Exacerbations in patients with chronic obstructive pulmonary disease receiving physical therapy: a cohort-nested randomised controlled trial

The definition of COPD by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) explicitly mentions COPD exacerbations as an enormous burden for patients [1] and health care systems [6]. Exacerbations are defined as “an event in the natural course of the disease characterised by an increase in dyspnoea, cough and/or sputum beyond normal day-to-day variations. The onset is seemingly acute and may require a change in regular medication or hospitalisation” [1, 7]. They are mostly precipitated by an infectious systemic inflammation of the upper respiratory tract and the tracheobronchial tree [1].

Since exacerbations are a significant cause of morbidity (e.g. acute muscle deconditioning and muscle weakness), hospital admissions, impaired health status, impaired quality of life and even death in patients [8‐10], prevention is indicated. A relatively small percentage of patients (10%) experiencing frequent exacerbations account for over 70% of all medical costs due to COPD [6]. A study of Pitta et al. (2006) showed that COPD patients tend to be severely inactive during and after an exacerbation; which is worrying since there seems to be a strong association between physical inactivity in patients who recently exacerbated and an elevated risk of (re)hospitalisation due to a COPD exacerbation [11, 12]. It appears that patients with recurrent exacerbations show a more rapid decline in their physical activity level than stable patients and their functional capacity gradually decreases faster over time [11]. Besides, their more pronounced skeletal muscle weakness and decreased six-minute walk distance (6MWD, a measure of functional exercise capacity), are risk factors for future exacerbations and higher mortality [9, 13]. Consequently, unstable patients, who frequently experience exacerbations, enter a downward spiral of inactivity and exacerbations. Hence, adequate management of exacerbation (prevention) in patients is considered worldwide as one of the main goals in controlling COPD [1].

Although medical treatment modalities for COPD have improved, there is still no pharmacological therapy available that reduces the progression of the disease [4]. Though, patients with COPD, irrespective of disease stage, have shown to benefit from exercise programmes [12] resulting in improved exercise performance and health status [4, 5, 14‐17].

Evidence, to support the biological plausibility of the positive effects of physical exercise training on COPD, points towards longer high-intensity exercise training programmes. High-intensity exercise training has shown to increase exercise tolerance [18, 19]. Firstly, exercise training improves muscle oxidative capacity and oxygen recovery kinetics in patients with COPD [20]. Secondly, patients with COPD who experience lactic acidosis during exercise can attain physiologic training responses from a physical exercise training programme [21, 22]. Exercise performance can be improved by reducing the ventilatory requirement for a certain activity level. As the bioenergetics of skeletal muscle improve, blood lactate levels are reduced at a given level of exercise; thereby decreasing the amount of non-metabolic carbon dioxide (CO₂) that is produced by the bicarbonate buffering system [12, 21]. Since lactic acid stimulates ventilation, decreasing lactate production during exercise can be very helpful for patients with COPD. Physical exercise training, in addition to optimal bronchodilatation, can reduce breathing frequency during exercise and consequently lower the degree of dynamic lung hyperinflation that many patients with severe COPD develop [22, 23]. In turn, decreased hyperinflation may mediate improvement in exercise endurance by delaying the attainment of a critically high inspiratory lung volume [22, 23]. Moreover, high-intensity exercise training, engendering high levels of blood lactate, are more effective than training work rates eliciting low lactate levels [21]. Although measurable physiological changes may occur within weeks, behavioural changes may require longer time periods and may be the reason that greater effects were shown in long-term exercise programmes [19]. In conclusion, extensive physical exercise training is beneficial in patients with COPD.

Patients with COPD often experience sudden worsening of symptoms, i.e. exacerbations. Previous studies already demonstrated that physical exercise training (the component that has shown to provide the most benefit of pulmonary rehabilitation programmes) [1] has important benefits for patients, such as improved exercise capacity and HRQL [9, 15, 24]. However, the effect of pulmonary rehabilitation and physical exercise training on the occurrence of exacerbations is less clear [4, 19, 25, 26]. Observational studies demonstrated that patients who perform regular physical activity have a reduced risk of hospital admission due to COPD and decreased all-cause and respiratory mortality [12, 27, 28], but neither of these outcomes are a substitute for reduction of exacerbation frequency, duration or severity. The factors determining utilisation of health care resources in patients with COPD are poorly understood [29]. Few studies reported significantly fewer exacerbations after a pulmonary rehabilitation program (including physical exercise training) [30, 31]. Reduction of exacerbations may be at least one of the factors explaining the reduction in health care utilisations as reported in observational studies. Moreover, a recent study suggested that an acute bout of exercise resulted in a reduction in sputum proinflammatory cytokines, suggesting some anti-inflammatory effect of exercise in the airways of patients with COPD [32]. Based on these few findings it is plausible to hypothesise that physical exercise training for patients with COPD may result in fewer exacerbations, or at least in less severe exacerbations, meaning exacerbations with a shorter duration or exacerbations without the necessity for hospital admission.

Prevention of exacerbations by means of physical exercise training would fit the prime management goal for COPD [27]. Based on expert’s opinion, it was stated that teaching patients how to recover quickly from an exacerbation will probably minimise the risk for relapse and improve long-term outcome [26]. Exercise training improves recovery in patients with COPD after an acute exacerbation [33]. Also, from previous studies it has been shown that especially early pulmonary rehabilitation (including physical therapy) after an acute exacerbation is most likely to result in clinically relevant improvements in functional exercise capacity and health-related quality of life [5, 16]. Puhan et al. (2011) found in nine small trials of moderate methodological quality that effects of pulmonary rehabilitation programmes immediately after an acute COPD exacerbation were visible when at least physical exercise was included [24]. However, they also concluded that more studies are needed to further investigate the role of pulmonary rehabilitation after an acute exacerbation and its potential to reduce costs [24, 34].

Evidence based physical exercise training and advice on physical activity can be delivered by physical therapists that follow evidence based guidelines for physical therapy in COPD patients, such as the guideline COPD developed by the Royal Dutch Society for Physical Therapy (KNGF) [35]. This study protocol hypothesis that early protocol-directed physical therapy for patients with COPD may reduce COPD exacerbation frequency, duration or severity.

The aim of this study is to assess the clinical effectiveness, cost-effectiveness and cost-utility of early protocol-directed physical therapy for patients with COPD on exacerbations (frequency, duration and severity), health status and quality of life in patients who have recently experienced a COPD exacerbation.

A cohort-nested, prospective, randomised controlled trial (cohort-nested RCT) will be conducted. This means that a RCT will be embedded within a COPD cohort (Figure 1). The cohort will consist of COPD patients who receive usual multidisciplinary COPD care and guideline-directed physical therapy (gdPT). The cohort will serve as an optimal recruitment population for the RCT to show the surpassing importance of physical therapy interventions on exacerbations. Therefore, a RCT that holds a large contrast of protocol-directed physical therapy (pdPT) versus sham treatment (ST) will be constructed. This means that when patients from the COPD cohort report an exacerbation, with an occurrence no longer than 56 days ago (a trade-off between threshold values of 35–91 days in which the majority of exacerbations have returned to baseline [36]), they are either randomised to the experimental group (protocol-directed physical therapy (pdPT)) or the control group (sham-treatment (ST)). This RCT will be used to study effectiveness of physical therapy in addition to an economic evaluation.

The ethics committee of Maastricht University has approved the study protocol, procedures and informed consent (NL28718.068.09).

The study population consists of patients who are treated by COPD-specialised physical therapists, after referral by a general practitioner (GP) or pulmonologist. Physical therapy practices, GPs and pulmonologists, in southern districts of the Netherlands, who are willing to participate in the study, will be recruited. Once a patient is referred to a participating physical therapy practice (with post-bronchodilator FEV₁/FVC < 0.7, GOLD 1–4), the patient will be asked to participate in the COPD cohort study. Patients in the cohort are monitored for health outcomes and exacerbation occurrence. Participants for the RCT will be recruited within the cohort by physical therapists, as soon a patient suffers from an exacerbation. Additionally, advertisements in local papers in southern regions of the Netherlands are used to reach potential COPD patients for the RCT who were missed out on inclusion with the former recruitment method. Those patients who are reached through advertising and presenting with an exacerbation will be recruited for the RCT by the researcher, while the mechanisms for alert and continuous trial recruitment are automatically organized within the cohort. By means of this unique cohort-nested RCT design (Figure 1), the likelihood that patients with a COPD exacerbation will be picked up is higher. A flowchart of the RCT is presented in Figure 2.

The following inclusion criteria will be checked during the eligibility screening of patients for the RCT: a GP/pulmonologist diagnosed COPD in GOLD stage 2, 3 or 4 (supported by a post-bronchodilator FEV₁/FVC < 0.7 and FEV₁ < 80% of predicted); eligible for reimbursement by health insurance companies for physical therapy (post-bronchodilator Tiffeneau-index < 0.6); experienced an COPD exacerbations in the past 56 days (defined as: unscheduled visit to their GP/pulmonologist or hospitalisation and possibly receiving a course of antibiotics and/or prednisone); having an adequate and optimal medication (inhalation) regimen by their referring physician; willing to sign informed consent before randomisation; competent enough to speak and understand the Dutch language; above 18 years of age.

Patients who meet the following criteria will be excluded from the RCT: suffering from significant exercise limitations or comorbidities that would prevent a patient from following the required intervention in this study; and expected to be lost for follow-up (for example because of a planned change of residency).

All patients entering the cohort have to give informed consent on the following two levels, whereas patients entering the RCT have to give informed consent on three levels: (1) oral consent to exchange patient information between physical therapists and other related health care providers (usual physical therapy procedure); (2) oral consent to participation in the COPD cohort (registration and use of data for research purposes); and (3) written consent to participate in the RCT, after experiencing an acute exacerbation.

For the cohort study 300 patients with COPD will be recruited. This number is based on the calculated sample size for the RCT part of the study. The sample size calculation for this RCT is based on the identification of a minimal relevant clinical difference in exacerbation frequency between the experimental and the control group. The difference in exacerbation rate is expected to be 22% (based on exacerbation rates found in previous studies with rehabilitation programmes) [37, 38]. The probability that the study will detect a treatment difference is 80% at a two-sided 5% significance level. This is based on the assumption that the intervention period will be 12 months, the follow-up period will be 24 months and the ratio control subjects to intervention subjects is 1:1. A sample size calculation for comparing event rates between two independent groups is used, resulting in 79 participants per group [39, 40]. Assuming outcome data will be analysed prospectively and considering a drop-out rate of 20%, 100 patients per group will be needed in this two treatment parallel-design study.

After taking baseline measurements and eligibility screening within 56 days after the start of the past exacerbation, informed consent is obtained and stratified block randomisation will take place (Figure 2). Pre-stratification will be applied for exacerbation severity and GOLD stage (six levels in total), since both factors are suspected to influence treatment outcome. Therewith, the influence of selection bias for severity of the disease on group configuration or comparability between groups may be minimized. The patients will be randomly assigned to the experimental group or the control group in a 1:1 ratio. The concealed randomisation procedure will be performed by a blinded, independent research assistant using a computerised system. A block-randomisation will be used with blocks of size four, six or eight, with random block sequences. A computerized system will refer the patients to a group, after which a blinded, independent research assistant will notify the treating physical therapist after receiving instructions on treatment group allocation through computer generated random number tables.

In this RCT full blinding of the patients and physical therapists is not feasible. However, Hawthorne effects are non-differential, since patients in the experimental group as well as patients in the control group will get attention from their physical therapist. Both groups receive periodic questionnaires and measurement sessions, avoiding non-random effect optimisation. Several measures are taken to avoid bias due to blinding issues. Although patients will be aware of the existence of two treatment arms, they are not informed about the exact content of the other treatment arm (e.g. determining intensity) to prevent influence on outcomes. The control group will be assessed at the same time intervals as the experimental group by trained physical therapists that do not assess the patients in the experimental group at the same time. The researcher is fully blinded, because all outcome measures are quantified by the patients and physical therapists. Physical therapists are blinded for a number of outcomes measurements (questionnaires CCQ, CRQ-SR, GPE, EQ-5D, DS14 and physical activity level), since part of the data that are provided by the patient alone and will be captured through an electronic patient record system. Moreover, a number of important objective outcomes (exacerbation frequency, duration and severity, mechanically assessed physical activity level and cost diaries) are less liable to patient manipulation in order to please their physical therapist, as these outcomes are directly collected by the researcher.

All participants in the cohort receive usual multidisciplinary COPD care including guideline-directed physical therapy. In the Netherlands usual COPD care is given by a pulmonologist and/or a GP. This usual COPD care entails lung function testing, medication prescription for COPD and counselling, including education about the disease, symptoms and risks and tailor-made advice, which basically comes down to two major aspects; stop smoking and increase physical activity in everyday life [41]. In the light of the latter, all patients in the cohort are referred for usual physical therapy and physical activity advice. Usual physical therapy in the Netherlands is guideline-directed physical therapy (gdPT), provided by registered physical therapists and based on the KNFG physical therapy guidelines for COPD [35]. These guidelines provides assistance for applying physical therapy intervention (diagnosis and treatment) in COPD patients coping with impairments in mucus clearance, pulmonary function, muscle function and exercise capacity, and with limited physical activities due to dyspnoea or exercise intolerance. In the guidelines the effectiveness of several treatment modalities (specifically exercise training, breathing exercises, peripheral and respiratory muscle training) was reported and evidence based recommendations for the application of these modalities in physical therapy programmes were made. Moreover, disease management strategies are integrated. Short term goals incorporate improvement of patient’s knowledge, self-management and confidence to accomplish activities. Medium term goals are relief of dyspnoea, improvement of impaired airway (mucus) clearance, and improving or retaining exercise performance and physical activity in everyday life [35]. Long term goals entail improvement or preservation of disease related quality of life. Physical therapists are free to compile a patient-centred program at one’s professional discretion, within the limitations of the guideline. Hence, frequency of the guideline-directed physical therapy for COPD in the Netherlands varies; patients visit their physical therapist generally one to three times a week, for one hour, ranging from one-time consultation to multiple consultations during 3–12 months, depending on disease severity (based on usual care given in participating physical therapy practices) (Table 1).

As patients enter the RCT, after experiencing a COPD exacerbation, they may be assigned to either the experimental group or control group. Contrasts between the experimental group, control group and the cohort, based on content, intensity, frequency and timing, are displayed in Table 1.

All interventions are carried out in primary care physical therapy practices. Registered physical therapists, experienced in COPD care, who are willing to participate in the study, will be recruited through local physical therapy networks in the Netherlands that already have mapped the specialised skills of these health professionals and registered who treats a sufficient number of patients with COPD (with a minimum of 5–10 per week).

Therapists will be invited to attend information/training sessions given by the research group and related COPD experts. Information will be given about the aim and content of the cohort and RCT along with information about the necessary clinical measurements. Lectures will be given on the latest information on COPD and updates on the current COPD guidelines and on counselling (in line with the Dutch college of general practitioners (NHG) standard COPD). Furthermore, a COPD master class will be given to the network of participating physical therapists in cooperation with the Dutch Paramedical Institute (NPi).

Participants will be monitored by physical therapists with the help of a high quality electronic patient record system that is COPD-specific and serves simultaneously as a research database for the experimental group as well as for the control group. Moreover, the system will be used by physical therapists as guidance for treatment of the experimental group, since the KNGF guidelines physical therapy for COPD is fully incorporated within this system (for example: an alert will be visible on the computer screen when a patient’s performance is below 80% of the predicted peripheral muscle strength or when FEV₁ <50% and Medical Research Council dyspnoea score (MRC) ≥2 an advice to initiate multidisciplinary evaluation and rehabilitation is given).

Primary and secondary study-specific outcome measures will be assessed with the help of the COPD-specific record system. In addition, the system will contain information about the content of physical therapy, the duration of physical therapy, the total amount of physical therapy sessions, the duration per session, and the adherence to physical therapy.

The project in total will take five years. During the first three years of the project, physical therapy practices and COPD patients will be recruited. Patients in the cohort will be followed at least until the end of the project. Patients included in the RCT will be followed for two years by means of the COPD-specific electronic patient record system, while the treatment will be one year. The last year of the project is reserved for the processing and analysis of data, as well as the publication of results.

To assure a high quality treatment according to KNGF guidelines physical therapy for COPD, the participating physical therapists will be trained before the start of the study. It is obvious that physical therapists as well as patients cannot be fully blinded during this study, since both groups are aware of the treatment procedures. Moreover, due to practical reasons physical therapists perform some exercise measurements instead of the researcher. This can lead to subjective interpretations of the research findings. Therefore, participating physical therapists will be instructed to make correct use of the measurement instruments for standardisation. To minimise social desirability answering, patients are told that there are no right or wrong answers before filling out questionnaires. In order to minimize differential Hawthorne effects, all patients from the cohort, the intervention group and the control group in the RCT will be monitored very precisely in a standardised way on first signs of exacerbations and other outcome measurements. To minimise bias, research findings will be analysed by a blinded researcher.

Potential problems regarding the execution of this study are twofold. Because COPD is a complex disease the KNGF guidelines for physical therapy for COPD patients requires a lot of effort from participating physical therapists regarding patient assessment, apart from the general KNGF Guidelines on Reporting in Physical Therapy. Although the outcome measures in this study are very well connecting to the requirements of these guidelines, complete registration remains difficult and costs time, so problems may be expected regarding the full registration of COPD patients in this study.

Besides, patients who enter the RCT may be assigned to the control group, which may come with some problems. To include patients in the control group means physical therapists are only allowed to offer no or very low-intensity exercise training. Due to the lower frequency of treatments, participation in the RCT may be financially unattractive to the physical therapy practice and physical therapists. Moreover, there is a chance that patients in the intervention group of the RCT are doing much better compared to the control group.