Aerobic Exercise on Functional Capacity and Quality of Life in COPD Patients: A systematic review and meta-analysis with trial sequential analysis

Aerobic Exercise on Functional Capacity and Quality of Life in COPD Patients: A systematic review and meta-analysis with trial sequential analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Aerobic Exercise on Functional Capacity and Quality of Life in COPD Patients: A systematic review and meta-analysis with trial sequential analysis Yue Guo, Keyue Hu, Faqiang Tang, Huidan Chen, Yifang Gao, Jun yang, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8126313/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective Research has indicated that pulmonary rehabilitation (PR) is effective in reducing symptoms in people with COPD. Exercise is part of overall PR, while the isolated effect of aerobic exercise in COPD patients remains unclear. Methods English and Chinese RCTs published from inception to the May 2025 were searched in online nine databases. The Cochrane Risk of Bias tool was used to assess the risk of bias in the included studies. Stata17.0 and RevMan5.3 were used to do the meta-analysis. We conducted a trial sequential analysis (TSA) that included all of the results in order to assess the stability and dependability of the study's findings. This study has been registered with PROSPERO under ID CRD42022377652. Results The meta-analysis comprised 25 trials with 2103 participants in total. According to the findings, aerobic exercise significantly improved the 6MWT, CAT, FEV1%pred, FEV1/FVC%. Subgroup and meta-regression analyses identified sources of heterogeneity. The TSA results show that the study outcomes for the three indicators 6MWT, CAT, and SGRQ are conclusive and reliable. Conclusion Patients with COPD benefit greatly from aerobic exercise in terms of their exercise capacity and quality of life, and to some extent, enhances lung function. Health sciences/Diseases Health sciences/Health care Health sciences/Medical research Health sciences/Risk factors Aerobic Exercise Chronic Obstructive Pulmonary Disease Randomized controlled trial Meta-analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction The respiratory condition known as COPD is defined by progressive and persistent airflow restriction and slow progression. It is typically brought on by inhaling hazardous particles [ 1 , 2 ]. COPD is one of the leading causes of death and morbidity in the globe. China is the most populous developing nation and has the highest number of active tobacco users (300 million adults) [ 3 ]. As the population ages over the next decades, it is anticipated that the economic and social cost of COPD will rise. Effective therapy is required to reduce symptoms and improve overall quality of life since people with COPD frequently encounter activity restriction and diminished exercise abilities [ 4 ]. The overall quality of life for people with COPD appears to be improved by pulmonary rehabilitation (PR), which is proven to be beneficial in reducing dyspnea and increasing exercise capacity [ 5 ]. PR mainly consists of exercise, education, nutritional support, and psychotherapy. A key component of PR is the concept of exercise training, which includes a variety of training modalities approved by the joint American Thoracic Society/European Respiratory Society guidelines, including resistance training, endurance training, neuromuscular electrical stimulation, interval training, and respiratory muscle training [ 6 ]. Among them, aerobic exercise is a training method to improve cardiopulmonary function and exercise capacity through repeated activities at low to moderate intensity levels [ 7 , 8 ]. Its exercise forms include walking, jogging, cycling, Qigong, and calisthenics. The evidence base supporting its effectiveness and safety, however, is scant. While previous studies had primarily concentrated on investigating the impact of PR as a whole on COPD patients [ 9 , 10 ], the efficacy of individual exercise modalities. could not be evaluated. Our study's goal was to determine whether aerobic exercise could benefit COPD patients with three key areas: exercise capacity, quality of life and pulmonary function. Although a representative meta-analysis found that aerobic exercise could lead to clinically significant enhancements in functional ability and in the health-related quality of life (HRQL) in patients with very severe COPD, whether the same improvements are seen within individuals suffering from mild to serious COPD has not been addressed [ 11 ]. The most recent investigation incorporated within this meta-analysis was published in 2014 [ 12 ], and several RCTs have since been reported. Moreover, the majority of the included studies involved resistance or strength training [ 12 – 16 ]. Another meta-analysis had the same problem in the included studies [ 17 – 20 ]; these techniques may not genuinely reflect the efficacy of aerobic exercise. Thus, we aimed to synthesize and analyze the evidence for evaluating the functional capacity, the quality of life and the pulmonary function of aerobic exercise in the treatment of COPD. Methods Registration On the website of the PROSPERO International Prospective Register of Systematic Reviews, the protocol was prospectively registered. (Registration #: CRD42022377652). The present review’s design and reporting are under the guidelines specified in the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) statement. Search strategy The search strategy, following the comprehensive guidelines outlined by the Cochrane Collaboration, was formulated and implemented across various online databases in May 2025 without any date limitations: Embase, PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, Web of Science, EBSCO, China National Knowledge Information Database (CNKI), China Science and Technology Journal Database (CSTJ) and WanFang Database. Both Chinese and English language publications were included in the study. All terms were searched using a combination of free text and relevant keywords. The search of scientific databases was conducted using four specific criteria: participants (“Chronic Obstructive Pulmonary Disease,” “COPD”), interventions (“aerobic exercise,” “pulmonary rehabilitation” or “exercise”), outcomes (“functional capacity,” “pulmonary function or lung function,” “quality of life,” “health-associated quality of life”) and study design (“RCT”). Appendix 1: Search strategies provided specifics on the search strings for each database. All publications were imported into the Endnote X9 program (Thomson Reuters, Carlsbad, CA, USA), and duplicates were automatically deleted. All titles and abstracts were screened by two investigators. Once abstracts indicated potential eligibility, full-text versions were screened and subsequently incorporated into the review if they satisfied the selection criteria. If there was disagreement, a third investigator was consulted. Selection Criteria 1. Inclusion Criteria Patients with a diagnosis of COPD as defined by the Global Initiative for the Diagnosis of Chronic Obstructive Lung Disease were included in the studies [ 21 ]. Research investigations comprised a minimum of two distinct groups: one group that underwent aerobic exercise (e.g., cycling, walking, Qigong, or treadmill training) and another group that received standard care or routine respiratory function training. Primary outcome measures encompassed any of the following: 6-min walk test/distance (6MWT/6MWD) [ 22 ], St. George’s Respiratory Questionnaire (SGRQ) [ 23 ], COPD Assessment Test (CAT) [ 24 ], forced expiratory volume in first second (FEV1% pred), or the ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC%). The selected studies have a randomized controlled trial design. Exclusion Criteria Exclusions were made for case reports, reviews, conference summaries, and research lacking complete text or adequate information and data. Participants who had a history of diabetes mellitus, heart disease, uncontrolled hypertension, or other concurrent respiratory conditions. Studies in which endurance exercise did not achieve the training intensity of aerobic exercise or aerobic exercise combined with other interventions (e.g. neuromuscular electrical stimulation, vibrating platforms, and resistance or strength training), were excluded. The process of extracting data and evaluating its quality Two investigators (GY and HKY) collected data independently based on inclusion criteria. If there is disagreement, the decision was discussed with the third investigator (LJP). If data were missing, we contacted the author by email. The obtained data contained the name of the first author, the year of publication, country, study design, mean age, sample size, forced expiratory volume in first second (FEV1), intervention type and details, outcome, and duration of treatment. The Cochrane Risk of Bias tool was used to evaluate bias risk [ 25 ]. Data synthesis and analysis We used Review Manager 5.3 for data synthesis and Stata 17.0 for meta-regression, sensitivity, and publication bias analyses. Mean and standard deviation (SD) were extracted at baseline and at the end of the intervention. When units and method of measurement were consistent across studies, we used the mean difference (MD) for continuous outcomes; when they weren't, we used the standardized mean difference (SMD). The significance of I 2 statistic determined whether a random effect or a fixed effects model was used. If the heterogeneity was significant (I 2 > 50%), the random effects model was employed. The results were presented using forest plots. With high heterogeneity (I 2 > 50%), subgroup analyses were conducted, and potential sources were further investigated with meta-regression in Stata 17.0. Each study was excluded individually in the sensitivity analysis. The publication bias was qualitatively detected by funnel plot and quantitatively evaluated by Egger's test. Trial sequential analysis (TSA) Traditional meta-analysis inevitably leads to repeated calculation of cumulative data after multiple updates, which causes Type I error. Thus, trial sequential analysis (TSA) was employed in this study to evaluate the reliability of the findings [ 26 ]. TSA software version 0.9 beta ( http://www.ctu.dk/tsa ) was used for the TSA process. DerSimonian–Laird was used to apply a random-effects model. The Type I error was set at 5% and the power at 80%. TSA was used to determine the minimal sample size necessary to attain maximum reliability, known as the required information size (RIS). To assess if the evidence was conclusive, TSA created a cumulative Z curve. TSA provided a termination criterion for clinical trials, thereby avoiding unnecessary waste of resources. OUTCOMES Research properties A total number of 5267 papers were obtained from nine databases. After removing the duplicate articles, the remaining titles and abstracts of the retrieved articles underwent a screening process, and 228 full-text papers were obtained for a comprehensive assessment. According to our screening criteria, 203 investigations were subsequently removed, and eventually, 25 investigations [ 27 – 51 ] were included in the meta-analysis. The article search procedure is shown in Fig. 1 . The baseline characteristics of the included studies were shown in Table 1 . Across 25 studies, 2103 individuals participated, with the number of participants fluctuating between 19 and 318 in each study. In the final analysis, 25 studies, including 13 English and 12 Chinese articles, were included. The articles included in this investigation were published from 2001 to 2025. Assessment of Risks of Bias A Cochrane Collaboration tool was used to evaluate the risk of bias. All studies reported that they used randomization. However, only 5 studies reported using allocation concealment [ 30 – 32 , 34 , 36 ], which included a central randomization system [ 30 ] and sealed opaque envelopes [ 31 , 32 , 34 , 36 ]. The design of the intervention made it impractical to blind patients, resulting in a significant risk of performance bias. Blinding to outcome assessment was reported in 7 studies [ 31 – 33 , 35 , 36 , 44 , 49 ]. The remaining studies did not report this. 21 studies [ 27 , 29 – 34 , 37 – 43 , 45 – 51 ] reported results that were evaluated as low risk due to data completeness, and four studies [ 28 , 35 , 36 , 44 ] were evaluated as high risk due to subject dropout for reasons such as exacerbation of disease. Because of insufficient information, selective outcome reporting was assessed as unclear risk of bias in all studies. In other areas of bias, including issues such as limited sample size, poor compliance, and short intervention duration, twelve studies [ 27 , 31 – 33 , 36 , 37 , 39 , 43 , 44 , 46 , 49 , 51 ] were assessed as high risk, while the remaining studies were unclear ( Figs. 2 A–B ). Exercise capacity 6- min’s walk test (6MWT) Exercise capacity was measured using the 6MWT in twenty-one studies [ 28 – 33 , 35 – 41 , 43 – 45 , 47 – 51 ] (1748 patients: 880 aerobics and 868 controls). A significant improvement in the 6MWT distance was observed [MD: 41.97; 95% CI: 33.63 to 50.32; P < 0.00001; \(\:{I}^{2}\) =77%] in the aerobic group compared with the control group ( Fig. 3 A ) . Quality of Life COPD Assessment Test (CAT) The CAT was reported in eleven studies [ 30 – 34 , 41 – 43 , 46 , 47 , 51 ] (1192 patients: 596 aerobics and 596 controls). The aerobic group showed significantly lower CAT scores (MD: -3.89; 95% CI: -5.32 to -2.46; P < 0.00001; \(\:{I}^{2}\) =92%) than the control group ( Fig. 3 B ) . St. George’s respiratory questionnaire (SGRQ) score The SGRQ total score was reported in 10 studies [ 27 , 31 , 35 , 36 , 39 , 43 , 45 , 46 , 50 , 51 ] (710 patients: 360 aerobics and 350 controls). The aerobic group showed significant changes (MD: -9.17; 95% CI: -9.99 to -8.36; P < 0.00001; \(\:{I}^{2}\) =94%) in the SGRQ total score. ( Fig. 3 C ) . Pulmonary function Forced expiratory volume in first second percentage of predicted (FEV1%pred) FEV1%pred was evaluated in 9 studies [ 30 , 31 , 33 , 34 , 41 , 42 , 44 , 47 , 51 ] (741 patients: 370 aerobics and 371 controls) and exhibited significant improvement (MD: 4.50; 95% CI: 1.28 to 7.73; P = 0.006; \(\:{I}^{2}\) =93%) between the aerobic and the control groups ( Fig. 3 D ) . The ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC%) FEV1/FVC% was evaluated in 10 studies [ 30 , 31 , 33 , 34 , 41 – 43 , 45 , 48 , 50 ] (898 patients: 450 in the aerobic group and 448 in the control group). The FEV1/FVC% exhibited significant improvement (MD: 4.08; 95% CI:3.02 to 5.13; P < 0.00001; \(\:{I}^{2}\) =57%) in the aerobic group compared with the control group ( Fig. 3 E ) . Subgroup analysis To explore the sources of heterogeneity, we performed subgroup analyses of 6MWT, CAT, SGRQ, FEV1%pred and FEV1/FVC% stratified by average age and different interventions of the aerobic group. The results were separately divided into 2 subgroups: the average age less than 65 years and those more than 65 years (Appendix 2: Subgroup analysis, Figure S1 -S5) ; and aerobic exercise with conventional exercises versus qigong (Appendix 2: Subgroup analysis, Figure S6-S10) . Subgroup analyses revealed that, compared with controls, the aerobic intervention conferred greater benefits on exercise capacity, quality of life and pulmonary function in COPD patients. Subgroup analysis outcomes revealed that when subgroup analysis was performed by average age, the heterogeneity of CAT and FEV1/FVC% decreased significantly; when subgroup analysis was conducted according to different aerobic interventions, the heterogeneity of FEV1%pred and FEV1/FVC% decreased significantly. This suggests that average age may be one of the sources of heterogeneity for CAT and FEV1/FVC%, while different aerobic interventions may represent a potential source of heterogeneity for FEV1%pred and FEV1/FVC%. Meta Regression High heterogeneity was observed in 6MWT and SGRQ. As a result, we ran a meta-regression study on these 2 outcomes to investigate potential sources of heterogeneity. The meta-regression indicated that nation was a significant source of heterogeneity for the 6MWT (p = 0.029, Appendix 3: Meta Regression, Table S1 ). Other examined factors, including intervention duration and sample size, had no statistically significant effect. For the SGRQ, none of the examined covariates—including nation, intervention duration, and sample size—reached statistical significance (Appendix 3: Meta Regression, Table S2). Sensitivity analysis An analysis focusing on sensitivity was performed to assess the robustness and dependability of the pooled findings, through a systematic exclusion of individual studies. The outcomes of sensitivity analyses were reported in the Appendix 4: Sensitivity analysis, Figure S11-S15 . The elimination of any single article had no significant effect on the findings, demonstrating the robustness of the results. Publication bias Indications of bias in publication were evident, as suggested by Egger's test (P = 0.0008) (Appendix 5: Publication bias, Figure S16) and by asymmetry in the funnel plot (Appendix 5: Publication bias, Figure S17) , which might have been related to small sample sizes and the non-publication of negative studies. After imputing 3 studies using the trim-and-fill method (Appendix 5: Publication bias, Figure S18) , the MD decreased from 43.743 (95% CI: 32.953–54.534) to 40.586 (95% CI: 26.952–54.221), suggesting that the original result might have been overestimated. Therefore, we must approach the interpretation of the results with prudence, and future research should further validate these findings by including grey literature and pre-registered studies. Trial sequential analysis 6-min’s walk test (6MWT) Trial sequential analysis was performed on 21 trials comparing the aerobic group with the control group for 6MWT ( Fig. 4 A ) . 1) The cumulative Z-curve (the blue line) crossed the required information size (RIS) (the vertical red line), which signaled that the accumulated studies were sufficient for meta-analysis. 2) The cumulative Z-curve crossed the conventional boundary for benefit (horizontal yellow line at z = 1.96), indicated a statistically significant reduction in 6MWT in the aerobic group compared with the control group. 3)The cumulative Z-curve crossed the trial sequential monitoring boundary for benefit (sloping red line), which established firm evidence supporting the superiority of the aerobic group. COPD Assessment Test (CAT) and St. George’s respiratory questionnaire (SGRQ) score Trial sequential analysis was conducted on 11 trials ( Fig. 4 B ) and 10 trials ( Fig. 4 C ) comparing the aerobic group with the control group for CAT and SGRQ, respectively. Both images showed that the cumulative Z-curve (the blue line) crossed the conventional boundary for benefit (horizontal yellow line at z = 1.96), the trial sequential monitoring boundary for benefit (sloping red line), and the RIS (the vertical red line), which indicated that the evidence was robust and conclusive. These findings further demonstrated that aerobic exercise led to significant reductions in CAT and SGRQ scores compared with the control group, and were robust, suggesting that similar clinical trials could be justifiably terminated. Forced expiratory volume in first second percentage of predicted (FEV1%pred) Trial sequential analysis was performed on 9 trials comparing the aerobic group with the control group for FEV1%pred ( Fig. 4 D ) . Although the results of the meta-analysis indicated that aerobic exercise was effective, as evidenced by the cumulative Z-curve (the blue line) crossing the conventional boundary for benefit (horizontal yellow line at z = 1.96), the evidence was still immature. This was because the accumulated sample size had not yet reached the required information size (RIS) (the vertical red line) of 1,517 participants, and the cumulative Z-curve did not cross the trial sequential monitoring boundary for benefit (sloping red line). Therefore, it was not yet possible to draw a reliable conclusion regarding the efficacy of aerobic exercise. Ongoing data collection was recommended until either the RIS was achieved or the trial sequential monitoring boundary for benefit was crossed. The ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC%) Trial sequential analysis was conducted on 10 trials comparing the aerobic group with the control group for FEV1/FVC% ( Fig. 4 E ) . The cumulative Z-curve (the blue line) reached the sample size corresponding to RIS (the vertical red line) and crossed the conventional boundary for benefit (horizontal yellow line at z = 1.96), which indicated a potentially statistically significant effect of aerobic exercise when the sample size was adequate. However, the cumulative Z- curve did not cross the trial sequential monitoring boundary for benefit (sloping red line). Therefore, the evidence remained insufficient to draw definitive conclusions, and additional studies were warranted to reduce the risk of Type I error and confirm the robustness of the observed effect. Discussion We carried out a thorough search for RCTs assessing the influence of aerobic exercise on functional capacity, quality of life and pulmonary function in COPD patients. A total of 25 studies encompassing 2103 COPD patients were included. Findings from the meta-analysis revealed notable statistical enhancements in exercise capacity (estimated via 6MWT), quality of life (estimated via SGRQ and CAT), and pulmonary function (estimated via FEV1%pred and FEV1/FVC%) in patients with COPD. TSA confirmed that aerobic exercise significantly improved exercise capacity (estimated via 6MWT) and quality of life (estimated via SGRQ and CAT) in COPD patients; further randomized trials on these outcomes could therefore be halted. Nevertheless, its benefit for pulmonary function (estimated via FEV1%pred and FEV1/FVC%) remained uncertain and was interpreted cautiously. High-quality studies were still needed to verify this conclusion. Patients diagnosed with COPD frequently experience limitations in their exercise capacity [ 52 ]. Aerobic exercise mainly involves endurance training. Endurance exercise training can effectively enhance the cardiopulmonary function and skeletal muscle function of COPD patients, thereby improving exercise capacity [ 53 , 54 ]. The 6MWT method was employed to assess the exercise ability of individuals diagnosed with COPD. This is a uniform assessment tool for objectively evaluating functional exercise ability with good reliability and validity [ 55 ]. After the intervention, the aerobic exercise group's 6MWT distance increased statistically significantly more than that of the control group in the included studies [ 28 – 33 , 35 – 41 , 43 – 45 , 47 – 51 ]. Previous meta-analyses have shown that aerobic exercise improves exercise capacity in patients with COPD [ 11 ], which aligns with our conclusions. Moreover, the trial sequential analysis (TSA) of the 6MWT crossed the trial sequential monitoring boundary for benefit and achieved the required information size (RIS), suggesting a true positive result and thereby providing robust support for this finding. Patients diagnosed with COPD typically have an older age at disease onset and commonly present with a concurrent cough, dyspnea, limitations in activities of daily living, insomnia, and pain symptoms, which severely affects patients’ quality of life [ 56 – 58 ]. One important indicator of therapy effectiveness is whether or not COPD patients can enhance their health-related quality of life. The CAT and SGRQ are strong, trustworthy instruments for evaluating health-related quality of life [ 59 , 60 ]. This meta-analysis showed that patients in the aerobic exercise group showed substantial decreases in both CAT and SGRQ scores when compared to the control group, suggesting that aerobic exercise interventions improved health-related quality of life. Moreover, the TSA of CAT and SGRQ further corroborated these findings. However, due to the high heterogeneity of the results, subgroup analyses and meta-regression were performed to explore the potential sources of heterogeneity. These results should be viewed cautiously because the data showed that the high heterogeneity of SGRQ could not be explained. COPD has been characterized by incompletely reversible airflow limitation, which mainly involves lung tissue and seriously impairs lung function [ 61 ]. Aerobic exercise induces conditioning of the accessory muscles related to breathing, strengthens the respiratory muscles and delays fatigue [ 62 ]. This helps patients with COPD improve their respiratory efficiency and, ultimately, their lung function. The global COPD diagnosis, management, and prevention strategy states that FEV1% pred and FEV1/FVC% are the traditional indices for assessing pulmonary function in COPD patients, which are simple and rapid. FEV1% pred is used to evaluate the severity of lung function impairment, and the degree of airflow limitation is assessed using the FEV1/FVC% [ 63 ]. Findings from the meta-analysis indicated a notable enhancement in FEV1%predicted and FEV1/FVC% in the group engaging in aerobic exercise, in contrast to the control group. Nevertheless, the cumulative Z-curve for FEV1 and FEV1/FVC merely exceeded the conventional boundary for benefit, according to the TSA plots, suggesting that more research is necessary to determine whether aerobic exercise can enhance pulmonary function. A meta-analysis showed that aerobic exercise cannot improve FEV1%pred and FEV1/FVC% in COPD patients [ 20 ], which is inconsistent with our results. This may be due to the fact that the training methods in that meta-analysis were not just limited to aerobic exercise but also included strength training, which cannot accurately reflect the efficacy of aerobic exercise alone. Limitation The primary limitations of the present meta-analysis are outlined below. First, in terms of methodological design, a majority of the included studies had flaws, mainly related to a significant risk of performance bias, and other domains showed poor scores. Second, most included studies did not report data on whether participants continued aerobic exercise after the intervention period. The long-term impact of aerobic exercise on patients with COPD remains unclear due to the absence of follow-up data. Conclusion Patients with COPD benefit greatly from aerobic exercise in terms of their exercise capacity and quality of life, and to some extent, enhances lung function. However, due to the scarcity of lung function studies and the presence of publication bias, larger, well-designed, randomized controlled trials are needed in the future. Strengths and limitations of this study Our research results indicate that aerobic exercise is beneficial to the exercise capacity and quality of life of COPD patients. Trial sequential analysis further confirmed the robustness of these findings. Most included studies did not report data on whether participants continued aerobic exercise after the intervention period. The long-term impact of aerobic exercise on patients with COPD remains unclear due to the absence of follow-up data. Abbreviations COPD Chronic Obstructive Pulmonary Disease RCTs Randomized Clinical Trials CENTRAL Cochrane Central Register of Controlled Trials CNKI China National Knowledge Information Database CSTJ China Science and Technology Journal Database 6MWT 6-Min Walk Test WMD weighted mean difference CI confidence interval CAT Chronic Obstructive Pulmonary Disease Assessment Test SGRQ St. George’s Respiratory Questionnaire FEV1%pred forced expiratory volume in the first second FEV1/FVC% The ratio of forced expiratory volume in the first second to forced vital capacity PR Pulmonary Rehabilitation TSA trial sequential analysis RIS required information size PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses SD Standard Deviation Declarations Acknowledgements We thank Home for Researchers editorial team (www.home-for-researchers.com) for language editing service. Author contributions LJP, CSQ, WSZ concepted and designed the study; HKY, TFQ, GY, CHD, GYF collected data; GY, HKY, CHD, GYF analysed data; CSQ and WSZ Supervised; LJP , GY and HKY completed the manuscript draft; CSQ and WSZ completed the manuscript revision; All authors have read and approved the manuscript for publication. GY, HKY and TFQ contributed equally to this work. Data availability statement Although the data supporting the findings in this study are available from [Jianping Lin], there are restrictions on the availability of these data, which were used under licence for the current study, and are therefore not publicly available. However, the data are available from the authors on reasonable request and with the permission of [Jianping Lin]. The protocol was registered prospectively and became available on the PROSPERO International Prospective Register for Systematic Reviews website (Registration #: CRD42022377652). Additional Information The authors declare that they have no competing interests. The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Consent for publication Not applicable. Funding information This work was supported by the National Natural Science Foundation of China (grant numbers 81874501) and Finance Department Project of Fujian Provincial (grant numbers 22SCZZX006). Ethics declarations Not applicable. References Christenson, S. A., Smith, B. M. & Bafadhel, M. Putcha, N. Chronic obstructive pulmonary disease. Lancet 399 (10342), 2227–2242 (2022). Dong, L. L. et al. The persistent inflammation in COPD: is autoimmunity the core mechanism? EUR. RESPIR REV. 33 (171) (2024). Wang, M. et al. Trends in smoking prevalence and implication for chronic diseases in China: serial national cross-sectional surveys from 2003 to 2013. Lancet Respir Med. 7 (1), 35–45 (2019). 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Properties of the COPD assessment test in a cross-sectional European study. Eur. Respir J. 38 (1), 29–35 (2011). Tantucci, C. & Modina, D. Lung function decline in COPD. Int. J. Chron. Obstruct Pulmon Dis. 7 , 95–99 (2012). Rochat, I., Cote, A. & Boulet, L. Determinants of lung function changes in athletic swimmers. A review. Acta Paediatr. 111 (2), 259–264 (2022). Vogelmeier, C. F. et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report. GOLD executive summary. Am. J. Respir Crit. Care Med. 195 (5), 557–582 (2017). Tables Table 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Appendix.Supplementaryinformation.docx Table1.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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16:40:30","extension":"xml","order_by":49,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":168735,"visible":true,"origin":"","legend":"","description":"","filename":"aec14eb920304c8eaa9f66caf9865a651structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8126313/v1/e4a795d3abf796536d816ba0.xml"},{"id":98427507,"identity":"8bf27ffe-b4d3-45f2-b18f-320e5d01c73b","added_by":"auto","created_at":"2025-12-17 16:40:36","extension":"html","order_by":50,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":187129,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8126313/v1/308e3ada9e73a0c56c8605cf.html"},{"id":98425953,"identity":"ce950bf1-82ad-4a89-baeb-0d4e0ce0c8b6","added_by":"auto","created_at":"2025-12-17 16:35:24","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":46153,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePRISMA 2020 flow diagram for new systematic reviews which included searches of databases and registers only\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e*Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers).\u003c/p\u003e\n\u003cp\u003e**If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8126313/v1/c6dc0ec4a9d44bf335c54259.png"},{"id":98425990,"identity":"66e071f6-589b-4592-b2c9-797314e00bd0","added_by":"auto","created_at":"2025-12-17 16:35:28","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":182578,"visible":true,"origin":"","legend":"\u003cp\u003eRisk of bias summary for the randomized trials included in the meta-analysis. (+): low risk of bias; (?): unclear risk of bias; (–): high risk of bias.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8126313/v1/97fcf6b2cd312c6ba3b0e525.png"},{"id":98427575,"identity":"713ce192-5ace-4854-b5c8-591764635b3e","added_by":"auto","created_at":"2025-12-17 16:40:45","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":401139,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of aerobic exercise in patients with COPD. (A) 6MWT; (B) CAT; (C) SGRQ; (D) FEV1%pred; (E) FEV1/FVC%.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8126313/v1/c37a9b9e95e9194d97ee172c.png"},{"id":98048383,"identity":"63c14aae-c66d-4cc2-8f92-682907dce72c","added_by":"auto","created_at":"2025-12-12 08:33:34","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":53700,"visible":true,"origin":"","legend":"\u003cp\u003eTrial sequential analysis (TSA). TSA plots of (A) 6MWT; (B) CAT; (C) SGRQ; (D) FEV1%pred; (E) FEV1/FVC%.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8126313/v1/8cb8fd3df867c913a058733a.png"},{"id":104779293,"identity":"83311ab5-fa9c-4569-9f58-4848c1d6b7a2","added_by":"auto","created_at":"2026-03-17 07:38:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1893906,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8126313/v1/c586d693-df4c-4a0f-9dd5-a2fee96e9b52.pdf"},{"id":98427794,"identity":"23293b42-1e08-4344-bbf2-dfa23f2f4230","added_by":"auto","created_at":"2025-12-17 16:41:13","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":915635,"visible":true,"origin":"","legend":"","description":"","filename":"Appendix.Supplementaryinformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-8126313/v1/d3b1810d663327d6498e3d92.docx"},{"id":98427568,"identity":"4e385c80-2614-40a8-9534-e9903f07ac83","added_by":"auto","created_at":"2025-12-17 16:40:45","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":28536,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8126313/v1/b0ece27e4c6e5d6ae64288f4.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Aerobic Exercise on Functional Capacity and Quality of Life in COPD Patients: A systematic review and meta-analysis with trial sequential analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe respiratory condition known as COPD is defined by progressive and persistent airflow restriction and slow progression. It is typically brought on by inhaling hazardous particles [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. COPD is one of the leading causes of death and morbidity in the globe. China is the most populous developing nation and has the highest number of active tobacco users (300\u0026nbsp;million adults) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. As the population ages over the next decades, it is anticipated that the economic and social cost of COPD will rise. Effective therapy is required to reduce symptoms and improve overall quality of life since people with COPD frequently encounter activity restriction and diminished exercise abilities [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe overall quality of life for people with COPD appears to be improved by pulmonary rehabilitation (PR), which is proven to be beneficial in reducing dyspnea and increasing exercise capacity [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. PR mainly consists of exercise, education, nutritional support, and psychotherapy. A key component of PR is the concept of exercise training, which includes a variety of training modalities approved by the joint American Thoracic Society/European Respiratory Society guidelines, including resistance training, endurance training, neuromuscular electrical stimulation, interval training, and respiratory muscle training [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Among them, aerobic exercise is a training method to improve cardiopulmonary function and exercise capacity through repeated activities at low to moderate intensity levels [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Its exercise forms include walking, jogging, cycling, Qigong, and calisthenics.\u003c/p\u003e\u003cp\u003eThe evidence base supporting its effectiveness and safety, however, is scant. While previous studies had primarily concentrated on investigating the impact of PR as a whole on COPD patients [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], the efficacy of individual exercise modalities. could not be evaluated. Our study's goal was to determine whether aerobic exercise could benefit COPD patients with three key areas: exercise capacity, quality of life and pulmonary function. Although a representative meta-analysis found that aerobic exercise could lead to clinically significant enhancements in functional ability and in the health-related quality of life (HRQL) in patients with very severe COPD, whether the same improvements are seen within individuals suffering from mild to serious COPD has not been addressed [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The most recent investigation incorporated within this meta-analysis was published in 2014 [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], and several RCTs have since been reported. Moreover, the majority of the included studies involved resistance or strength training [\u003cspan additionalcitationids=\"CR13 CR14 CR15\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Another meta-analysis had the same problem in the included studies [\u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]; these techniques may not genuinely reflect the efficacy of aerobic exercise.\u003c/p\u003e\u003cp\u003eThus, we aimed to synthesize and analyze the evidence for evaluating the functional capacity, the quality of life and the pulmonary function of aerobic exercise in the treatment of COPD.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eRegistration\u003c/h2\u003e\u003cp\u003e On the website of the PROSPERO International Prospective Register of Systematic Reviews, the protocol was prospectively registered. (Registration #: CRD42022377652). The present review\u0026rsquo;s design and reporting are under the guidelines specified in the \u0026ldquo;Preferred Reporting Items for Systematic Reviews and Meta-Analyses\u0026rdquo; (PRISMA) statement.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eSearch strategy\u003c/h3\u003e\n\u003cp\u003e The search strategy, following the comprehensive guidelines outlined by the Cochrane Collaboration, was formulated and implemented across various online databases in May 2025 without any date limitations: Embase, PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, Web of Science, EBSCO, China National Knowledge Information Database (CNKI), China Science and Technology Journal Database (CSTJ) and WanFang Database. Both Chinese and English language publications were included in the study. All terms were searched using a combination of free text and relevant keywords. The search of scientific databases was conducted using four specific criteria: participants (\u0026ldquo;Chronic Obstructive Pulmonary Disease,\u0026rdquo; \u0026ldquo;COPD\u0026rdquo;), interventions (\u0026ldquo;aerobic exercise,\u0026rdquo; \u0026ldquo;pulmonary rehabilitation\u0026rdquo; or \u0026ldquo;exercise\u0026rdquo;), outcomes (\u0026ldquo;functional capacity,\u0026rdquo; \u0026ldquo;pulmonary function or lung function,\u0026rdquo; \u0026ldquo;quality of life,\u0026rdquo; \u0026ldquo;health-associated quality of life\u0026rdquo;) and study design (\u0026ldquo;RCT\u0026rdquo;). \u003cb\u003eAppendix 1: Search strategies\u003c/b\u003e provided specifics on the search strings for each database. All publications were imported into the Endnote X9 program (Thomson Reuters, Carlsbad, CA, USA), and duplicates were automatically deleted. All titles and abstracts were screened by two investigators. Once abstracts indicated potential eligibility, full-text versions were screened and subsequently incorporated into the review if they satisfied the selection criteria. If there was disagreement, a third investigator was consulted.\u003c/p\u003e\u003cp\u003e\u003cb\u003eSelection Criteria\u003c/b\u003e\u003c/p\u003e\n\u003ch3\u003e1. Inclusion Criteria\u003c/h3\u003e\n\u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003ePatients with a diagnosis of COPD as defined by the Global Initiative for the Diagnosis of Chronic Obstructive Lung Disease were included in the studies [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eResearch investigations comprised a minimum of two distinct groups: one group that underwent aerobic exercise (e.g., cycling, walking, Qigong, or treadmill training) and another group that received standard care or routine respiratory function training.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003ePrimary outcome measures encompassed any of the following: 6-min walk test/distance (6MWT/6MWD) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], St. George\u0026rsquo;s Respiratory Questionnaire (SGRQ) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], COPD Assessment Test (CAT) [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], forced expiratory volume in first second (FEV1% pred), or the ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC%).\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eThe selected studies have a randomized controlled trial design.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eExclusion Criteria\u003c/b\u003e\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eExclusions were made for case reports, reviews, conference summaries, and research lacking complete text or adequate information and data.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eParticipants who had a history of diabetes mellitus, heart disease, uncontrolled hypertension, or other concurrent respiratory conditions.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eStudies in which endurance exercise did not achieve the training intensity of aerobic exercise or aerobic exercise combined with other interventions (e.g. neuromuscular electrical stimulation, vibrating platforms, and resistance or strength training), were excluded.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e\n\u003ch3\u003eThe process of extracting data and evaluating its quality\u003c/h3\u003e\n\u003cp\u003eTwo investigators (GY and HKY) collected data independently based on inclusion criteria. If there is disagreement, the decision was discussed with the third investigator (LJP). If data were missing, we contacted the author by email. The obtained data contained the name of the first author, the year of publication, country, study design, mean age, sample size, forced expiratory volume in first second (FEV1), intervention type and details, outcome, and duration of treatment. The Cochrane Risk of Bias tool was used to evaluate bias risk [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eData synthesis and analysis\u003c/h3\u003e\n\u003cp\u003e We used Review Manager 5.3 for data synthesis and Stata 17.0 for meta-regression, sensitivity, and publication bias analyses. Mean and standard deviation (SD) were extracted at baseline and at the end of the intervention. When units and method of measurement were consistent across studies, we used the mean difference (MD) for continuous outcomes; when they weren't, we used the standardized mean difference (SMD). The significance of I\u003csup\u003e2\u003c/sup\u003e statistic determined whether a random effect or a fixed effects model was used. If the heterogeneity was significant (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026gt;\u0026thinsp;50%), the random effects model was employed. The results were presented using forest plots. With high heterogeneity (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026gt;\u0026thinsp;50%), subgroup analyses were conducted, and potential sources were further investigated with meta-regression in Stata 17.0. Each study was excluded individually in the sensitivity analysis. The publication bias was qualitatively detected by funnel plot and quantitatively evaluated by Egger's test.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eTrial sequential analysis (TSA)\u003c/h2\u003e\u003cp\u003eTraditional meta-analysis inevitably leads to repeated calculation of cumulative data after multiple updates, which causes Type I error. Thus, trial sequential analysis (TSA) was employed in this study to evaluate the reliability of the findings [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. TSA software version 0.9 beta (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.ctu.dk/tsa\u003c/span\u003e\u003cspan address=\"http://www.ctu.dk/tsa\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) was used for the TSA process. DerSimonian\u0026ndash;Laird was used to apply a random-effects model. The Type I error was set at 5% and the power at 80%. TSA was used to determine the minimal sample size necessary to attain maximum reliability, known as the required information size (RIS). To assess if the evidence was conclusive, TSA created a cumulative Z curve. TSA provided a termination criterion for clinical trials, thereby avoiding unnecessary waste of resources.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eOUTCOMES\u003c/h3\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003eResearch properties\u003c/h2\u003e\u003cp\u003eA total number of 5267 papers were obtained from nine databases. After removing the duplicate articles, the remaining titles and abstracts of the retrieved articles underwent a screening process, and 228 full-text papers were obtained for a comprehensive assessment. According to our screening criteria, 203 investigations were subsequently removed, and eventually, 25 investigations [\u003cspan additionalcitationids=\"CR28 CR29 CR30 CR31 CR32 CR33 CR34 CR35 CR36 CR37 CR38 CR39 CR40 CR41 CR42 CR43 CR44 CR45 CR46 CR47 CR48 CR49 CR50\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e] were included in the meta-analysis. The article search procedure is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The baseline characteristics of the included studies were shown in \u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e. Across 25 studies, 2103 individuals participated, with the number of participants fluctuating between 19 and 318 in each study. In the final analysis, 25 studies, including 13 English and 12 Chinese articles, were included. The articles included in this investigation were published from 2001 to 2025.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eAssessment of Risks of Bias\u003c/h2\u003e\u003cp\u003eA Cochrane Collaboration tool was used to evaluate the risk of bias. All studies reported that they used randomization. However, only 5 studies reported using allocation concealment [\u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], which included a central randomization system [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] and sealed opaque envelopes [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. The design of the intervention made it impractical to blind patients, resulting in a significant risk of performance bias. Blinding to outcome assessment was reported in 7 studies [\u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. The remaining studies did not report this. 21 studies [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan additionalcitationids=\"CR30 CR31 CR32 CR33\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan additionalcitationids=\"CR38 CR39 CR40 CR41 CR42\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan additionalcitationids=\"CR46 CR47 CR48 CR49 CR50\" citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e] reported results that were evaluated as low risk due to data completeness, and four studies [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e] were evaluated as high risk due to subject dropout for reasons such as exacerbation of disease. Because of insufficient information, selective outcome reporting was assessed as unclear risk of bias in all studies. In other areas of bias, including issues such as limited sample size, poor compliance, and short intervention duration, twelve studies [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e] were assessed as high risk, while the remaining studies were unclear \u003cb\u003e(\u003c/b\u003eFigs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA\u0026ndash;B\u003cb\u003e).\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eExercise capacity\u003c/h2\u003e\u003cdiv id=\"Sec13\" class=\"Section3\"\u003e\u003ch2\u003e6- min\u0026rsquo;s walk test (6MWT)\u003c/h2\u003e\u003cp\u003eExercise capacity was measured using the 6MWT in twenty-one studies [\u003cspan additionalcitationids=\"CR29 CR30 CR31 CR32\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan additionalcitationids=\"CR36 CR37 CR38 CR39 CR40\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan additionalcitationids=\"CR44\" citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan additionalcitationids=\"CR48 CR49 CR50\" citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e] (1748 patients: 880 aerobics and 868 controls). A significant improvement in the 6MWT distance was observed [MD: 41.97; 95% CI: 33.63 to 50.32; P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001; \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{I}^{2}\\)\u003c/span\u003e\u003c/span\u003e=77%] in the aerobic group compared with the control group \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eQuality of Life\u003c/h2\u003e\u003cdiv id=\"Sec15\" class=\"Section3\"\u003e\u003ch2\u003eCOPD Assessment Test (CAT)\u003c/h2\u003e\u003cp\u003eThe CAT was reported in eleven studies [\u003cspan additionalcitationids=\"CR31 CR32 CR33\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan additionalcitationids=\"CR42\" citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e] (1192 patients: 596 aerobics and 596 controls). The aerobic group showed significantly lower CAT scores (MD: -3.89; 95% CI: -5.32 to -2.46; P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001; \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{I}^{2}\\)\u003c/span\u003e\u003c/span\u003e=92%) than the control group \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eSt. George\u0026rsquo;s respiratory questionnaire (SGRQ) score\u003c/h2\u003e\u003cp\u003eThe SGRQ total score was reported in 10 studies [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e] (710 patients: 360 aerobics and 350 controls). The aerobic group showed significant changes (MD: -9.17; 95% CI: -9.99 to -8.36; P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001; \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{I}^{2}\\)\u003c/span\u003e\u003c/span\u003e=94%) in the SGRQ total score. \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003ePulmonary function\u003c/h2\u003e\u003cdiv id=\"Sec18\" class=\"Section3\"\u003e\u003ch2\u003eForced expiratory volume in first second percentage of predicted (FEV1%pred)\u003c/h2\u003e\u003cp\u003eFEV1%pred was evaluated in 9 studies [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e] (741 patients: 370 aerobics and 371 controls) and exhibited significant improvement (MD: 4.50; 95% CI: 1.28 to 7.73; P\u0026thinsp;=\u0026thinsp;0.006; \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{I}^{2}\\)\u003c/span\u003e\u003c/span\u003e=93%) between the aerobic and the control groups \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eD\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\u003ch2\u003eThe ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC%)\u003c/h2\u003e\u003cp\u003eFEV1/FVC% was evaluated in 10 studies [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan additionalcitationids=\"CR42\" citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e] (898 patients: 450 in the aerobic group and 448 in the control group). The FEV1/FVC% exhibited significant improvement (MD: 4.08; 95% CI:3.02 to 5.13; P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001; \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{I}^{2}\\)\u003c/span\u003e\u003c/span\u003e=57%) in the aerobic group compared with the control group \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eE\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\u003ch2\u003eSubgroup analysis\u003c/h2\u003e\u003cp\u003eTo explore the sources of heterogeneity, we performed subgroup analyses of 6MWT, CAT, SGRQ, FEV1%pred and FEV1/FVC% stratified by average age and different interventions of the aerobic group. The results were separately divided into 2 subgroups: the average age less than 65 years and those more than 65 years \u003cb\u003e(Appendix 2: Subgroup analysis, Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e-S5)\u003c/b\u003e; and aerobic exercise with conventional exercises versus qigong \u003cb\u003e(Appendix 2: Subgroup analysis, Figure S6-S10)\u003c/b\u003e. Subgroup analyses revealed that, compared with controls, the aerobic intervention conferred greater benefits on exercise capacity, quality of life and pulmonary function in COPD patients.\u003c/p\u003e\u003cp\u003eSubgroup analysis outcomes revealed that when subgroup analysis was performed by average age, the heterogeneity of CAT and FEV1/FVC% decreased significantly; when subgroup analysis was conducted according to different aerobic interventions, the heterogeneity of FEV1%pred and FEV1/FVC% decreased significantly. This suggests that average age may be one of the sources of heterogeneity for CAT and FEV1/FVC%, while different aerobic interventions may represent a potential source of heterogeneity for FEV1%pred and FEV1/FVC%.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e\u003ch2\u003eMeta Regression\u003c/h2\u003e\u003cp\u003eHigh heterogeneity was observed in 6MWT and SGRQ. As a result, we ran a meta-regression study on these 2 outcomes to investigate potential sources of heterogeneity. The meta-regression indicated that nation was a significant source of heterogeneity for the 6MWT (p\u0026thinsp;=\u0026thinsp;0.029, \u003cb\u003eAppendix 3: Meta Regression, Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/b\u003e). Other examined factors, including intervention duration and sample size, had no statistically significant effect. For the SGRQ, none of the examined covariates\u0026mdash;including nation, intervention duration, and sample size\u0026mdash;reached statistical significance \u003cb\u003e(Appendix 3: Meta Regression, Table S2).\u003c/b\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec22\" class=\"Section2\"\u003e\u003ch2\u003eSensitivity analysis\u003c/h2\u003e\u003cp\u003eAn analysis focusing on sensitivity was performed to assess the robustness and dependability of the pooled findings, through a systematic exclusion of individual studies. The outcomes of sensitivity analyses were reported in the \u003cb\u003eAppendix 4: Sensitivity analysis, Figure S11-S15\u003c/b\u003e. The elimination of any single article had no significant effect on the findings, demonstrating the robustness of the results.\u003c/p\u003e\u003cdiv id=\"Sec23\" class=\"Section3\"\u003e\u003ch2\u003ePublication bias\u003c/h2\u003e\u003cp\u003eIndications of bias in publication were evident, as suggested by Egger's test (P\u0026thinsp;=\u0026thinsp;0.0008) \u003cb\u003e(Appendix 5: Publication bias, Figure S16)\u003c/b\u003e and by asymmetry in the funnel plot \u003cb\u003e(Appendix 5: Publication bias, Figure S17)\u003c/b\u003e, which might have been related to small sample sizes and the non-publication of negative studies. After imputing 3 studies using the trim-and-fill method \u003cb\u003e(Appendix 5: Publication bias, Figure S18)\u003c/b\u003e, the MD decreased from 43.743 (95% CI: 32.953\u0026ndash;54.534) to 40.586 (95% CI: 26.952\u0026ndash;54.221), suggesting that the original result might have been overestimated. Therefore, we must approach the interpretation of the results with prudence, and future research should further validate these findings by including grey literature and pre-registered studies.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec24\" class=\"Section2\"\u003e\u003ch2\u003eTrial sequential analysis\u003c/h2\u003e\u003cp\u003e\u003cb\u003e6-min\u0026rsquo;s walk test (6MWT)\u003c/b\u003e\u003c/p\u003e\u003cp\u003eTrial sequential analysis was performed on 21 trials comparing the aerobic group with the control group for 6MWT \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e1) The cumulative Z-curve (the blue line) crossed the required information size (RIS) (the vertical red line), which signaled that the accumulated studies were sufficient for meta-analysis.\u003c/p\u003e\u003cp\u003e2) The cumulative Z-curve crossed the conventional boundary for benefit (horizontal yellow line at z\u0026thinsp;=\u0026thinsp;1.96), indicated a statistically significant reduction in 6MWT in the aerobic group compared with the control group.\u003c/p\u003e\u003cp\u003e3)The cumulative Z-curve crossed the trial sequential monitoring boundary for benefit (sloping red line), which established firm evidence supporting the superiority of the aerobic group.\u003c/p\u003e\u003cdiv id=\"Sec25\" class=\"Section3\"\u003e\u003ch2\u003eCOPD Assessment Test (CAT) and St. George\u0026rsquo;s respiratory questionnaire (SGRQ) score\u003c/h2\u003e\u003cp\u003eTrial sequential analysis was conducted on 11 trials \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eB\u003cb\u003e)\u003c/b\u003e and 10 trials \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eC\u003cb\u003e)\u003c/b\u003e comparing the aerobic group with the control group for CAT and SGRQ, respectively. Both images showed that the cumulative Z-curve (the blue line) crossed the conventional boundary for benefit (horizontal yellow line at z\u0026thinsp;=\u0026thinsp;1.96), the trial sequential monitoring boundary for benefit (sloping red line), and the RIS (the vertical red line), which indicated that the evidence was robust and conclusive. These findings further demonstrated that aerobic exercise led to significant reductions in CAT and SGRQ scores compared with the control group, and were robust, suggesting that similar clinical trials could be justifiably terminated.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec26\" class=\"Section3\"\u003e\u003ch2\u003eForced expiratory volume in first second percentage of predicted (FEV1%pred)\u003c/h2\u003e\u003cp\u003eTrial sequential analysis was performed on 9 trials comparing the aerobic group with the control group for FEV1%pred \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eD\u003cb\u003e)\u003c/b\u003e. Although the results of the meta-analysis indicated that aerobic exercise was effective, as evidenced by the cumulative Z-curve (the blue line) crossing the conventional boundary for benefit (horizontal yellow line at z\u0026thinsp;=\u0026thinsp;1.96), the evidence was still immature. This was because the accumulated sample size had not yet reached the required information size (RIS) (the vertical red line) of 1,517 participants, and the cumulative Z-curve did not cross the trial sequential monitoring boundary for benefit (sloping red line). Therefore, it was not yet possible to draw a reliable conclusion regarding the efficacy of aerobic exercise. Ongoing data collection was recommended until either the RIS was achieved or the trial sequential monitoring boundary for benefit was crossed.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec27\" class=\"Section3\"\u003e\u003ch2\u003eThe ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC%)\u003c/h2\u003e\u003cp\u003eTrial sequential analysis was conducted on 10 trials comparing the aerobic group with the control group for FEV1/FVC% \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eE\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e\u003cp\u003eThe cumulative Z-curve (the blue line) reached the sample size corresponding to RIS (the vertical red line) and crossed the conventional boundary for benefit (horizontal yellow line at z\u0026thinsp;=\u0026thinsp;1.96), which indicated a potentially statistically significant effect of aerobic exercise when the sample size was adequate. However, the cumulative Z- curve did not cross the trial sequential monitoring boundary for benefit (sloping red line). Therefore, the evidence remained insufficient to draw definitive conclusions, and additional studies were warranted to reduce the risk of Type I error and confirm the robustness of the observed effect.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe carried out a thorough search for RCTs assessing the influence of aerobic exercise on functional capacity, quality of life and pulmonary function in COPD patients. A total of 25 studies encompassing 2103 COPD patients were included. Findings from the meta-analysis revealed notable statistical enhancements in exercise capacity (estimated via 6MWT), quality of life (estimated via SGRQ and CAT), and pulmonary function (estimated via FEV1%pred and FEV1/FVC%) in patients with COPD. TSA confirmed that aerobic exercise significantly improved exercise capacity (estimated via 6MWT) and quality of life (estimated via SGRQ and CAT) in COPD patients; further randomized trials on these outcomes could therefore be halted. Nevertheless, its benefit for pulmonary function (estimated via FEV1%pred and FEV1/FVC%) remained uncertain and was interpreted cautiously. High-quality studies were still needed to verify this conclusion.\u003c/p\u003e\u003cp\u003ePatients diagnosed with COPD frequently experience limitations in their exercise capacity [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]. Aerobic exercise mainly involves endurance training. Endurance exercise training can effectively enhance the cardiopulmonary function and skeletal muscle function of COPD patients, thereby improving exercise capacity [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e, \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. The 6MWT method was employed to assess the exercise ability of individuals diagnosed with COPD. This is a uniform assessment tool for objectively evaluating functional exercise ability with good reliability and validity [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e]. After the intervention, the aerobic exercise group's 6MWT distance increased statistically significantly more than that of the control group in the included studies [\u003cspan additionalcitationids=\"CR29 CR30 CR31 CR32\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan additionalcitationids=\"CR36 CR37 CR38 CR39 CR40\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan additionalcitationids=\"CR44\" citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan additionalcitationids=\"CR48 CR49 CR50\" citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. Previous meta-analyses have shown that aerobic exercise improves exercise capacity in patients with COPD [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], which aligns with our conclusions. Moreover, the trial sequential analysis (TSA) of the 6MWT crossed the trial sequential monitoring boundary for benefit and achieved the required information size (RIS), suggesting a true positive result and thereby providing robust support for this finding.\u003c/p\u003e\u003cp\u003ePatients diagnosed with COPD typically have an older age at disease onset and commonly present with a concurrent cough, dyspnea, limitations in activities of daily living, insomnia, and pain symptoms, which severely affects patients\u0026rsquo; quality of life [\u003cspan additionalcitationids=\"CR57\" citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e]. One important indicator of therapy effectiveness is whether or not COPD patients can enhance their health-related quality of life. The CAT and SGRQ are strong, trustworthy instruments for evaluating health-related quality of life [\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e, \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e]. This meta-analysis showed that patients in the aerobic exercise group showed substantial decreases in both CAT and SGRQ scores when compared to the control group, suggesting that aerobic exercise interventions improved health-related quality of life. Moreover, the TSA of CAT and SGRQ further corroborated these findings. However, due to the high heterogeneity of the results, subgroup analyses and meta-regression were performed to explore the potential sources of heterogeneity. These results should be viewed cautiously because the data showed that the high heterogeneity of SGRQ could not be explained.\u003c/p\u003e\u003cp\u003eCOPD has been characterized by incompletely reversible airflow limitation, which mainly involves lung tissue and seriously impairs lung function [\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e]. Aerobic exercise induces conditioning of the accessory muscles related to breathing, strengthens the respiratory muscles and delays fatigue [\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e]. This helps patients with COPD improve their respiratory efficiency and, ultimately, their lung function. The global COPD diagnosis, management, and prevention strategy states that FEV1% pred and FEV1/FVC% are the traditional indices for assessing pulmonary function in COPD patients, which are simple and rapid. FEV1% pred is used to evaluate the severity of lung function impairment, and the degree of airflow limitation is assessed using the FEV1/FVC% [\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e]. Findings from the meta-analysis indicated a notable enhancement in FEV1%predicted and FEV1/FVC% in the group engaging in aerobic exercise, in contrast to the control group. Nevertheless, the cumulative Z-curve for FEV1 and FEV1/FVC merely exceeded the conventional boundary for benefit, according to the TSA plots, suggesting that more research is necessary to determine whether aerobic exercise can enhance pulmonary function. A meta-analysis showed that aerobic exercise cannot improve FEV1%pred and FEV1/FVC% in COPD patients [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], which is inconsistent with our results. This may be due to the fact that the training methods in that meta-analysis were not just limited to aerobic exercise but also included strength training, which cannot accurately reflect the efficacy of aerobic exercise alone.\u003c/p\u003e\u003cdiv id=\"Sec29\" class=\"Section2\"\u003e\u003ch2\u003eLimitation\u003c/h2\u003e\u003cp\u003eThe primary limitations of the present meta-analysis are outlined below. First, in terms of methodological design, a majority of the included studies had flaws, mainly related to a significant risk of performance bias, and other domains showed poor scores. Second, most included studies did not report data on whether participants continued aerobic exercise after the intervention period. The long-term impact of aerobic exercise on patients with COPD remains unclear due to the absence of follow-up data.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003ePatients with COPD benefit greatly from aerobic exercise in terms of their exercise capacity and quality of life, and to some extent, enhances lung function. However, due to the scarcity of lung function studies and the presence of publication bias, larger, well-designed, randomized controlled trials are needed in the future.\u003c/p\u003e"},{"header":"Strengths and limitations of this study","content":"\u003cp\u003eOur research results indicate that aerobic exercise is beneficial to the exercise capacity and quality of life of COPD patients. Trial sequential analysis further confirmed the robustness of these findings.\u003c/p\u003e\n\u003cp\u003eMost included studies did not report data on whether participants continued aerobic exercise after the intervention period.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe long-term impact of aerobic exercise on patients with COPD remains unclear due to the absence of follow-up data.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCOPD Chronic Obstructive Pulmonary Disease\u003c/p\u003e\n\u003cp\u003eRCTs Randomized Clinical Trials\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCENTRAL Cochrane Central Register of Controlled Trials\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCNKI China National Knowledge Information Database\u003c/p\u003e\n\u003cp\u003eCSTJ China Science and Technology Journal Database\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e6MWT 6-Min Walk Test\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWMD weighted mean difference\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCI confidence interval\u003c/p\u003e\n\u003cp\u003eCAT Chronic Obstructive Pulmonary Disease Assessment Test\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSGRQ St. George\u0026rsquo;s Respiratory Questionnaire\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFEV1%pred forced expiratory volume in the first second\u003c/p\u003e\n\u003cp\u003eFEV1/FVC% The ratio of forced expiratory volume in the first second to forced vital capacity\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePR Pulmonary Rehabilitation\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTSA trial sequential analysis\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRIS required information size\u003c/p\u003e\n\u003cp\u003ePRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSD Standard Deviation\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Home for Researchers editorial team (www.home-for-researchers.com) for language editing service.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLJP, CSQ, WSZ concepted and designed the study; HKY, TFQ, GY, CHD, GYF collected data; GY, HKY, CHD, GYF analysed data; CSQ and WSZ Supervised; LJP , GY and HKY completed the manuscript draft; CSQ and WSZ completed the manuscript revision; All authors have read and approved the manuscript for publication. GY, HKY and TFQ contributed equally to this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAlthough the data supporting the findings in this study are available from [Jianping Lin], there are restrictions on the availability of these data, which were used under licence for the current study, and are therefore not publicly available. However, the data are available from the authors on reasonable request and with the permission of [Jianping Lin]. The protocol was registered prospectively and became available on the PROSPERO International Prospective Register for Systematic Reviews website\u0026nbsp;(Registration #: CRD42022377652).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional Information\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests. The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the National Natural Science Foundation of China (grant numbers 81874501) and Finance Department Project of Fujian Provincial (grant numbers 22SCZZX006).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eChristenson, S. A., Smith, B. M. \u0026amp; Bafadhel, M. Putcha, N. 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A review. \u003cem\u003eActa Paediatr.\u003c/em\u003e \u003cb\u003e111\u003c/b\u003e (2), 259\u0026ndash;264 (2022).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVogelmeier, C. F. et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report. GOLD executive summary. \u003cem\u003eAm. J. Respir Crit. Care Med.\u003c/em\u003e \u003cb\u003e195\u003c/b\u003e (5), 557\u0026ndash;582 (2017).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Aerobic Exercise, Chronic Obstructive Pulmonary Disease, Randomized controlled trial, Meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-8126313/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8126313/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e\u003cp\u003eResearch has indicated that pulmonary rehabilitation (PR) is effective in reducing symptoms in people with COPD. Exercise is part of overall PR, while the isolated effect of aerobic exercise in COPD patients remains unclear.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eEnglish and Chinese RCTs published from inception to the May 2025 were searched in online nine databases. The Cochrane Risk of Bias tool was used to assess the risk of bias in the included studies. Stata17.0 and RevMan5.3 were used to do the meta-analysis. We conducted a trial sequential analysis (TSA) that included all of the results in order to assess the stability and dependability of the study's findings. This study has been registered with PROSPERO under ID CRD42022377652.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eThe meta-analysis comprised 25 trials with 2103 participants in total. According to the findings, aerobic exercise significantly improved the 6MWT, CAT, FEV1%pred, FEV1/FVC%. Subgroup and meta-regression analyses identified sources of heterogeneity. The TSA results show that the study outcomes for the three indicators 6MWT, CAT, and SGRQ are conclusive and reliable.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003ePatients with COPD benefit greatly from aerobic exercise in terms of their exercise capacity and quality of life, and to some extent, enhances lung function.\u003c/p\u003e","manuscriptTitle":"Aerobic Exercise on Functional Capacity and Quality of Life in COPD Patients: A systematic review and meta-analysis with trial sequential analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-12 08:33:28","doi":"10.21203/rs.3.rs-8126313/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4ceac539-e511-4099-bacb-27d7520c95bd","owner":[],"postedDate":"December 12th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":59442854,"name":"Health sciences/Diseases"},{"id":59442855,"name":"Health sciences/Health care"},{"id":59442856,"name":"Health sciences/Medical research"},{"id":59442857,"name":"Health sciences/Risk factors"}],"tags":[],"updatedAt":"2026-03-06T19:09:54+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-12 08:33:28","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8126313","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8126313","identity":"rs-8126313","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}