Lampiran EBM (Journal)

AJRCCM Articles in Press. Published on 09-September-2016 as 10.1164/rccm.
201603-0602OC
Page 1 of 33
BENEFITS OF LONG-TERM PULMONARY REHABILITATION MAINTENANCE

PROGRAM IN SEVERE COPD PATIENTS: 3 YEAR FOLLOW-UP
Maria-Rosa Gell1, Pilar Cejudo2 , Francisco Ortega2, M. Carmen Puy1, Gema
Rodrguez-Trigo3, Jos Ignacio Pijoan4,5,6, Lorea Martinez- Indart4, Amaia Gorostiza4,
Khaled Bdeir7, Bartolome Celli8, Juan B. Galdiz4,9.
1
Hospital de la Santa Creu I Sant Pau. Barcelona; 2 Hospital Virgen Roco. Sevilla;
IBIS (Instituto de Biomedicina de Sevilla; 3 Hospital Clnico San Carlos. Madrid
4
Hospital Universitario Cruces, Barakaldo-Biocruces Health Research Institute,
5
CIBER de Epidemiologa y Salud Pblica (CIBERESP), Madrid, 6Spanish Clinical
Research Network (SCReN), Madrid, 7 Hospital La Madalena. Castelln. 8Pulmonary
and Critical Care Medicine. Brigham and Womens Hospital. Boston. USA. ;
9
CibeRes.
Clinical trials NCT01090999

Supported By FIS 2006 PI 060792 and SEPAR 2007
Corresponding Author: M R Gell, Departament de Pneumologia, Hospital de la

Santa Creu i Sant Pau, C/Mas Casanova n 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 issues table
of content online at www.atsjournals.org
Copyright 2016 by the American Thoracic Society

AJRCCM Articles in Press. Published on 09-September-2016 as 10.1164/rccm.201603-0602OC
Page 2 of 33
At a Glance Commentary
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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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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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
This is a Spanish multi-center (Hospital de la Santa Creu I Sant Pau.

Barcelona; Hospital Virgen Rocio. Sevilla; Hospital Clnico 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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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 patients
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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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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We sought for potential associations between clinical and demographic

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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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 peoples 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 FEV1 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 patients 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: Merc
Sangenis, Gina Mateu ,Adriana Castanyer, Lluis Paz, Amaia Gorostiza, Monica
Regueiro, Rosa Vzquez 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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endurance activity following pulmonary rehabilitation in COPD patients. Eur Respir J
2012, 39 (2) 272-278
21.- Gema Rodriguez-Trigo, Pilar Cejudo, Carme Puy, Juan Bautista Galdiz, Khaled
Bdeir, Amaia Gorostiza, Rosa Vzquez Sanchez, Elena Lopez de Santamaria, Lorea
Martinez-Indart, Fatima Morante, Monica Regueiro, Gomez Luis, Ortega
Francisco,Rosa Gell. 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 Vzquez-Snchez, Gema Rodriguez Trigo, Khaled Bdeir, Ftima Morante,
Elena Lopez Santarmara, Mnica Regueiro, Rosa Gell. Outcomes Evaluation of a
Maintenance 3-Year Follow.Up Pulmonary Rehabilitation Program. (Paper presented
at the annual ATS Congress San Diego. May 16-21, 2014. . Abstracts.A3645)
23.-Vestbo J, Hurd S, Agust 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,

Page 19 of 33
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: 784790
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; 104:771776
29- Gell 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: 15381540.

Page 20 of 33
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, Prez M, Guirao L, Samitier B, Ortega P, Vila X,. Solans M.,
Riera A.,Moreno E., Mer A., Miravitlles M.. Improving physical activity in patients
with COPD with urban walking circuits. Respiratory Medicine. 2013;107(12):1948-
1956.
38.-Resqueti V, Gorostiza A, Gldiz J, De Santa Mara E, Casan P, Gell-Rous R.
Beneficios de un programa de rehabilitacin 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): 651659.
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.

Page 21 of 33
Eligible COPD patients N=143

Intensive PR
for 8 weeks
Randomised =138
Intervention group Control group

n=68 n=70
Withdrawal n=11 Withdrawal n=8

Clinical worsening n=3 Clinical worsening n=8
Death n=1 Death n=4
12-months 12-months
n=53 n=50
Follow up Clinical worsening n=0 Clinical worsening n=4
Death n=3 Death n=3
24-months 24-months
n=43 n=39

Clinical worsening n=4 Clinical worsening n=1
Death n=2 Death n=2
36-months 36-months
n=34 n=31
FIGURE 1. Consort flow diagram. COPD: chronic obstructive pulmonary disease; PR:
pulmonary rehabilitation

Page 22 of 33
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).

Page 23 of 33
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).

Page 24 of 33
Subjects n 143
M/F n 127/16
Age (years) 64 9
BMI 27 5
FEV1/FVC % 39 1 0
FVC % 66 18
FEV1 % 34 10
6MWT 375 104
PaO2 69 10
PaCO2 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.
FEV1: forced expiratory volume in the first second.
6MWT: distance in the 6 minute walking test (meters)
PaO2: Partial pressure of arterial oxygen (mmHG)
PaCO2; Partial pressure of arterial carbon dioxide (mmHG).
BODE: Bode index.
Values are mean
Standard deviations unless otherwise specified.

Page 25 of 33
Month -2 Month 0 (baseline)
IG IG CG
CG (Control
(Intervention p-value (Intervention p-value* (Control p-value* p-value**
group)
group) group) group)
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 0.699 275 0.969 285 0.566 0.688
FVC % 66 19 66 16 0.921 6721 0.424 6921 0.121 0.572
FEV1/FVC
40 10 39 10 0.646 46 13 0.006 46 16 0.027 0.934
%
FEV1 % 34 11 34 9 0.932 36 10 0.023 37 11 0.055 0.940
PaO2 70 9 69 10 0.573 6812 0.346 6812 0.896 0.587
PaCO2 41 6 43 7 0.183 427 0.806 437 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)

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 Group*
Timee
measure (n=68) (n=70) valuea (n=53) (n=50) valueb (n=43) (n=39) valuec (n=34) (n=31) valued Timef
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
d
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).

Page 27 of 33
ONLINE DATA SUPPLEMENT
BENEFITS OF LONG-TERMPULMONARY REHABILITATION MAINTENANCE PROGRAM IN
SEVERE COPD PATIENTS: 3 YEARS FOLLOW-UP
Authors: Gell MR., Cejudo P., Ortega F., Puy MC., Rodriguez-Trigo G., Pijoan JI.,
Martinez-Indart L., Gorostiza A Bdeir K, Celli B., Galdiz JB.

Page 28 of 33
METHODS
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 (FEV1 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 patients 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,

Page 29 of 33
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 SpO2 (+/- 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

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, SpO2 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 3years 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

Page 31 of 33
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.

Page 32 of 33
Statistical analysis
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 () of 5%, statistical power (1-) 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.

Page 33 of 33
REFERENCES
1. Vestbo J, Hurd S, Agust 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:
784790
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; 104:771776
7. Gell 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.

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

BENEFITS OF LONG-TERM PULMONARY REHABILITATION MAINTENANCE

Clinical trials NCT01090999

Corresponding Author: M R Gell, Departament de Pneumologia, Hospital de la

Running title: Long-term benefits of pulmonary rehabilitation.

Copyright 2016 by the American Thoracic Society

Scientific knowledge on the subject: An intense program of pulmonary

Copyright 2016 by the American Thoracic Society

Introduction: In COPD, the benefits of Pulmonary Rehabilitation (PR) tend to wane

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

Copyright 2016 by the American Thoracic Society

Copyright 2016 by the American Thoracic Society

Copyright 2016 by the American Thoracic Society

MATERIAL AND METHODS

This is a Spanish multi-center (Hospital de la Santa Creu I Sant Pau.

Recruited patients attended an initial 8-week outpatient PR program

Pulmonary Rehabilitation Program

Copyright 2016 by the American Thoracic Society

Patients in the CG group were advised to maintain the exercise at home,

Copyright 2016 by the American Thoracic Society

Moreover, in the IG patients we quantified adherence using the number of

Copyright 2016 by the American Thoracic Society

Patient characteristics and intensive program

At the end of this intensive rehabilitation program, all outcome measures

Effect of Maintenance program

The flow-chart diagram of the patients recruited is shown in Figure 1. The

Copyright 2016 by the American Thoracic Society

We sought for potential associations between clinical and demographic

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

Copyright 2016 by the American Thoracic Society

Efficacy of maintenance pulmonary rehabilitation program

Copyright 2016 by the American Thoracic Society

maintenance technique is effective for preserving PR benefits, only in exercise

Copyright 2016 by the American Thoracic Society

Copyright 2016 by the American Thoracic Society

by Hogg et al (33) analyzing the attendance and completion of an 8-week PR

Limitations of the study

Copyright 2016 by the American Thoracic Society

Finally, the psychosocial morbidity probably impacts heavily on program

Copyright 2016 by the American Thoracic Society

Copyright 2016 by the American Thoracic Society

Copyright 2016 by the American Thoracic Society

18- Williams, J. E. A. The challenge of increasing uptake of pulmonary rehabilitation:

23.-Vestbo J, Hurd S, Agust A, Jones P, Vogelmeier C, Anzueto A , Barnes PJ,

Copyright 2016 by the American Thoracic Society

Copyright 2016 by the American Thoracic Society

35.- Foglio K. Is It Really Useful To Repeat Outpatient Pulmonary Rehabilitation

Copyright 2016 by the American Thoracic Society

Eligible COPD patients N=143

Intervention group Control group

Withdrawal n=11 Withdrawal n=8

Withdrawal n=3 Withdrawal n=5

Copyright 2016 by the American Thoracic Society

Copyright 2016 by the American Thoracic Society

Copyright 2016 by the American Thoracic Society

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

Copyright 2016 by the American Thoracic Society

Month -2 Month 0 (baseline)

Copyright 2016 by the American Thoracic Society

Copyright 2016 by the American Thoracic Society

ONLINE DATA SUPPLEMENT

BENEFITS OF LONG-TERMPULMONARY REHABILITATION MAINTENANCE PROGRAM IN

SEVERE COPD PATIENTS: 3 YEARS FOLLOW-UP