Differential response to pulmonary rehabilitation in COPD: multidimensional profiling

Baseline characteristics

On average, patients had moderate-to-very severe COPD, an impaired exercise capacity, a poor health status, and experienced problems during the performance of activities of daily life. Moreover, patients were on multiple pulmonary and non-pulmonary drug treatments (table E1 in the supplementary material). Patients with long-term oxygen therapy generally had more symptoms of dyspnoea, and worse exercise performance, mood status and health status compared with patients without long-term oxygen therapy (table 1).

Response to pulmonary rehabilitation: whole group

Significant improvements were found for symptoms of dyspnoea (MRC: −0.4±1.1), 6MWD (27±57 m), cycle endurance time (208±328 s), performance of problematic activities of daily life (COPM-P: 2.0±1.7 points), the satisfaction with the performance of the problematic activities of daily life (COPM-S: 2.6±2.1 points), symptoms of anxiety (HADS-A: −1.4±3.5 points), symptoms of depression (HADS-D: −1.4±3.5 points), and health status (SGRQ total score: −5.3±12.6 points) (all p<0.01).

Multidimensional response profiling: whole sample

The 2068 patients with COPD were clustered into four groups with distinct multidimensional response profiles: n=378 (18.3%) in the cluster “very good responder”, n=742 (35.9%) in the cluster “good responder”, n=731 (35.4%) in the cluster “moderate responder”, and n=217 (10.5%) in the cluster “poor responder” (table 2). The response to PR was best in the very good responder cluster on all outcome measures compared with the other clusters (table 2, figure 1). Indeed, a clinically relevant improvement was achieved in 85% of the outcomes of the patients in cluster “very good responder”, while this was only achieved in 11% of the outcome of the patients in poor responder cluster (table 2, figure 2).

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FIGURE 1

Panels generated using Viscovery (Viscovery Software GmbH, Vienna, Austria). The Viscovery program placed all patients on a specific position on all maps based on their multidimensional response profile. The more subjects resemble in terms of their response to pulmonary rehabilitation the closer they are on the map. Contrarily, the more they differ the further they are away from each other. When looking at an outcome measure of pulmonary rehabilitation, patients “raise a red flag” if they had a very good response, “a green flag” when the response was good to moderate, and “a blue flag” when the response was poor. In this way the maps can be interpreted. Using the topology of the self-organising map, the Viscovery program could identify four different clusters of patients with chronic obstructive pulmonary disease (COPD) with a significantly different multidimensional response profile. C1: cluster 1 “very good responder” (n=378); C2: cluster 2 “good responder” (n=742); C3: cluster 3 “moderate responder” (n=731); C4: cluster 4 “poor responder” (n=217). a) Left panel shows the multidimensional response outcome. All other attribute pictures in a) are the absolute change in Medical Research Council (MRC) dyspnoea grade, 6-min walk distance (6MWD), cycle endurance time (constant work-rate test; CWRT), Canadian Occupational Performance Measure, Performance (COPM-P), Canadian Occupational Performance Measure, Satisfaction (COPM-S), Hospital Anxiety and Depression Scale, anxiety (HADS-A), Hospital Anxiety and Depression Scale, depression (HADS-D), and St. George's Respiratory Questionnaire total score (SGRQ-T). b) Left panel shows the proportion of clinically relevant outcomes (exceeding at least 1× minimally clinical important difference (MCID)). All other panels are the proportion of patients per outcome showing a clinically relevant improvement (exceeding at least 1× MCID). c) First panel shows the proportion of clinically relevant outcomes (exceeding at least 2× MCID). All other panels are the proportion of patients per outcome showing a clinically relevant improvement (exceeding at least 2× MCID).

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FIGURE 2

Proportion of outcomes which exceed the pre-defined minimal clinically important difference (MCID) at least a) once or b) twice, or c) have negative outcomes, in the very good, moderate and poor responders.

Cluster characteristics: whole sample

Table 3 summarises the baseline characteristics of the patients after stratification for the multidimensional response clusters. Age, the proportion of women, the degree of airflow limitation and the transfer factor for carbon monoxide were comparable between clusters. Patients in the very good responder cluster had significantly higher symptoms of dyspnoea, number of hospital admissions in the last 12 months, a worse exercise performance, worse performance and satisfaction scores for problematic activities of daily life, more symptoms of anxiety and depression, a worse health status, and a higher proportion of patients following an inpatient PR programme compared with the other three clusters. Moreover, patients from the very good responder cluster had a higher proportion of long-term oxygen therapy users, a higher body mass index and a higher fat-free mass index at baseline compared with the patients of the moderate responder and poor responder clusters.

Multidimensional response profiling, after stratification for sex and use of long-term oxygen therapy

The current sample consisted of 1012 male and 740 female COPD patients without long-term oxygen therapy, and 168 male and 148 female COPD patients with long-term oxygen therapy. These four subgroups were also divided up into four clusters with distinct multidimensional response profiles (see tables E2 to E5 and figures E1 to E4 in the online supplementary material for all details). The response to PR was best in the very good responder cluster on all outcome measures compared with the other clusters, irrespective of sex and the use of long-term oxygen therapy.

Cluster characteristics after stratification for sex and use of long-term oxygen therapy

Tables E6 to E9 in the online supplementary material summarise the baseline characteristics of the four clusters of each subgroup. In brief, in the male patients without long-term oxygen therapy (table E6), baseline scores for problematic activities of daily life, symptoms of anxiety and depression, and health status were significantly worse in the very good responder cluster compared to the other clusters. The degree of dyspnoea and the 6MWD was significantly worse in the patients of the very good responder cluster compared with the good responder or moderate responder clusters, but were comparable to values of the patients of the poor responder cluster.

In the female patients without long-term oxygen therapy (table E7), the patients in the very good response cluster had a significantly higher baseline degree of dyspnoea, and worse health status compared with the other three clusters. Moreover, baseline 6MWD was lower compared with moderate response and poor response clusters.

In the male patients with long-term oxygen therapy (table E8), the patients in the poor response cluster had a significantly lower body mass index and fat-free mass index compared with the other three clusters. Moreover, the patient in the very good response cluster had a significantly worse health status compared to the patients of the moderate response and poor response clusters.

In the female COPD patients with long-term oxygen therapy (table E9), baseline 6-min walk distance was significantly lower in the patients of the very good response cluster compared with the other three clusters. Moreover, the patients in the poor response cluster had a significantly better satisfaction scores for the problematic activities of daily life compared to the other three clusters.

Differential response to PR

Generally, PR is beneficial for adults with chronic respiratory disease, including COPD [1]. Nevertheless, the response to PR may vary considerably between patients with COPD [5, 8, 9, 14, 30, 31]. Moreover, individual patients respond differential on various types of outcome measures [8, 11]. The current results in a convenience sample of 2068 well-characterised patients with COPD corroborate these findings (figure 1). These findings emphasise that key performance measures to evaluate the efficacy of PR in patients with COPD have to be chosen very carefully and should focus on multiple domains. The choice for exercise performance and/or health status as key performance measure is too simple. Indeed, to better understand the response to PR in patients with COPD, non-linear statistics were needed. The unbiased approach to cluster patients based on their multidimensional response in a large sample of well-characterised patients with COPD is a major strength of the current analyses. Indeed, the use of Viscovery SOMs allows detailed insight in the differential responses to PR (figure 1). This is a true novelty of the current analyses.

Clinically relevant improvements

In the very good responder cluster, the minimal clinically relevant improvement was achieved in 85% of the outcomes at least once and, in 67% of the outcomes, at least twice (table 2; figure 1). These findings suggest that the patients with COPD in the very good responder cluster are truly benefiting from PR, on (almost) all domains. Moreover, patients in the other clusters also still achieved a clinically relevant improvement in 60% (good responder cluster), 30% (moderate responder cluster) and 11% of the outcomes (poor responder cluster) (table 2). These findings prove again the clinical value of PR in patients with COPD who are still symptomatic even though they did receive the optimal medical care before enrolment. The fact that patients in the poor response cluster still have some clinically relevant improvements in individual outcomes also confirms, that we have to be very careful in defining key outcome measures of PR.

Poor response to pulmonary rehabilitation

The poor response in a subgroup of patients with COPD (figure 2) may be surprising at first sight, as PR provides a comprehensive approach. Then again, the heterogeneity in pulmonary and extra-pulmonary features [32–34] is a clinical challenge to personalise PR programmes for patients with COPD. Consequently, not all patients with COPD are expected to benefit from PR [5, 8, 9, 14, 30, 31]. These are clinically relevant observations, as patients, members from their social circle, healthcare professionals, policy makers and payers have a clear interest in the cost-effectiveness of interventions related to the integrated care of patients with COPD. So, to provide true transparency to its main stakeholders, PR services need to give detailed insights in the efficacy of pulmonary rehabilitation on the individual outcome measures, as well as in a multidimensional outcome measure.

The poor response to rehabilitation in a subgroup of patients does not seem to be COPD-specific and/or rehabilitation-specific. Indeed, also subgroups of patients with chronic neurological diseases [35], chronic cardiac diseases [36], or chronic musculoskeletal diseases [37] respond poorly to specialised rehabilitative interventions. Moreover, response to pharmacological therapy [38, 39], ambulatory oxygen therapy [40], bronchoscopic interventions [41] and lung volume reduction surgery [42] is also poor in subgroups of patients with COPD. These findings emphasise the need for a personalised approach of patients with chronic conditions, and the awareness that a “one size fits all” approach will not result in optimal chronic disease management [43].

Response prediction

It was beyond the aim of the current study to predict response based on the baseline characteristics. Nevertheless, it seems difficult to predict at the start of the programme who will end up in which cluster, as only 22.2%, 6.5% or 2.8% of the baseline values differed significantly (p<0.01) between the poor responder cluster and the very good responder, good responder and moderate responder clusters, respectively (tables E6 to E9). The analyses do emphasise that sex, age and the degree of airflow limitation cannot be used to identify possible responders (or non-responders) to PR as these were comparable between response clusters. Moreover, the baseline mean Charlson comorbidity score was comparable between the response clusters (table 3). These findings suggest that self-reported comorbidities generally do not influence the multidimensional response to PR. Recently, Mesquita et al. [44] also showed that changes in exercise performance and health status were not affected by comorbidities that were based on objective measurements.

Methodological considerations

The PR programme at CIRO+ is executed according to the 2013 ATS/ERS Statement on Pulmonary Rehabilitation [1], and provided by a skilled and dedicated team. Nevertheless, individual programmes most probably varied between patients based on the results of the initial assessment [16]. Indeed, the key to success may, at least in part, be hidden in the actual content of the PR programme. Detailed information on the exact content of the individual programme is lacking in the current study. Therefore, the present results are hypothesis-generating rather than definitive. Interestingly, the proportion of outpatients increased while the multidimensional response to PR worsened, in particular in the patients without long-term oxygen therapy (tables E6 and E7). Whether and to what extent these differences are due to the PR setting (inpatient versus outpatient) and/or the frequency of the programme (5 days per week for 8 weeks versus 3 days per week for 8 weeks followed by 2 days per week for 8 weeks) remains to be determined in a randomised controlled trial.

The current multidimensional response profiling was based on eight outcome measures, including two types of functional exercise performance, health status, mood status, a situational measure of dyspnoea, and problematic activities of daily life, which were identified by healthcare professionals as essential [4]. Obviously, other PR outcome measures, such as physical activity, self-efficacy and disease-specific knowledge, may also be of interest for patients with COPD [1]. The current statistical approach allows the addition of other outcome measures to the multidimensional response profiling. Future, prospective studies need to apply their own multidimensional response profiling and, in turn, should try to corroborate the current cluster findings. Obviously, to enable concise statistical analyses at any point in time, the entire PR process (e.g., referral, baseline assessment, the rehabilitative interventions, short-term outcome assessment and follow up) must be managed and monitored by appropriate information and computer technology infrastructure. Indeed, it may even be a critical success factor for chronic disease management in general, and PR in particular.

To conclude, the current study is the first to profile the multidimensional response to PR using a non-parametric regression technique. The current approach allows us to cluster patients with COPD into groups, and, in turn, identify who benefits most or least from PR after completion of the programme. For the poor responders, we may need to redesign ongoing PR programmes. The current results are the next step in providing detailed insights in the performance metrics of PR in patients with COPD and the future optimisation of the impact of PR. Healthcare professionals and payers need to start realising that patients with COPD will respond differentially on the PR outcome measures that are regularly used [1]. Choosing only one or two outcomes as key performance indicators (e.g., exercise performance and health status) seems to ignore the clinical complexity of rehabilitating patients with COPD. The time has come to start using multidimensional outcome profiling to identify the right COPD patients for the right PR programme.