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AJRCCM Articles in Press. Published on 09-September-2016 as 10.1164/rccm.201603-0602OC

BENEFITS OF LONG-TERM PULMONARY REHABILITATION MAINTENANCE PROGRAM IN SEVERE COPD PATIENTS: 3 YEAR FOLLOW-UP Maria-Rosa Güell 1 , Pilar Cejudo 2 , Francisco Ortega 2 , M. Carmen Puy 1 , Gema Rodríguez-Trigo 3 , José Ignacio Pijoan 4,5,6 , Lorea Martinez- Indart 4 , Amaia Gorostiza 4 , Khaled Bdeir 7 , Bartolome Celli 8 , Juan B. Galdiz 4,9 .

1 Hospital de la Santa Creu I Sant Pau. Barcelona; 2 Hospital Virgen Rocío. Sevilla; IBIS (Instituto de Biomedicina de Sevilla; 3 Hospital Clínico San Carlos. Madrid 4 Hospital Universitario Cruces, Barakaldo-Biocruces Health Research Institute, 5 CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, 6 Spanish Clinical Research Network (SCReN), Madrid, 7 Hospital La Madalena. Castellón. 8 Pulmonary and Critical Care Medicine. Brigham and Women’s Hospital. Boston. USA. ; 9 CibeRes.

Clinical trials NCT01090999 Supported By FIS 2006 PI 060792 and SEPAR 2007

Corresponding Author: M R Güell, Departament de Pneumologia, Hospital de la Santa Creu i Sant Pau, C/Mas Casanova nº 90. 08041 Barcelona, Phone: 34 93 556 5972, FAX: 34 93 556 5601, Email: mguellr@santpau.cat

Running title: Long-term benefits of pulmonary rehabilitation.

Author Contributions: All authors played a role in the clinical investigation and writing of the manuscript. In addition: MRG was the principal investigator and contributed the original idea for the study. All authors, except BC collected the data; and JIP and LM-I performed data analysis and prepared it for presentation.

This article has an online data supplement, which is accessible from this issue’s table of content online at www.atsjournals.org

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AJRCCM Articles in Press. Published on 09-September-2016 as 10.1164/rccm.201603-0602OC

At a Glance Commentary

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Scientific knowledge on the subject: An intense program of pulmonary rehabilitation (PR) in patients with COPD, results in improvements in functional capacity, dyspnea, health related quality of life and health care resource utilization. After completion of the program, the benefits of PR tend to wane gradually over time. Without strong evidence, experts recommend that all patients completing pulmonary rehabilitation should be encouraged to continue to exercise beyond the end of the PR program. However, there are very few controlled trials testing the effects of a maintenance program on patient related outcomes.

What this study adds to the field: This 3 year multicenter, randomized trial that enrolled patients with moderate and severe COPD, provides evidence that a maintenance pulmonary rehabilitation program implemented after an initial conventional one, results in improvement in functional capacity and in the BODE index compared with usual care. This improvement was maintained over 24 months, but after the two years, there no longer was a beneficial effect. Only a limited number of patients reached the 3 years mark.

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AJRCCM Articles in Press. Published on 09-September-2016 as 10.1164/rccm.201603-0602OC

ABSTRACT

Introduction: In COPD, the benefits of Pulmonary Rehabilitation (PR) tend to wane over time. Whether maintenance techniques may help sustain the benefits achieved after completion of the initial PR program remains controversial. Objective: To determine whether a long-term (3-years) maintenance program after PR preserves the short-term effects on outcomes in patients with COPD. Method: This was a multi-center prospective randomized trial including 143 patients with moderate-severe COPD, with 3 years of PR maintenance following an 8-week outpatient PR program. Patients were randomized to: 1- maintenance intervention group (IG) and 2- standard monitoring program or control group (CG). The effects on BODE index, 6 minute walk distance (6MWT) and Health Related Quality of Life (HRQoL) were compared at 12, 24 and 36 months. Results: One hundred and thirty eight patients (96.5%) completed the 8-week program. At this time, all outcomes (BODE, 6MWT and HRQoL) showed clinically and statistically significant improvements (p≤ 0.001). During the follow-up period, the magnitude of change in 6MWT distance differed between IG and CG (p = 0.042), with a slight initial increase in the IG during the first year and smaller decline afterwards. The BODE index changes differed between baseline and measurements at month-24 (p=0.043). At 3 years, the adherence rate of IG patients was 66% and 17% for the CG group (p<0.001). Conclusions: This study shows a two-year beneficial effect of a program of rehabilitation maintenance on the BODE index and 6MWT when compared with a standard strategy. This effect vanishes after the second year of follow-up.

Key word: Pulmonary rehabilitation, COPD, maintenance technique, long-term benefits

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INTRODUCTION Pulmonary Rehabilitation (PR) has shown benefits in patients with Chronic Obstructive Pulmonary Disease (COPD) with high level of evidence and strength of recommendation in terms of exercise capacity, symptoms and Health-Related- Quality-of-Life (HRQoL) (1-4). These improvements vary depending on the length of the PR programs since longer duration PR programs (12 weeks) produce greater sustained benefits, in comparison with shorter ones (1-8). Several clinical trials have found that 6-12 week-long programs maintain benefits for about 12-18 months, without any specific maintenance technique (1-4). The benefits of PR tend to wane gradually over time, and continuation of supervised exercise training beyond initial pulmonary rehabilitation could protect the patient from a decline in exercise capacity (1). Experts recommend that all patients completing pulmonary rehabilitation should be encouraged to continue to exercise beyond the PR program (1-4). Indeed, strategies to preserve the benefits following PR investigated to date, seem to have only modest, if any, effect on long-term outcomes (1-3). Some studies have shown that the benefits of PR programs last no more than one year with a maintenance technique (9,10), whereas others demonstrate that maintenance techniques manage to extend the benefits of PR somewhat longer, whether using simple techniques (11,12), implementing the PR maintenance programs in the community (13,14) or implementing them at home (11,15). Therefore, the effectiveness of maintenance programs is currently a controversial issue (1-3) and the difference in results may arise from the different approaches regarding exercise type, level of supervision, education and physiotherapy strategies, psychological support, adjustment of medications, and mostly duration and frequency of the maintenance program (2,3). Other factors include patient adherence to the program (16, 17), severity of the disease (18), co- morbidities (19) or ease of access to exercise (20). We hypothesized that in patients with moderate-severe COPD, a well supervised maintenance program after PR would be beneficial in maintaining the improvement in symptoms, exercise capacity and HRQoL compared with a minimal standard monitoring program. To test this hypothesis we conducted a three year multicenter randomized trial of supervised maintenance versus standard care, after intensive rehabilitation, in patients with moderate-severe COPD. Some of the results

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AJRCCM Articles in Press. Published on 09-September-2016 as 10.1164/rccm.201603-0602OC

of this study have been previously reported in the form of abstracts in international congresses (21, 22).

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MATERIAL AND METHODS

Study design

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This is a Spanish multi-center (Hospital de la Santa Creu I Sant Pau. Barcelona; Hospital Virgen Rocio. Sevilla; Hospital Clínico San Carlos. Madrid; Hospital Universitario Cruces. Barakaldo; Hospital La Madalena. Castellon.), prospective randomized controlled trial, with a scheduled 3-year follow-up period after PR. Patients with moderate-severe COPD were enrolled consecutively from the COPD clinics. Inclusion criteria were: 1) having a diagnosis of COPD according to the international guidelines (23), with spirometric grade II-IV severity, and 2) being clinically stable during the previous four weeks (details are provided in the online supplement). The study was conducted between October 2006 and December 2012 and was approved by the Institutional Review Board at all participating hospitals. All patients signed the informed consent.

Recruited patients attended an initial 8-week outpatient PR program conducted in the hospital setting. Following completion of this program patients were allocated at random to one of the two following strategies: 1.- Maintenance pulmonary rehabilitation program (intervention group or IG) or 2.- Standard, current practice control monitoring program (control group or CG). Randomization was computerized and performed by an independent statistician (see the online supplement). Technicians blinded to the patients’ allocation group conducted testing and the questionnaire administration at recruitment stage (month -2), at the end of the PR program (month 0), and over the follow-up period, at 12, 24 and 36 months.

Pulmonary Rehabilitation Program Intensive program Eight-week hospital-based outpatient program, for two hours, three times weekly, including: four education sessions. Chest physiotherapy. The exercise program consisted of 30-minutes weight-lifting sessions, starting with 1/2 kg in each hand and progressively increasing by 1 Kg every week until peak tolerance, and 30- minutes of leg cycle ergometry starting at 50% of the maximal load achieved during

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AJRCCM Articles in Press. Published on 09-September-2016 as 10.1164/rccm.201603-0602OC

an exercise test. The load was progressively increased by 10 watts if the patient's heart rate (HR), SpO2 were stable and the exercise was well tolerated. The sessions ended with relaxation techniques.

Maintenance program During the three years of the maintenance program, patients in IG were asked to continue at home with a similar program to that completed in the hospital including 15 minutes of chest physiotherapy, 30 minutes of arm training and 30 minutes of leg training (at least 3 days weekly).The cycle ergometers were provided by the team while the patients bought the weights.

During the 3 years, the physiotherapist called the IG patients every 15 days using a standardized protocol that included questions about health status, compliance with medications and exercise. During the alternate week, the patient attended the hospital for a supervised training session that reviewed similar questions as well as the exercise protocol performed at home. If the exercise was well tolerated, the home training was increased to one guided by the patient’s dyspnea, SpO2 and HR.

Patients in the CG group were advised to maintain the exercise at home, without any supervision, and they only visited the hospital for evaluations. We did not provide them with the cycle ergometers, but we advised them to walk at least 1 hour or buy a cycle ergometer.

Adherence To monitor adherence at home in both groups, we quantified the activity on a self-reported card registered by the patients, and the attendance to the scheduled visits with physician over the 3-years of follow-up.

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Moreover, in the IG patients we quantified adherence using the number of responses to the phone calls placed every 15 days by the physiotherapist as well as the attendance to the supervised training sessions. An IG patient was classified as compliant if he/she completed at least 75% of the scheduled training sessions, phone calls, and scheduled visits with the physician. In the CG, adherence was assessed during the clinical interview by quantifying the frequency and intensity of accomplished exercises (walking or cycling and weight lifting) at each scheduled visit with the physician. A patient was deemed to be adherent if he/she attended at least 75% of planned visits and reported completing at least 75% of the recommended levels of exercise.

Outcome measures Description of the methods used for lung function testing, BODE index (24, 25), six minute walking test (6MWT) (26, 27), and HRQoL ─SF-36 (28) and CRQ (29- 30) ─ assessments is provided in the online supplement.

Statistical analysis Descriptive statistics are provided in the online supplement. Changes in outcome measures over the intensive PR period were assessed by the use of paired t-tests. We applied linear mixed-effects models to estimate and contrast mean change differences between control and intervention groups for all continuous outcomes in the planned follow-up visits periods (0, 12, 24, 36 months). No imputation was done for missing values. A sample size of 75 patients per arm was estimated (see online supplement). Analyses were performed using SAS v9.4 and R v3.2.3 statistical software.

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AJRCCM Articles in Press. Published on 09-September-2016 as 10.1164/rccm.201603-0602OC

RESULTS

Patient characteristics and intensive program

The baseline characteristics of the 143 patients recruited are shown in Table I. One hundred and thirty eight patients (96.5%) completed the 8-week outpatient program. Five patients dropped out: one needed abdominal surgery, a second refused to continue, the third accepted lung-transplantation and 2 patients died because of COPD exacerbation.

At the end of this intensive rehabilitation program, all outcome measures showed statistically highly significant improvements (p≤ 0.001). Mean BODE index decreased 0.8 points (95% confidence interval 0.6-1.0) and mean 6MWT increased 34.0 meters (24.2-43.8); SF-36 physical and mental dimensions improved on average 3.6 points (1.5-5.8) and 4.6 points (2.1-7.1) respectively. Finally, mean scores of all CRQ components improved between 0.4 and 0.6 points with 95% confidence intervals ranging from 0.2 to 0.7. A post hoc analysis showed that the magnitude of changes in each of the outcomes was similar in those subsequently randomized to the IG and the CG group.

Effect of Maintenance program Patients that successfully completed the outpatient hospital-based rehabilitation phase were randomly allocated to the two alternative programs IG or CG. Both groups had similar baseline characteristics (Table II). The dropout rate over the study time was also similar in both groups: 34 patients in the IG group and 39 in the CG group. For both groups, 15/20 dropped out in the first year, 10/11 between the one-year and 2-year visits and 9/8 in the third year of follow-up.

The flow-chart diagram of the patients recruited is shown in Figure 1. The most important reasons for withdrawal were: 38 patients refused to continue the assigned program, 20 patients had clinical worsening (hospitalizations, need of oxygen therapy and difficulties to complete exercise because of dyspnea) and 15 patients died: 8 from respiratory failure; 2 from pneumonia; 2 due to cardiac failure, one from lung cancer, one for bowel disease and one from cerebral hemorrhage.

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AJRCCM Articles in Press. Published on 09-September-2016 as 10.1164/rccm.201603-0602OC

We sought

for

potential associations

between clinical

and

demographic

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characteristics at baseline, in the full study cohort and the 3-year dropout risk.

Patients who did not finish the program, had lower exercise tolerance measured by the 6MWT (393± 93 meters for drop-outs vs 436 ± 103 meters for full compliers; p=0.015) and had worse self-perceived dyspnea measured by the CRQ questionnaire (4.5 ± 1.3 vs 5.0 ± 1.3; p=0.042).

Main outcome data and differences between both groups over the 3-year study period are shown in Table III. There was a statistically significant difference in BODE index changes between baseline values and measurements at month-24 (p=0.043) in favor of IG (Fig. 2). There also were significant differences in the slopes of change over time of the 6MWT between the two groups (p=0.042 for group-time interaction) with differences favoring IG and diminishing as the time span analyzed increased (Fig 3). Regarding HRQoL scores, there was statistically significant impairment of perceived health over the study time for all SF-36 and CRQ dimensions except the physical dimension of SF-36 (Table III). However, there were no statistical significant differences between groups.

No patient reported adverse effects related to the home-based exercise training.

Adherence The adherence rate of IG patients was 66% (42 patients of 64 with accurate information on follow-up).There were 4 additional patients with no accurate information on level of exercise. Patients in the CG had 17% of adherence rate (8 patients of 46 with accurate information on follow-up). There were 24 additional patients with no accurate information on level of exercise during the follow-up period. The differences in adherence rate between groups were statistically significant

(p<0.001).

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AJRCCM Articles in Press. Published on 09-September-2016 as 10.1164/rccm.201603-0602OC

DISCUSSION This study showed that patients with moderate to severe COPD who were randomly assigned to a supervised maintenance program of exercise after completing 8 weeks of intense pulmonary rehabilitation, preserved the benefits obtained with the PR intensive program as measured by the BODE index and 6 MWT over at least 2 years. This pattern was not observed in patients randomized to usual post-rehabilitation clinical care.

Efficacy of maintenance pulmonary rehabilitation program In this study, the results obtained during the initial intensive phase of pulmonary rehabilitation are in agreement with previous studies that showed improvements in HRQoL and exercise capacity that were not only statistically significant, but also clinically relevant (1-3). However, during the maintenance period only the IG maintained the improvements achieved in the BODE index, the 6MWT and some areas of HRQoL during the first two years of follow-up. It is difficult to compare these results with those of other randomized trials in the literature, because the longest reported follow-up after PR program has been two years (10, 12, 14). Only Foglio et al (31) in an observational study, followed patients for 7 years while performing an intense maintenance technique, as represented by a yearly 8-week hospital based pulmonary rehabilitation program. In that study, the benefits peaked and persisted for the next 6 months following the intensive program and started to decline after the third year, as was the case in our study, but required a more intense maintenance program. Using a simple technique, our program was able to maintain the benefits continuously for two years, suggesting that an intense yearly program may not be needed. In a previous study by our group, only a third of the outpatients enrolled in an intensive PR program obtained benefits in terms of HRQoL and exercise capacity (12). These benefits were maintained for 2 years with a simple, inexpensive maintenance technique but with a longer initial intensive program than the one applied in the present study (6 months vs 2 months). In a recent systematic review (32) which includes 619 patients from 7 randomized trials comparing usual care vs. post rehabilitation supervised exercise programs, the authors concluded that a

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maintenance technique is effective for preserving PR benefits, only in exercise capacity (measured by 6MWT) but not in HRQoL, at 6 months, but not at 12 months. The results here provided suggest otherwise. Indeed, a simple maintenance technique, as here applied, appears to extend the benefits obtained after the intensive phase over a longer period of time in comparison with other studies (33-36). Although our results are partly in agreement with previous reports describing the effect of maintenance rehabilitation programmes, we ought to be cautious because only a few interactions effects achieved significant value for some outcomes and the levels of statistical significance were very close to the predefined limits. Thus, the observed difference in estimated effects may have been due, at least in part, to some baseline differences among the randomized groups or to the fact that we simultaneously conducted multiple mixed regression models which increases the likelihood of type I error.

A closer look at the available data suggests that the duration of the intensive program impacts positively on the way that longer programs maintain the benefits achieved (1, 12). However, the intensity of exercise or the duration of the maintenance program may not influence long-term results. Accordingly, Foglio et al (35) and Troosters et al (5), with a very intensive maintenance program, reached similar benefits to those who applied more simple techniques, like the one here described and that of other trials (12, 14, 37-39) .

Adherence In our study, adherence over a 3-year follow up period was higher in IG compared with usual care. Overall, the low adherence for program completion was related to higher MRC dyspnea rate and lower exercise capacity at baseline, which is in agreement with other trials of shorter duration (1-3, 33). Based on published literature, alternative strategies not evaluated in this study, such as ambulatory program (8, 12, 13), community based PR (14, 36, 37) or even home programs (11, 15, 38) may be more effective in maintaining adherence than hospital-based PR. Emerging interventions that tap into technological advances such as the telemedicine based programs could probably be effective, however we started this trial on 2006 and this technology was not yet available in our environment. The very high adherence rate in 5 different hospitals suggests that this simplified program is well

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accepted by the patients participating in it. Probably, the experience of the team, the continuous health team support and the weekly controls (alternating phone contacts and supervised training sessions), a strong family and social support, as well as the ease of the program access are factors that can explain this excellent adherence, as Pitta et al have suggested (38). Perhaps, as the international guides highlight (2-4), the key to maintain benefits is to reach real change in life habits and to promote physical activity in patients after they finish a PR program (40).

Dropout In our study, the dropout rate in the intensive period was lower (<4%) than in other trials (1-4). According to published findings (32), some of the factors that impede people’s attendance to intensive outpatient PR programs include travel and transport barriers, lack of perceived benefits, or depression. One likely reason for the low dropout rate in the current trial along the intensive PR program relates to the demographic characteristics of our cities, which limit any transport or home barriers for the majority of patients. Only 5 patients abandoned in this period, and the reason was primarily medical; one needed abdominal surgery, a second accepted lung- transplantation, 2 patients died because of COPD exacerbation and only one refused to continue in the study In contrast, over 50% of the patients recruited into the study failed to reach the pre-specified 3 years of maintenance and follow-up goal. Studies analyzing long-term dropout are scarce. After one year of follow-up, a dropout rate between 10% and 40% has been described (5, 13, 32), and after two years, around 22% (11, 12). To our knowledge, there are no randomized controlled studies following patients more than 2 years after PR program, with or without the use of maintenance techniques. Only Foglio et al (31) reported a longer follow up, with a 74% dropout rate at 7 years, but the study was an observational trial of patients with less severe disease than those recruited into our trial (mean FEV 1 35% vs 58%). In the current study, many patients abandoned pulmonary rehabilitation because exacerbations of COPD, comorbidities, or death, while only a few patients abandoned because of difficulties related to the program itself. Soicher et al (20) pointed out that patients with low activity over time were characterized by having more severe disease and greater respiratory impairment. Moreover, in a recent study

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by Hogg et al (33) analyzing the attendance and completion of an 8-week PR program involving hospital and community sites, it was observed that patients with higher MRC dyspnea scores had a greater risk of abandoning the program. These results are in agreement with ours, since patients who did not finish the 3-year program had lower exercise capacity and worse dyspnea at baseline. Interestingly, Spruit et al (34) have suggested that good responders to PR are those patients with more symptoms and lower exercise capacity. However, the follow-up time of that study was shorter than here reported and this may have a beneficial impact on the dropout rate. It seems that the severity of disease, the magnitude of dyspnea and limited exercise capacity may impact the short-and long-term outcomes differentially; whereby more impaired patients may reach greater benefits during the intensive treatment, but they may have more difficulties to maintain the benefits over time. Therefore, our results suggest that there is an important proportion of COPD patients that may not be a realistic target for long-term home-based rehabilitation programs because of the severity of their underlying pulmonary problems and/or comorbidities.

Limitations of the study The main limitation of our study is the analysis of at-home compliance with the program. In the control group, the assessment relied on patients´ self-report of compliance with the exercises, mimicking the information obtained in current clinical practice. In the intervention group, there was a more formal recording procedure that was however completed by the patient. We can only guarantee the session attendance adherence and have to rely on the information provided by the individual at regular phone calls and study visits. However important, adherence was not the objective of the study. Another limitation was the severity of our patients, which may have limited their continuation in the program because they became severely ill over the follow-up period. However, they represent patients commonly referred for rehabilitation and the results of treatment on this population can be most informative. In addition, this study involved primarily men, so the conclusions cannot be fully extrapolated to women, who may be more compliant and likely to live longer. The observed gender differences in recruitment were not by design but reflect the gender distribution of COPD in Spain. Studies of women with COPD are badly needed.

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Finally, the psychosocial morbidity probably impacts heavily on program adherence thus influencing the results. Unfortunately we did not analyze this important aspect of a patient’s substrate.

SUMMARY Our study demonstrates that in patients with moderate-severe COPD, a weekly maintenance program is modestly effective to extend benefits in the BODE index, 6MWT and health status for up to 2 years after an intensive rehabilitation program. In this population the dropout rate is high during three years of follow-up, primarily in those patients with more severe disease. Because of the variability of available resources and the unknown impact of local cultural and social factors, the results of this maintenance program may not be broadly applicable in all health systems.

Acknowledgements The authors would like to acknowledge the following personnel for their work: Mercè Sangenis, Gina Mateu ,Adriana Castanyer, Lluis Paz, Amaia Gorostiza, Monica Regueiro, Rosa Vázquez Sanchez and Francisco Garcia Perez for their daily work with COPD patients implementing the exercise training program and its follow-up. We would also like to thank Elena Lopez de Santamaria, Fatima Morante and Anna Mola for their assistance in data collection.

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21.- Gema Rodriguez-Trigo, Pilar Cejudo, Carme Puy, Juan Bautista Galdiz, Khaled

Bdeir, Amaia Gorostiza, Rosa Vázquez Sanchez, Elena Lopez de Santamaria, Lorea

Martinez-Indart, Fatima Morante, Monica Regueiro, Gomez Luis, Ortega Francisco,Rosa Güell. Long term pulmonary rehabilitation programs for chronic obstructive pulmonary disease (COPD). Two years follow-up. Eur Respir J 2011, 38 (Suppl 55) p 3645

22.- Pilar Cejudo, Batxi Galdiz, Carme Puy, Lorea Martinez Indart, Francisco Ortega, Rosa Vázquez-Sánchez, Gema Rodriguez Trigo, Khaled Bdeir, Fátima Morante, Elena Lopez Santarmaría, Mónica Regueiro, Rosa Güell. Outcomes Evaluation of a Maintenance 3-Year Follow.Up Pulmonary Rehabilitation Program. (Paper presented

at the annual ATS Congress San Diego. May 16-21,

Abstracts.A3645)

23.-Vestbo J, Hurd S, Agustí A, Jones P, Vogelmeier C, Anzueto A , Barnes PJ, Fabbri LM, Martinez FJ, Nishimura M, Stockley RA, Sin DD, Rodriguez-Roisin R. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2013;187(4):347-365. 24.- Celli BR., Cote Claudia G., Marin JM., Casanova C., Montes de Oca M., Mendez R., Pinto Plata V., Cabral Howard J. The Body-Mass Index, Airflow Obstruction Dyspnea, and Exercise Capacity Index in Chronic Obstructive Pulmonary Disease. N Engl J Med 2004; 350: 1005-12. 25.- Martinez FJ, Han MK, Andrei AC, Wise R, Murray S, Curtis JL, Sternberg A, Criner G, Gay SE, Reilly J, Make B, Ries AL, Sciurba F, Weinmann G, Mosenifar Z,

Copyright © 2016 by the American Thoracic Society

Page 19 of 33

AJRCCM Articles in Press. Published on 09-September-2016 as 10.1164/rccm.201603-0602OC

DeCamp M, Fishman AP, Celli BR; National Emphysema Treatment Trial Research Group. Longitudinal Change in the BODE Index Predicts Mortality in Severe Emphysema Am J respir Crit Care Med 2008;178:491-499. 26.-ATS statement: Guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166: 111-117 27.- Puhan MA., Chandra D., Mosenifar Z., Riese A., Make B., Hansel NN., Wise RA., Sciurba F. For the National Emphysema Treatment Trial (NETT) Research Group. The minimal important difference of exercise tests in severe COPD. Eur Respir J 2011; 37: 784–790 28- Alonso J, Prieto L, Anto JM. The Spanish version of the SF-36 Health Survey (the SF-36 health questionnaire): an instrument for measuring clinical results. Med Clin (Barc) 1995; 104:771–776 29- Güell R, P.Casan, M.Sangenis, F. Morante, J. Belda, GH Guyatt . Quality of life in patients with chronic respiratory disease: the Spanish version of the Chronic Respiratory Questionnaire (CRQ). Eur. Respir. J. 1998;11: 55-60. 30.- Redelmeier DA, Bayoumi AM, Goldstein RS, Guyatt GH. Assessment of the minimal important differences in symptom: a comparison of two techniques. J Clin Epidemiol 1996; 49:1215-1219. 31.- Foglio, K., Bianchi, L., Bruletti, G., Porta, R., Vitacca, M., Balbi, B., & Ambrosino N. Seven-year time course of lung function, symptoms, health-related quality of life, and exercise tolerance in COPD patients undergoing pulmonary rehabilitation programs. Respiratory medicine, 2007;101(9): 1961-70. 32- Keating A., Lee A., Holland AE. What prevents people with chronic obstructive pulmonary disease from attending pulmonary rehabilitation? A systematic review. Chronic respiratory disease 2011; 8 (2): 89-99 33.- Hogg L., Garrod R., Thomton H., MacDonnell L., Bellas H., White P. Effectiveness, attendance and completion of an Integrated, System-Wide Pulmonary Rehabilitation Service for COPD: Prospective observational study. COPD 2012; 9:

546-554.

34.- Spruit MA., Augustin IML., Vanfleteren LE., Janssen DJA., Gaffron S., Pennings H-J., Smeenk F, Pieters W., van der Bergh JAM., Michels A-J., Groenen MTJ.,Rutten E, Wouters E., Franssen . Differential response to pulmonary rehabilitation in COPD: multidimensional profiling. Eur Respir J 2015; 46: 1538–1540.

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35.- Foglio K. Is It Really Useful To Repeat Outpatient Pulmonary Rehabilitation Programs in Patients With Chronic Airway Obstruction? A 2-year controlled study. Chest. 2001;119(6):1696. 36.-Steele B, Belza B, Cain K, Coppersmith J, Lakshminarayan S, Howard J., Haselkorn JK. A Randomized Clinical Trial of an Activity and Exercise Adherence Intervention in Chronic Pulmonary Disease. Archives of Physical Medicine and Rehabilitation. 2008;89(3):404-412.

37.- Pleguezuelos E, Pérez M, Guirao L, Samitier B, Ortega P, Vila X,. Solans M.,

Riera A.,Moreno E., Merı A., Miravitlles M

with COPD with urban walking circuits. Respiratory Medicine. 2013;107(12):1948-

Improving physical activity in patients

1956.

Page 20 of 33

38.-Resqueti V, Gorostiza A, Gáldiz J, De Santa María E, Casan P, Güell-Rous R. Beneficios de un programa de rehabilitación respiratoria domiciliaria en pacientes con EPOC grave. Archivos de Bronconeumol. 2007;43(11):599-604. 39.- Liu, W.-T., Wang, C.-H., Lin, H.-C., Lin, S.-M., Lee, K.-Y., Lo, Y.-L., Kuo, H.-P. Efficacy of a cell phone-based exercise programme for COPD. European Respiratory Journal, 2008; 32(3): 651–659. 40.- Pitta F., Troosters T., Spruit M., Probst V., Decramer M., Gosselink R. Characteristics of Physical Activities in Daily Life in Chronic Obstructive Pulmonary disease. Am J Respir Crit Care Med. 2005; 171 (9): 972-977.

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Eligible COPD patients N=143 Intensive PR for 8 weeks Randomised =138
Eligible COPD patients N=143
Intensive PR
for 8 weeks
Randomised =138

Follow up

Intervention group

n=68

8 weeks Randomised =138 Follow up Intervention group n=68 Withdrawal n=11 Clinical worsening n=3 Death n=1

Withdrawal n=11 Clinical worsening n=3 Death n=1

12-months

n=53

Withdrawal n=7 Clinical worsening n=0 Death n=3

24-months

n=43

Withdrawal n=3 Clinical worsening n=4 Death n=2

36-months

n=34

Control group

 

n=70

Withdrawal n=8 Clinical worsening n=8 Death n=4

Withdrawal n=8 Clinical worsening n=8 Death n=4

12-months

 

n=50

Withdrawal n=4 Clinical worsening n=4 Death n=3

24-months

 

n=39

Withdrawal n=5 Clinical worsening n=1 Death n=2

36-months

n=31

FIGURE 1. Consort flow diagram. COPD: chronic obstructive pulmonary disease; PR:

pulmonary rehabilitation

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Page 22 of 33

as 10.1164/rccm.201603-0602OC Page 22 of 33 Fig 2 Patterns of change of BODE over study follow-up.

Fig 2

Patterns of change of BODE over study follow-up. Data shown are mean values with error bars representing standard errors. Month 0: baseline following the completion of in-hospital pulmonary rehabilitation.

: control group CG; ●: intervention group IG; *:significant difference in

mean changes from month 0 to month 24 between groups (p=0.043).

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AJRCCM Articles in Press. Published on 09-September-2016 as 10.1164/rccm.201603-0602OC

Published on 09-September-2016 as 10.1164/rccm.201603-0602OC Fig 3 Patterns of change of 6m walking test (6MWT) over

Fig 3

Patterns of change of 6m walking test (6MWT) over study follow-up. Data shown are mean values with error bars representing standard errors. Month 0: baseline following the completion of in-hospital pulmonary rehabilitation.

: control group CG; ●: intervention group IC; *:significant difference

in mean changes from month 0 to month 12 between groups (p=0.004); ◊:significant difference in mean changes from month 0 to month 24 between groups (p=0.046).

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Subjects n

143

M/F n

127/16

Age (years)

64 ± 9

BMI

27 ± 5

FEV 1 /FVC %

39 ±1 0

FVC %

66 ± 18

FEV 1 %

34 ± 10

6MWT

375 ± 104

PaO 2

69 ± 10

PaCO 2

42 ± 6

BODE

4.8 ±1.8

Table 1. Subject characteristics at recruitment (month -2):

M: male; F: female; BMI: body mass index; FVC: forced vital capacity. FEV 1 : forced expiratory volume in the first second. 6MWT: distance in the 6 minute walking test (meters) PaO 2 : Partial pressure of arterial oxygen (mmHG) PaCO 2 ; Partial pressure of arterial carbon dioxide (mmHG). BODE: Bode index. Values are mean ± Standard deviations unless otherwise specified.

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Page 25 of 33

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Month -2

Month 0 (baseline)

 

IG

IG

CG

 

(Intervention

group)

CG (Control

group)

p-value

(Intervention

group)

p-value*

(Control

group)

p-value*

p-value**

Subjects n

68

70

 

M/F n

59/9

64/6

0.379

 

Age(years)

64 ± 9

64 ± 8

0.822

 

BMI

27 ± 5

28 ± 5

0.699

27±5

0.969

28±5

0.566

0.688

FVC %

66 ± 19

66± 16

0.921

67±21

0.424

69±21

0.121

0.572

FEV 1 /FVC

40± 10

39± 10

0.646

46± 13

0.006

46± 16

0.027

0.934

%

FEV 1 %

34 ± 11

34± 9

0.932

36± 10

0.023

37± 11

0.055

0.940

PaO 2

70 ± 9

69 ± 10

0.573

68±12

0.346

68±12

0.896

0.587

PaCO 2

41 ± 6

43 ± 7

0.183

42±7

0.806

43±7

0.358

0.654

Table II. Clinical, demographic and functional variables at months -2 and 0 by group for patients randomized at month 0 (trial baseline)

p-value: comparison of values between groups at recruitment (month -2) (unpaired t-tests) p-value*: comparison of values between month -2 and month 0 for each group (paired t-tests) p-value**: comparison of changes [month -2 to month 0] between groups (unpaired t-tests)

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Page 26 of 33

   

month 0

 

change month 12-month 0

change month 24-month 0

change month 36-month 0

 

Outcome

IG

CG

p

IG

CG

p

IG

CG

p

IG

CG

p

Time e

Group*

measure

(n=68)

(n=70)

value a

(n=53)

(n=50)

value b

(n=43)

(n=39)

value c

(n=34)

(n=31)

value d

Time f

6MWT

405 ± 111

423

± 88

0.287

-2.9

-39.3

0.004

-23.3

-48.8

0.046

-32.2

-51.7

0.119

<0.001

0.042

BODE

4.0

± 1.6

3.7

± 1.4

0.408

+0.0

+0.3

0.344

+0.3

+0.8

0.043

+0.3

+0.5

0.181

<0.001

0.228

Sf36f

42

± 15

43

± 18

0.732

-1.2

-2.3

0.613

-3.8

-2.7

0.783

-0.7

-1.4

0.719

0.142

0.787

Sf36m

57

± 18

56 ± 2

0.708

-3.0

-1.2

0.312

-6.5

-3.6

0.203

-1.2

-3.0

0.244

0.001

0.478

CRQ

4.8

± 1.3

4.8

± 1.4

0.921

-0.4

-0.3

0.468

-0.4

-0.6

0.617

-0.3

-0.7

0.287

0.003

0.294

Dyspnea

   

CRQ fatigue

4.7

± 1.4

4.6

± 1.4

0.529

-0.3

-0.2

0.481

-0.6

-0.4

0.380

-0.6

-0.2

0.193

<0.001

0.610

CRQ

                           

emotional

5.2

± 1.3

5.0

± 1.4

0.624

-0.4

-0.4

0.967

-0.5

-0.4

0.734

-0.6

-0.3

0.274

<0.001

0.690

factor

   

CRQ mastery

5.3

± 1.5

5.0

± 1.5

0.244

-0.3

-0.3

0.653

-0.6

-0.1

0.100

-0.4

-0.3

0.894

0.023

0.204

Table III: Full available data analysis of time changes in outcome variables over the 3-year follow-up period (linear mixed models). Values shown at month 0 are means ± standard deviations. Changes shown between visits are mean changes with respect to month 0 (baseline) values

IG: intervention group; CG: Control group. 6MWT: distance in the 6 minute walking test (meters); SF36f: physical dimension of the short form 36; SF36m: mental dimension of the short form 36; CRQ: Chronic

respiratory questionnaire

a p-values for the comparison of outcome variables between groups at month 0. b p-values for the comparison of mean changes of outcome variables from month 0 to month 12 between groups. c p-values for the comparison of mean changes of outcome variables from month 0 to month 24 between groups. d p-values for the comparison of mean changes of outcome variables from month 0 to month 36 between groups. e p-values for tests of time effects (within-group changes over follow-up time). f p-values for tests of time by group interaction (assessment of differences in time change patterns between groups).

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ONLINE DATA SUPPLEMENT

BENEFITS OF LONG-TERMPULMONARY REHABILITATION MAINTENANCE PROGRAM IN

SEVERE COPD PATIENTS: 3 YEARS FOLLOW-UP

Authors: Güell MR., Cejudo P., Ortega F., Puy MC., Rodriguez-Trigo G., Pijoan JI., Martinez-Indart L., Gorostiza A Bdeir K, Celli B., Galdiz JB.

1

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METHODS

Page 28 of 33

Study participants The inclusion criteria were: a diagnosis of COPD, according to the GOLD guidelines (1) with spirometric grade II-IV severity, between 18 and 75 years old ; ex-smokers or with intention to quit; BODE index value (2) between 3-10, and no acute exacerbation during the last four weeks prior to enrollment. We excluded COPD patients showing a bronchodilator response (FEV 1 increment >15% of the baseline value after 200 mcg of inhaled bronchodilator), a clinical diagnosis of respiratory disease other than COPD, severe coronary artery disease, orthopedic diseases seriously limiting mobility, life expectancy lower than 2 years, or inability to co-operate.

The medical treatment for all patients was conducted by the primary care physician and was not changed in the program. Exacerbations were treated following usual clinical practice by the patient’s medical team in both groups.

PR program and randomization.

All patients attended an initial 8-week outpatient PR program (intensive program). Following completion of this program patients were allocated at random to one of the two maintenance strategies: 1.- a supervised maintenance pulmonary rehabilitation program (intervention group- IG) or 2.- a standard control minimal monitoring program (control group-CG). Randomization was implemented through the generation of a computer-based random allocation list, stratified by center, with a 1:1 allocation ratio, that used permuted blocks of varying size to maximize balance in sample size between groups.

Technicians

blinded

to

the

patients’

allocation

group

conducted

testing

and

questionnaire administration at baseline, at the end of the intensive PR program, and over

the follow-up period.

Intensive program

Patients attended an 8-week hospital-based outpatient program, for two hours, three times weekly. Components were: 1.- Four sessions of education, targeted to the patient and family, including basic knowledge of pulmonary disease, alarm signs,

2

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instruction in medication management and energy saving. 2.- Chest physiotherapy

consisted of 30 minutes sessions of breathing retraining, and, if indicated, postural

drainage; 3.- exercise program with: a). arm training consisting of a 30-minute weight-

lifting session, starting with 1/2 kg in each hand, and progressively increasing by 1 Kg

every week until peak tolerance; b). lower extremity training consisted of a 30-minute

session of pedaling on a cycle ergometer. To determine the level of effort to be established

for training, the patients performed a symptom-limited progressive cycle ergometer

exercise test. Exercise started with a work load equivalent to 50% of the maximal load

(Wmax) achieved during the baseline progressive exercise test. The load increased by

increments of 10 watts provided the patient's heart rate (HR) (+/- 10 beats/minute), SpO2

(+/- 2%) and blood pressure were stable and exercise was well tolerated. The sessions

ended with relaxation techniques.

Maintenance period

Patients on IG group were asked to continue at home with a program similar to that

conducted at the hospital including 15 minutes of chest physiotherapy, 30 minutes of arm

training with weight-lifting and 30 minutes of leg training with cycle ergometer (at least 3

days a week).

During this period, the physiotherapist called the IG patients every 15 days, and

patients attended the hospital for a training session, every 15 days alternatively (the

patients had weekly contact with either a phone call or a hospital visit). The calls were

standardized and the staff reviewed the clinical situation and use of medications and

checked if the patient performed the home exercises properly.

On the alternate week, the patient attended the hospital for a supervised training

session. First, the physiotherapist interviewed the patient regarding his/her clinical

situation, the use of medications as well as the exercise performed at home with special

emphasis on the intensity and duration of the protocol. Then the patient started a 30-

minute leg exercise test with the same work load that had been reached in the previous

session. If patient maintained a stable HR (+/- 10 beats/minute) and SpO 2 (+/- 2%) and if

they tolerated the work level in terms of dyspnea and fatigue, the physiotherapist

increased the load by 10 watts until the next hospital control visit when the process was

3

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Page 30 of 33

repeated. Finally, patients did the 30-minute weight-lifting session starting at the same level than the last hospital-based session and if they maintain stable HR, SpO 2 and adequate clinical tolerance in terms of dyspnea, the physiotherapist increased the load by half a Kg in each arm. The patient never increased the load of any of the exercises at home without supervision by the physiotherapist. Only 5 patients needed oxygen support during exercise sessions and this was done when oxygen saturation dropped below 88% during the training. The cycle ergometers were provided by the team. Patients bought the weights. The maintenance program lasted for the duration of the 3–years follow-up.

The physiotherapist was made aware of any exacerbation by a call or directed a call

during these events. After the exacerbation, the IG patient was then called periodically

until the patients improved to the point where they felt they could return to the exercise

program and came to the hospital for an evaluation. Also, at this point, the patients had a

choice of abandoning the program if they felt they could no longer continue. For those

patients in the program, no changes were made to the medications, once adjusted by their

physicians. After an exacerbation, some patients needed to start the exercise program at a

lower intensity than previously achieved and the exercise intensity was slowly increased

until the previous level of fitness was reached.

Patients in the CG group were advised to maintain the exercises at home, without

any supervision, and they only visited the hospital for evaluations. We did not provide them

with the cycle ergometers, but we advised them to walk at least 1 hour or buy a cycle

ergometer.

Outcome measures

4

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BODE Index

The BODE Index is a multidimensional scale in which higher scores indicate a higher risk of death. The index includes: body-mass index (B), the degree of airflow obstruction (O) dyspnea measured by the MRC scale (D), and exercise capacity (E) as assessed by the six-minute-walk test (6MWT). It is graded on 10 points, 10 representing the worse clinical situation and 1 the best one (2, 3).

Exercise capacity

A 6MWT was conducted according to the ATS statement (4). An improvement after training equal to or greater than 26 meters was considered clinically important (5).

Health-Related-Quality of Life (HRQoL).

To assess HRQoL, we used two questionnaires: The SF-36 and the Chronic Respiratory Questionnaire (CRQ). The short form-36 (SF-36) (6) is a general questionnaire that measures HRQoL and covers nine domains: physical functioning, role physical, role emotional, social functioning, general health perceptions, mental health, bodily pain, vitality, and overall HRQoL. For all measures, scores were transformed linearly to scales of 0 to 100, 0 indicating maximal impairment and 100 indicating minimal impairment.

The interviewer-administered version of the CRQ, is a specific questionnaire, translated and validated for use in Spanish (7). The questionnaire includes 20 items in four domains: Dyspnea (five items), Fatigue (four items), Emotional Function (seven items) and Mastery (four items). Each item was graded on a seven-point scale, in which 1 is the worse HRQoL and 7 the better perceived quality of life. We defined the minimal important difference as an improvement of 0.5 per item (8).

All the tests were performed one week prior to the beginning of the PR program and repeated immediately at the end of the intensive period and at 12, 24 and 36-month visits during the maintenance program.

5

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Statistical analysis

Page 32 of 33

Qualitative variables were described in percentages and quantitative variables using means and standard deviations or median and inter-quartile ranges depending on their distributional characteristics. Changes in mean outcome measures over the intensive period were assessed by the use of paired t-test. Characteristics in month 0, were set as the baseline, reference measurements for the comparisons between groups and over study time.

We applied linear mixed-effects models to estimate and contrast mean change differences between control and intervention groups for all continuous outcomes in the planned follow-up visits periods (0, 12, 24, 36 months). Mixed models make full use of all available data for all randomized participants, and incorporate also in the estimates of effects of interest the time correlation between repeated measures. Effects tested were differences between groups (treatment effect), differences within groups (effect of time on outcomes) and the interaction between these effects (assessment of differences in change over time of outcomes between treatment groups). No imputation was done for missing values. Sample size: using the BODE index values in patients with COPD of similar severity and in the same country as a reference, we estimated that 75 patients in each group were required to detect a statistically significant difference of 1 point between groups, assuming a common standard deviation of 2 points in the index, two-sided significance level (α) of 5%, statistical power (1-β) of 80% and a common dropout rate of 15%. It has been shown that the difference in one point in the BODE index has clinical relevance and is associated with an increased risk of mortality of 33%. Analyses were performed using SAS v9.4 and R v3.2.3 statistical software.

6

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REFERENCES

1. Vestbo J, Hurd S, Agustí A, Jones P, Vogelmeier C, Anzueto A et al. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2013;187(4):347-365.

2. Celli BR., Cote Claudia G., Marin JM., Casanova C., Montes de Oca M., Mendez R., Pinto Plata V., Cabral Howard J.The Body-Mass Index, Airflow Obstruction Dyspnea, and Exercise Capacity Index in Chronic Obstructive Pulmonary Disease. N Engl J Med

2004;350:1005-12.

3. Fernando J. Martinez, Han MK, Andrei AC, Wise R, Murray S, Curtis JL, Sternberg A, Criner G, Gay SE, Reilly J, Make B, Ries AL, Sciurba F, Weinmann G, Mosenifar Z, DeCamp M, Fishman AP, Celli BR; for the National Emphysema Treatment Trial Research Group* Longitudinal Change in the BODE Index Predicts Mortality in Severe Emphysema AJRCCM 2008;178:491-499

4. ATS statement: Guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166: 111-117

5. Puhan MA., Chandra D., Mosenifar Z., Riese A., Make B., Hansel NN., Wise RA., Sciurba F. For the National Emphysema Treatment Trial (NETT) Research Group. The minimal important difference of exercise tests in severe COPD. Eur Respir J 2011; 37:

784–790

6. Alonso J, Prieto L, Anto JM. The Spanish version of the SF-36 Health Survey (the SF- 36 health questionnaire): an instrument for measuring clinical results. Med Clin (Barc) 1995; 104:771–776

7. Güell R, P.Casan, M.Sangenis, F. Morante, J. Belda, GH Guyatt . Quality of life in patients with chronic respiratory disease: the Spanish version of the Chronic Respiratory Questionnaire (CRQ). Eur Respir J 1998;11: 55-60.

8. Redelmeier DA, Bayoumi AM, Goldstein RS, Guyatt GH.

Assessment of the minimal

important differences in symptom: a comparison of two techniques. J Clin Epidemiol

1996; 49:1215-1219.

7

Copyright © 2016 by the American Thoracic Society