Barcelona, Spain. 2 Pneumology Department, Obstruct Pulmon Dis. 2018;13:203–15. President of ACINAR, Hospital Universitario Marqués de Valdecilla, Santander, 18. Riley JH, Kalberg CJ, Donald A, Lipson DA, Shoaib M, Tombs L. Effects of Spain. 3 Boehringer Ingelheim España S.A., Barcelona, Spain. 4 TFS Health Sci‑ umeclidinium/vilanterol on exercise endurance in COPD: a randomised ence, Barcelona, Spain. 5 Market Access AreaPharmalex Spain, Barcelona, Spain. study. ERJ Open Res. 2018;4:00073–2017. 6 Pneumology Department, Hospital de Sabadell, Hospital Universitari Parc 19. O’Donnell DE, Elbehairy AF, Faisal A, Neder JA, Webb KA. Sensory- TaulíInstitut Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de mechanical effects of a dual bronchodilator and its anticholinergic Barcelona, Sabadell, Spain. component in COPD. Respir Physiol Neurobiol. 2018;247:116–25. 20. Maltais F, O’Donnell D, GáldizIturri JB, Kirsten A-M, Singh D, Hamilton A, Received: 26 May 2022 Accepted: 29 November 2022 et al. Effect of 12 weeks of once-daily tiotropium/olodaterol on exercise endurance during constant work-rate cycling and endurance shuttle walking in chronic obstructive pulmonary disease. 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Lung. 2016;194:249–57. 51. Matkovic Z, Tudoric N, Cvetko D, Esquinas C, Rahelic D, Zarak M, et al. Easy Ready to submit your research ? Choose BMC and benefit from: to perform physical performance tests to identify COPD patients with low physical activity in clinical practice. Int J Chron Obstruct Pulmon Dis. • fast, convenient online submission 2020;15:921–9. 52. Demeyer H, Mohan D, Burtin C, Vaes A, Heasley M, Bowler RP, et al. Objec‑ • thorough peer review by experienced researchers in your field tively measured physical activity in patients with COPD: recommenda‑ • rapid publication on acceptance tions from an international task force on physical activity. Chron Obstruct • support for research data, including large and complex data types Pulmon Dis J COPD Found. 2021;8:528–50. 53. Fotheringham I, Meakin G, Punekar Y, Riley J, Cockle S, Singh S. Compari‑ • gold Open Access which fosters wider collaboration and increased citations son of laboratory- and field-based exercise tests for COPD: a systematic • maximum visibility for your research: over 100M website views per year review. Int J Chron Obstruct Pulmon Dis. 2015;10:625. At BMC, research is always in progress. Learn more biomedcentral.com/submissions