Effectiveness of pulmonary rehabilitation performed through exercise training for patients with stable COPD: A meta-analysis of randomized controlled trials

Chronic obstructive pulmonary disease (COPD) “is a common, preventable, and treatable disease characterised by persistent respiratory symptoms and airflow limitation due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases” (4). Airflow limitation in COPD is caused by chronic inflammation and is characterized by obstructive bronchitis and emphysema. Systemic inflammation also plays an important role in the comorbidity of patients with COPD (1), including a markedly increased risk of cardiovascular diseases (2).

COPD is considered an important public health issue. It is the third leading cause of death worldwide (3), and is particularly prevalent in the aging population that has been exposed to tobacco smoke (4). The global prevalence of COPD in adults is estimated to be 11.7% (5). Due to the high prevalence of smoking and the increase in the elderly population in developing countries, the prevalence of COPD is expected to increase (6).

Pharmacological treatment of COPD is required to reduce the symptoms, severity, and frequency of exacerbation of the disease, improve exercise tolerance, and general health (4). Treatment of stable COPD also includes pulmonary rehabilitation (PR) as a key component in the management of COPD patients (4, 7). PR is a multicomponent intervention usually based on smoking cessation counselling, influenza and pneumococcal vaccination, education on the proper use of prescribed inhalation therapy, nutrition, and exercise training (4, 8). Exercise intolerance and limb muscle dysfunction are among the most troubling symptoms of COPD (7, 9). Considering an individual`s characteristics and comorbidities (7), institution- and home-based PR improves functional capacity and health related quality of life (HQoL) at all stages of disease severity (4).

HQoL is an important indicator of the impact of chronic disease, and can be severely impaired in patients with COPD (10). The St. George’s Respiratory Questionnaire (SGRQ) is a disease-specific instrument designed to measure the impact on general health, daily life, and perceived well-being in patients with obstructive airway disease (11). When monitoring these patients, a favourable change in the SGRQ score may indicate the effectiveness of a given treatment (12).

Exercise training is an important component of PR to stabilize COPD. It is the best available means to improve exercise tolerance and muscle function (13), and also contributes to cardiovascular health in COPD patients (14, 15). For example, COPD as an endothelial disorder (16) increases the risk of cardiovascular diseases (2). Apparently, impaired blood flow worsens endothelial dysfunction in moderate to severe COPD (17). Patients with severe airway obstruction who are physically active are less susceptible to significant disfunction of flow-mediated vasodilatation (17). It appears that higher levels of physical activity and/ or long-term PR including exercise may improve quality of life and reduce cardiovascular risk in COPD patients (14). Before starting an exercise programme, an assessment of physical fitness is necessary to individualize the training protocol (18). Endurance training (EDT) programmes generally increase endurance performance by inducing adaptations in the cardiorespiratory and neuromuscular systems (18). Improved endurance performance results in reduced ventilatory demand, which is why EDT is strongly recommended in COPD (19). The American College of Sports Medicine recommends daily aerobic exercise (30-60 minutes) at moderate level. Exercise should be rhythmic, using large muscle groups, such as walking, cycling, and swimming (20). When endurance training is supplemented with resistance training (RT), muscle mass and strength improve (21). RT for the major muscle groups should be performed at least 2 days per week with moderate intensity (20). Flexibility exercises for the upper and lower limbs performed 2-3 days per week are commonly included in PR (22). A minimum of 8 weeks of training is required for clinically meaningful changes in exercise capacity and quality of life (22). Therefore, a maintenance program or at least sufficient support should be offered to patients with COPD (4).

The six minute walk test (6MWT) can be used to predict cardiorespiratory fitness in the healthy population (23), and the usual result of the related tests is the six-minute walking distance (6MWD). Current data confirm that the 6MWT is valid and reliable for assessing functional exercise capacity and response to treatment in diverse patients’ groups (23, 24). The feasibility of the 6MWT has been studied in pulmonary diseases. It was found to be feasible in patients after mechanical ventilation (25) or lung transplantation (26), and in patients with chronic obstructive pulmonary disease (27, 28). Consequently, the 6MWT is a widely accepted method for evaluating the effects of PR performed through physical activity or exercise on functional exercise capacity in COPD (18).

The aim of this study was to perform a review and meta-analysis to investigate the effects of PR, as performed by exercise training (as at PR-ET), on functional capacity (measured by 6MWT) and health-related quality of life (measured by SGRQ) of patients with stable COPD.

In addition, the above effects will be assessed by comparing home- and institution-based PR-ET and PR-ET with a duration of ≤8 weeks and >8 weeks. Supervised institutional-based PR-ET is expected to have a greater impact on 6MWD and SGRQ total score than home-based PR-ET. Based on summation of effects, PR-ET with longer duration would likely be more effective than the shorter ones.

COPD is considered an important public health issue. In this context, we present the following hypotheses (H), both of which refer to patients with stable COPD:

H1: PR-ET has a positive effect on 6MWD.

H2: PR-ET has a positive effect on SGRQ total score.

Pulmonary rehabilitation (PR), including exercise training (ET), is recognized as an important component of treatment for patients with chronic respiratory disease. PR is designed to reduce symptoms and improve functional capacity and health-related quality of life in COPD (13). In this study, the effect of PR, performed by exercise training (PR-ET), on the six-minute walk distance (6MWD) and St. George’s Respiratory Questionnaire (SGRQ) total scores in patients with stable COPD was investigated.

The 6MWT is the gold standard for assessing functional capacity in COPD patients (18) and a valid predictor of potential hospitalisation (56) – the longer the 6MWD, the lower the risk of hospitalization. Our meta-analysis shows that PR-ET including various forms of exercise training significantly improves 6MWD (31.73m) (Figure 2), indicating the relevant beneficial effect of PR-ET on functional capacity in COPD. A number of studies have reported a threshold for the minimal clinically significant difference in changes in 6MWD of 25-35m (57). Therefore, according to the study hypothesis H1, i.e. that PR-ET has a positive effect on 6MWD in COPD, can be confirmed. Moreover, the increase in 6MWD after PR-ET was of clinical significance. Our meta-analysis included studies that considered different forms of exercise training relevant to increasing functional capacity. This variability of PR-ET is probably one of the main reasons for the moderate heterogeneity of the results (I2=66%, p<0.0001).

Considering that PR-ET is very effective in improving functional capacity in COPD (13), our meta-analysis examined the effects of institutional- and home-based PR-ET on 6MWD. The results suggest that significant improvement in 6MWD is also achieved with home-based PR-ET. However, 23.73 m (Figure 2) for the mean change in 6MWD in the case of home-based PR-ET does not reach the minimum clinically relevant required change of 25 m (57). This suggests that home-based PR-ET significantly improves the functional capacity of COPD patients, but institutional-based PR-ET produces a clinically relevant mean change in 6MWD (39.30 m). Home-based PR-RT could be an alternative to outpatient or hospital-based programs for those patients who, for various reasons, cannot attend PR-ET in specialized institutions. One way to improve the efficiency of home-based PR-ET could be to enable patients to self-manage their own training, not to mention to receive adequate expert support (22). For example, PR-ET, which is performed partly under professional supervision and partly without, increases tolerance to exercise (37). The use of multimedia in the home-based PR also improves exercise performance in COPD patients (58). Certain forms of home-based PR-ET may facilitate the maintenance of benefits acquired in outpatients PR (59).

Compared with baseline, a significant improvement in walking distance was observed for PR-ET of duration ≤8 weeks (31.45 m) and PR-ET of duration >8 weeks (31.92 m) in patients with stable COPD (Figure 2). Therefore, to achieve clinically meaningful gains in functional capacity, PR-ET ≤8 weeks may be acceptable. This is encouraging in terms of patient motivation. We must consider that in our meta-analysis, most RCTs that included a short PR-ET were exactly 8 weeks long, and no studies were shorter than 4 weeks. Indeed, the GOLD report (4) summarizes that the optimal benefit of PR is achieved in programmes lasting 4-8 weeks. The available evidence suggests that extending PR to 12 weeks does not add any benefit. However, if the results of PR are not supported, its benefits diminish over time. Therefore, it is important to participate in maintenance programmes after PR (4, 60). In our meta-analysis, RCTs that included PR-ET lasting >8 weeks showed a significant, moderate heterogeneity of the results (Figure 2b: I2=60%, p=0.020). The reason for this is likely to be found in the study by Xi et al. (44), in which a significant improvement in walking distance was observed after PR-ET consisted of high-frequency training (≥5 times per week). While, in the study by Román et al. (52), no improvement in walking distance was found in patients with COPD and low impairment when PR-ET includes low-intensity peripheral muscle training.

The SGRQ is suitable to assess health-related quality of life (HRQoL) in patients with COPD (12, 49). In our meta-analysis, the overall effect of PR-ET on the SGRQ score and thus on the quality of life of COPD patients was favourable and statistically significant (Figure 3: -8.09). Based on this result H2, i.e., PR-ET has a positive effect on SGRQ total score, can be confirmed. Similarly, other meta-analyses found a statistically significant effect of PR-ET on HRQoL as assessed by SGRQ (62, 63, 64). The submeta-analyses of the institution-based PR-ET (Figure 3a) and also PR-ET with a duration of ≤8 weeks (Figure 3b) were found to be favourable and statistically significant, in contrast to the submeta-analyses of the home-based PR-ET and PR-ET with a duration of >8 weeks, where the results were not statistically significant. Before making further conclusions, it should be noted that the latter two submeta-analyses were performed on only three RCTs, which is below the recommended minimum (65). Therefore, further studies should be conducted to evaluate the effects of PR-ET on SGRQ score in home-based PR, and those that have a duration of >8 weeks.

Before drawing any further conclusions about the results of the meta-analyses, the following limitations shoud be considered. In this study there were RCTs with different types of ET and different groups of patients with stable COPD. This probably contributed to the substantial heterogeneity of the results. Our results suggest that different types of ET, included in PR, are beneficial for COPD patients. However, further meta-analyses with different types of ET and different groups of COPD patients should be performed to determine the efficacy of each type of PR-ET. Currently, because of the relatively small number of RCTs that satisfy the inclusion criteria, it is not possible to meet the criterion of the recommended minimum number of RCTs in the meta-analysis by grouping the RCTs according to different types of ET and different groups of COPD (please, refer also to Appendix 2). Another important limitation of this study is the problem of adherence – that is, the degree to which an intervention was delivered in the manner planned by the investigators – in the RCTs included in the meta-analysis. As shown in Appendix 1, of the 18 RCTs included in our study, only nine reported how adherence to the intervention should be assessed (item 11 of the TIDieR), and of these, only two RCTs reported the actual extent to which the intervention was delivered as planned (item 12). Furthermore, the results of certainty of evidence (GRADE) were low for both meta-analyses. This fact certainly detracts from the relevance of our meta-analyses, and particular caution should be exercised in generalizing our results. Moreover, this fact is also an urgent call to researchers in the field to improve the design and reporting of RCTs in this area.

Our meta-analyses show that PR-ET including different types of ET has a significant, beneficial effect on functional capacity and HRQoL in COPD patients because: (i) overall it improves 6MWD and SGRQ total scores; (ii) produces a clinically significant improvement in 6MWD when performed as institutional-based PR-ET, and in the case of PR-ET≤8 weeks and PR-ET>8 weeks; (iii) the institutional-based PR-ET and PR-ET≤8 weeks subcategories also show significant, favourable effects on SGRQ total scores.

The results are positive in that they suggest that patients can include the exercise training that is most appropriate for them in their PR. They also suggest that the benefits to functional capacity in COPD can be achieved even when PR-ET is performed at home. To achieve clinically important improvements in functional capacity, PR-ET proved more effective when performed in specialized institutions. Special attention should be paid to determining the impact of home-based PR-ET and PR-ET>8 weeks on the SGRQ score.

Therefore, it is recommended that healthcare institutions include PR-ET in the management of patients with stable COPD, as it is an effective, complementary intervention to conventional pharmacological treatments. However, for better planning of PR-ET in COPD patients, further studies should be conducted to clarify the effects of different training variables on their functional capacity.