Physical activity and longitudinal change in 6-min walk distance in COPD patients

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Physical activity and longitudinal change in6-min walk distance in COPD patients

Bente Frisk a,b,*, Birgitte Espehaug a, Jon A. Hardie b,Liv I. Strand c,d, Rolf Moe-Nilssen c, Tomas M.L. Eagan b,e,Per S. Bakke b, Einar Thorsen b,f

a Centre for Evidence-Based Practice, Bergen University College, Bergen, Norwayb Dept. of Clinical Science, University of Bergen, Bergen, Norwayc Dept. of Global Public Health and Primary Care, University of Bergen, Bergen, Norwayd Dept. of Physiotherapy, Haukeland University Hospital, Bergen, Norwaye Dept. of Thoracic Medicine, Haukeland University Hospital, Bergen, Norwayf Dept. of Occupational Medicine, Haukeland University Hospital, Bergen, Norway

Received 26 June 2013; accepted 5 September 2013Available online 13 September 2013

KEYWORDSChronic obstructivepulmonary disease;Functional capacity;Long-term follow-up;Spirometry;Six-min walk test

Summary

Background: The 6-min walk distance (6MWD) is widely used to evaluate functional capacity inpatients with chronic obstructive pulmonary disease (COPD).Aim: To examine predictors for longitudinal change in 6MWD including self-reported phys-ical activity, smoking habits, body composition, exacerbations, comorbidity and lung func-tion.Methods: The cohort included 389 patients aged 44e75 years, with clinically stable COPD inGOLD stages IIeIV. The follow-up time was 3 years. Measurements included 6MWD, spirom-etry, fat and fat free mass index (FMI and FFMI), and assessment of physical activity, smok-ing habits, comorbidities and exacerbations by questionnaires. Generalized estimatingequations (GEE) regression analyses were used to analyze predictors for the changein 6MWD.Results: There was a reduction in 6MWD from baseline to 3 years for patients in GOLD stagesIII and IV (B Z �36 m, 95% CI Z �51 to �7, p Z 0.009 and B Z �79 m, CI Z �125 to �20,p Z 0.007). The unadjusted GEE analysis demonstrated that baseline self-reported physicalactivity level, forced expiratory volume in one second (FEV1), forced vital capacity, FFMI,GOLD stages and age predicted change in 6MWD, but in the adjusted GEE analysis onlyself-reported physical activity level (p Z 0.001) and FEV1 (p Z 0.019) predicted changeover time.

* Corresponding author. Centre for Evidence-Based Practice, Bergen University College, Pb. 7030, 5020 Bergen, Norway. Tel.: þ47 55 58 7143, þ47 970 03 111.

E-mail address: [email protected] (B. Frisk).

0954-6111/$ - see front matter ª 2013 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.rmed.2013.09.004

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Respiratory Medicine (2014) 108, 86e94

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Conclusion: Patients in GOLD stage II maintained their functional capacity assessed by 6MWDover 3 years, while it was significantly reduced for patients in GOLD stages III and IV. Level ofphysical activity and FEV1 were predictors for longitudinal change in functional capacity.ª 2013 Elsevier Ltd. All rights reserved.

Introduction

Exercise intolerance is the main factor limiting participa-tion in activities of daily living in patients having chronicobstructive pulmonary disease (COPD) [1]. The degree ofexercise intolerance is related to disease severity and is aresult of complex interactions between ventilatory me-chanical impairment, limitations of gas exchange, periph-eral muscle function and symptoms [1,2]. Functionalcapacity in COPD is most commonly measured with the 6-min walk test (6MWT) and the distance walked in six mi-nutes (6MWD) used as the primary outcome [3,4].

Improvement in the 6MWD has been demonstrated afterparticipation in a pulmonary rehabilitation program [5].Physical training is a corner stone in rehabilitation programsand improves aerobic capacity and health related quality oflife. [1] Maintaining the benefits requires continued trainingwhich may be a challenge for these patients when outsideorganized training programs. The improved functional ca-pacity after a rehabilitation program has shown to betransient and has declined 1e2 years after rehabilitation[6].

The natural long-term changes in 6MWD in COPD pa-tients, not recruited through a pulmonary rehabilitationprogram or assessment for surgery, have been examined infour previous studies, with follow-up times between oneand five years [7e10]. The mean annual decline in 6MWDvaried between 2 and 40 m per year [7e10]. In the Eclipsestudy [10], the change in 6MWD was related to age, gender,body mass index (BMI) and lung function by the GlobalInitiative for Chronic Obstructive Lung Disease [11] (GOLD)stage. The patients had no restriction receiving prescribedmedication or other therapies during the study period,including rehabilitation, and such interventions were notregistered. The effect of habitual physical activity was notassessed in any of these studies. The aim of the presentstudy was to examine predictors for the longitudinal changein the 6MWD. We hypothesized that high habitual physicalactivity is associated with a lower longitudinal decline in6MWD, and included self-reported physical activity, lungfunction, smoking habits, body composition, exacerbationsand comorbidity in the analysis.

Methods

Study population

Of 433 patients with clinically stable COPD from the BergenCOPD Cohort Study (2006e2010), 389 patients aged 44e75years completed the 6MWT at baseline and were included inthe current study. The follow-up time was three years(Fig. 1). Selection of the study population and the inclusion

and exclusion criteria have been described in detail previ-ously [12]. In brief, all patients were diagnosed with COPD,had a smoking history of �10 pack years, a post-bronchodilation forced expiratory volume in one second(FEV1)/forced vital capacity (FVC) ratio <0.7 and a post-bronchodilation FEV1 <80% of predicted value accordingto Norwegian reference values [13]. Exacerbations thatrequired medical treatment during the last four weeks priorto inclusion, led to deferment of inclusion. Patients withinflammatory disorders like rheumatoid arthritis, systemiclupus erythematosus or other connective tissue disorders,inflammatory bowel disease, and any active cancer in thelast five years were excluded. Common chronic diseaseswith known inflammatory components like chronic heartdisease, diabetes and hypertension were not a cause forexclusion.

The Bergen COPD Cohort Study, in which the patientswere a subsample of the ECLIPSE study [14], made no re-strictions to treatment in the study period, and the par-ticipants were therefore free to receive medication andtherapies, including rehabilitation, prescribed by theirphysician. In the Bergen COPD Cohort Study additional in-formation on treatment and habitual physical activity dur-ing the study period was registered, which was not part ofthe ECLIPSE study. Of the 389 patients that completed6MWT at baseline, 89 had participated in a pulmonaryrehabilitation program during the study period, all of themwithin the first two years of the observation period. Therehabilitation program lasted for 7 weeks, and consisted of17 sessions, each lasting for about 5.5 h.

Ethics

The study was approved by the Western Norway RegionalResearch Ethics Committee. Participation in the study wasvoluntary. Written and oral information was given, andwritten consent was obtained prior to the inclusion.

Assessment tools

Six-min walk testThe 6MWT [4] was performed at baseline and after one andthree years after inclusion in the study. The 6MWD was usedas the primary outcome measure of functional capacity.The test was performed indoor, along a 30 m flat, straightenclosed corridor, according to the American Thoracic So-ciety (ATS) guidelines [3]. A trained technician supervisedthe patients. The test was performed once each time, and apractice 6MWT was not done. Oxygen saturation (SpO2) andheart rate (HR) were measured before and at the end of thetest using a pulseoxymeter (NONIN Medical Inc., Plymouth,MN). The patients graded their level of dyspnea and fatigueby the Borg CR 10 scale [15] at the beginning and at the end

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of the test, and the 6MWD was registered. The use of ox-ygen during the test was registered.

Self-reported physical activitySelf-reported physical activity was recorded at baselineand after one and three years. There were two questionsrelated to spare time physical activity, one for light andone for hard physical activity. The delineation between thetwo was whether the activity resulted in breathlessnessand sweating or not. The response categories were none,less than 1 h per week, 1e2 h per week and three or morehours per week. These questions are validated [16,17] andhave been used in a large Norwegian general populationstudy [18].

Body composition, spirometry, dyspnea and Charlsonindex for comorbiditiesHeight and body mass were measured. The patients un-derwent bioelectrical impedance measurements of fatmass and fat free mass (Bodystat 1500, Isle of Man, En-gland) after an overnight fast. The body mass index (BMI)was calculated as the body mass divided by the square ofheight, the fat free mass index (FFMI) as the fat free massdivided by the square of height, and the fat mass index(FMI) as the fat mass divided by the square of height [19].Spirometry, both pre- and post- inhalation of 0.4 mg sal-butamol, was conducted on a Viasys Masterscope (Viasys,Hoechberg, Germany). The spirometer was calibratedtwice daily with a 3-L calibration syringe. The modified

Medical Research Council (mMRC) dyspnea scale [20] wasused to measure symptoms of dyspnea. Charlson index forcomorbidities was determined from the information regis-tered by the physician during the clinical examination atbaseline [21].

Statistics

Descriptive statistics were used to characterize the studypopulation (mean and standard deviation (SD) andpercent). Independent t-tests were used to comparecontinuous variables and chi square-tests for categoricalvariables across gender. Generalized estimating equations(GEE) regression analyses [22] with robust standard errorswere used to identify potential predictors for the longitu-dinal change in 6MWD per year. An unstructured workingcorrelation structure was applied to adjust for within-patient correlation. Time was modeled as both a categori-cal variable (baseline, year 1, and year 3) and a continuousvariable when longitudinal change in 6MWD was analyzed.The variables examined at baseline were age, gender,number of exacerbations 12 months prior to inclusion,FEV1, FVC, FMI, FFMI, pack years, Charlson index forcomorbidities and self-reported physical activity. Contin-uous predictor variables were centered at their meanvalues to obtain interpretable regression coefficients: Ageat 64 years, FEV1 at 1.5 l, FVC at 3.3 l, and FMI at 8.4 kg/m2,FFMI at 17.0 kg/m2 and pack years at 40.9 pack years.

Figure 1 The study population during 3 years of follow-up. COPD: chronic obstructive pulmonary disease, 6MWT: six-min walktest.

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Interaction terms between each of the predictor variablesand time were included to investigate the effects of thesevariables on change in 6MWD during follow-up. For unad-justed estimates, we calculated one GEE analysis for each

predictor variable, which included the variable, time andthe interaction term of variable and time. For the adjustedGEE analysis, we fitted a model where all the predictorvariables and time and the interaction terms of variable

Table 1 Characteristics of the 389 COPD-patients at baseline.

Variables Total Female Male Sex. diff. p-value

Sex, n (%) 389 (100) 153 (39.3) 236 (60.7)Age (years) 63.6 � 6.8 62.6 � 6.3 64.2 � 7.0 0.034Smoking status n (%) 0.215

Current 167 (43.0) 72 (47.0) 95 (40.0)Former 222 (57.0) 81 (53.0) 141 (60.0)

Pack years 40.9 � 22.8 33.4 � 16.5 45.5 � 25.0 <0.001BMI (mean, kg/m2) 25.4 � 5.2 24.6 � 5.7 25.9 � 4.8 0.015FMI (mean, kg/m2) 8.4 � 3.3 9.9 � 3.7 7.4 � 2.6 <0.001FFMI (mean, kg/m2) 17.0 � 3.2 14.7 � 2.4 18.5 � 2.8 <0.001FEV1 (l) 1.5 � 0.5 1.3 � 0.4 1.7 � 0.5 <0.001FEV1 (% pred) 48.7 � 14.0 49.6 � 13.6 48.1 � 14.3 0.296FVC (l) 3.3 � 0.9 2.7 � 0.6 3.7 � 0.8 <0.001FVC (% pred) 85.2 � 16.6 85.2 � 17.1 85.6 � 16.4 0.791FEV1/FVC (%) 45.7 � 11.1 47.7 � 11.0 44.5 � 11.0 0.008GOLD category (%)

II n 179 (46) 77 (50) 102 (43)III n 169 (43) 65 (42) 104 (44)IV n 41 (11) 12 (8) 29 (12)

6MWD 423 � 112 405 � 104 435 � 116 0.009SpO2

Before 6MWT 94 � 2.7 94 � 2.9 94 � 2.6 0.621After 6MWT 91 � 5.7 91 � 6.1 91 � 5.4 0.804

Heart rateBefore 6MWT 86 � 14.8 89 � 14.7 85 � 14.7 0.013After 6MWT 110 � 18.0 114 � 17.9 108 � 17.5 <0.001

Borg CR-10 dyspnea score (median)Before 6MWT 0.5 1.5 0.3 0.050After 6MWT 4.0 4.0 3.0 0.090

mMRC dyspnea grade 2.2 � 2.3 2.3 � 2.4 2.1 � 2.2 0.441Experienceda �2 exacerbations last year (%)

No n 310 (81) 114 (75) 196 (84) 0.027Yes n 75 (19) 38 (25) 37 (16)

Charlson comorbidity index (%) 0.0111 225 (58) 99 (65) 126 (53)2 93 (24) 38 (25) 55 (23)3 46 (12) 12 (8) 34 (15)4 25 (6) 4 (2) 21 (9)

Hard physical activity per week n (%) 0.117No activity 146 (41) 64 (46) 82 (38)

<1 h 69 (19) 21 (15) 48 (22)1e2 h 80 (23) 35 (25) 45 (21)3 h> 61 (17) 19 (14) 42 (19)

Light physical activity per week n (%) 0.723No activity 46 (13) 19 (13) 27 (12)

<1 h 51 (14) 18 (13) 33 (15)1e2 h 107 (30) 46 (33) 61 (28)3 h> 156 (43) 58 (41) 98 (45)

Data are presented as mean � SD, unless otherwise stated. BMI: body mass index; FMI: fat mass index; FFMI: fat free mass index; FEV1:forced expiratory volume in one second; FVC: forced vital capacity; 6MWD: 6 min walking distance; mMRC: modified Medical ResearchCouncil.a Exacerbations requiring either hospitalization with oral antibiotics or oral steroids. Chi square for categorical variables and inde-

pendent t-test for continuous variables.

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and time were included in the model. Analysis for multi-collinearity between FEV1 and FVC, and between FMI andFFMI did not indicate multicollinearity, therefore all pre-dictor variables, except GOLD stages were included in thesame analysis. A possible confounder could be participationin rehabilitation during the study period. Separate GEEanalysis with adjustment for participation in rehabilitationwas done. In addition, we did separate GEE analysis forpatients who did and did not participate in rehabilitationaccording to examine predictors for longitudinal change in6MWD.

Multivariate logistic regression was applied to assesspredictors for physical activity at 3 years follow-up withadjustment for participation in pulmonary rehabilitation(yes/no), age, gender, number of exacerbations 12 monthsprior to inclusion FEV1, FVC, FMI, FFMI, pack years andCharlson index for comorbidities.

Self-reported light and hard physical activity had fourpossible response categories, but in the GEE analysis and inthe multivariate logistic regression, we transformed it totwo response categories for both light and hard physicalactivity (no activity/light physical activity and no activity/hard physical activity).

Estimated regression coefficients are presented with 95%confidence intervals (CI) and p-values. The significancelevel was set at 0.05. The data analyses were performedusing IBM SPSS Statistics 20 (SPSS Inc. Chicago, Illinois,USA).

Results

Of the 389 patients who completed the baseline 6MWT, 319(82%) and 264 (68%) completed the test at year 1 and 3respectively (Fig. 1). At baseline, 13 (3.3%) patients usedoxygen during the 6MWT, and at 1 and 3 years follow-up 11(3.4%) and 10 (3.8%) did so. Baseline characteristics of thepopulation are presented in Table 1. The patients’ meanage was 64 � 7 years, 61% were males and mean FEV1 inpercent of predicted value was 49 � 14%. According toGOLD stage, 179 (46%) patients were in stage II, 169 (43%) instage III, and 41 (11%) in stage IV.

There was no significant difference in baseline charac-teristics, including 6MWD, between patients participatingin pulmonary rehabilitation during the study period andnon-participants. The dropout rates were 10% and 20%, and20% and 36% at 1 and 3 years follow-up in those who did anddid not participate in rehabilitation respectively. Thefraction of subjects performing hard physical activity atthree years was higher in those who had participated in arehabilitation program, odds ratio 2.4 (95% CI 1.4e4.2,p Z 0.001) (Table 2).

Longitudinal change in 6MWD

There were no differences in effort during the 6MWTs. Theadjusted GEE analysis showed that the differences in SpO2,HR and Borg score between measurements immediatelybefore and immediately after the 6MWT were not signifi-cantly different at any time.

The distribution of the individual change in 6MWD frombaseline to 3 years is shown in Fig. 2. The median reduction

was 16 m. Estimated unadjusted mean 6MWD at baselineand after 1 and 3 years was 423 (95% CI: 412e434), 431 (95%CI: 419e433) and 400 (95% CI: 385e415) meters, respec-tively. The decrease in 6MWD from baseline to 3 years wasstatistically significant (B Z �23, 95% CI: �34 to �12,p < 0.001). The decrease over time in 6MWD was onlyevident for patients in GOLD stage III (BZ �36, 95% CI: �51to �7, pZ 0.009) and in GOLD stage IV (BZ �79 m, 95% CI:�125 to �20, p Z 0.007) (Fig. 3).

Predictors for longitudinal change in 6MWD

The unadjusted GEE analysis demonstrated that baselinehabitual hard physical activity, FEV1, FVC, GOLD stage,FFMI and age were predictors for change in 6MWD, but inthe adjusted GEE analysis only hard physical activity andFEV1 predicted change in 6MWD. Yearly change in 6MWD forperforming regular hard physical activity was positive,3.9 m per year (p Z 0.001), and for FEV1 it was positive,12.4 m per year per liter increase in FEV1 (p Z 0.019)(Table 3). When excluding patients who used oxygen duringthe 6MWT, the results from the adjusted GEE analysis wasthe same as when all the patients were included in theanalysis. When separate GEE analyses were done for pa-tients who did and did not participate in rehabilitation,hard physical activity and FEV1 remained as significantpredictors for change in 6MWD.

Discussion

The main findings of the study were 1) Patients in GOLDstage II maintained their 6MWD during the follow-up periodof 3 years, while it was significantly reduced in patients in

Table 2 Participation in pulmonary rehabilitation aspredictor of hard physical activity at 3-years follow-up asestimated by logistic regression.

Variable OR (95% CI) p-Value

RehabilitationNo 1Yes 2.42 (1.41, 4.15) 0.001

SexFemale 1.00Male 0.55 (0.22, 1.34) 0.186

Age 0.96 (0.93, 1.00) 0.047FEV1 1.15 (0.59, 2.26) 0.678FVC 1.05 (0.68, 1.62) 0.837FFMI 1.11 (0.97, 1.27) 0.128FMI 0.95 (0.85, 1.05) 0.312Pack years 0.99 (0.98, 1.00) 0.037Exacerbations last year 1.05 (0.84, 1.31) 0.672Charlson comorbidity index1 12 1.31 (0.74, 2.32) 0.3563 1.14 (0.51, 2,57) 0.7494 0.47 (0.15, 1.48) 0.199

Odds ratio (OR) and 95% confidence interval (CI) examined bylogistic regression in multivariate analyses (p < 0.05).

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GOLD stages III and IV. 2) The predictors at baseline forlongitudinal change in 6MWD were self-reported hardphysical activity and FEV1. 3) Patients that had partici-pated in a pulmonary rehabilitation program during the

study period reported a higher physical activity level at 3years.

In normal subjects and in patients with mild COPD the6MWD is biomechanically limited by their maximal walkingspeed rather than by their ventilatory capacity. This couldbe a reason why the patients in GOLD stage II maintainedtheir 6MWD over 3 years. Some of the COPD patients had a6MWD not different from the normal population. BothCasanova et al. [7] and Spruit et al. [10] demonstrated that6MWD declined over time, but this finding was only signifi-cant in patients with severe airflow limitation. Even thoughthere was a decline in 6MWD in our study for patients inGOLD stage III and IV, and the other follow-up studies[7,9,10], the mean annual change in 6MWD was less thanthe minimal clinically important change that has beenestimated to be 54 m. [23]. The patients in our study were asubsample of the larger ECLIPSE study. The results withrespect to the longitudinal change in 6MWD were consistent[10]. However, Kapella et al. [8] found the 6MWD to bestable during a follow-up period of three years.

To our knowledge, this is the first study to report thatphysical activity was a significant predictor for change in6MWD. The analyses showed that reporting hard physicalactivity at baseline influenced the longitudinal change in6MWD positively. At 3 years follow-up, the fraction ofsubjects reporting regular hard physical activity was highercompared to baseline, and patients who had participated inpulmonary rehabilitation during the study period did so

Figure 2 The distribution of the change in the six-min walk distance (6MWD), 3 years minus baseline.

Figure 3 Mean six-min walk distance (6MWD) by GOLD-stagesestimated with unadjusted generalized estimating equations(GEE) regression analyses during 3 years of follow-up.

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more often than the others did. Physical training does notimprove the FEV1 [24], but it does improve skeletal-musclefunction and endurance [24]. Dynamic hyperinflation hasbeen demonstrated to be reduced when exercising regu-larly, which leads to mitigation in dyspnea [25]. High in-tensity training at an intensity of at least 60% of maximalexercise tolerance is necessary to achieve improvements inphysical performance [1]. Our results demonstrated thatonly subjects reporting hard physical activity had an effecton the 6MWD.

The activity in our study was self-reported and therebysubject to bias by overestimation. The correlation betweenphysical activity reported by questionnaire and objectivelyassessed activity by accelerometer has been shown to beweak [26]. However, a moderate correlation between self-reported physical activity and 6MWD was demonstrated byWalker et al. [26] and Nguyen et al. [27] Troosters et al.[28] measured physical activity objectively with an activitymonitor for a period of 5e7 days in a group of cystic fibrosispatients. Moderate physical activity was related to peakoxygen uptake and quadriceps force, but not to 6MWD.Activity monitors are more accurate than self-reportedquestionnaire, but monitoring is usually done for shorterperiods only, and awareness of the ongoing monitoring mayincrease activity level above the habitual. Rehabilitationmay have a similar effect on awareness with respect tophysical activity. Rehabilitation took place in the first yearof the observation period for most patients. The effect ofrehabilitation wanes over time [6], and such an effect willprobably be small at 3 years.

FEV1 was the other significant predictor for change in6MWD. Spruit et al. [10] found that age and baseline bodyweight predicted change in 6MWD, while there was adifferential effect of GOLD stage. We could not find thatage and body mass index influenced the longitudinalchange in 6MWD. GOLD stages are related to FEV1, whichwas a significant predictor in our study. Ventilatory ca-pacity is related to maximal expiratory flow rates andFEV1, and ventilatory capacity will at some point be thelimiting factor for exercise performance. It is reasonablethen, to find an association between 6MWD and FEV1.There is an association between maximal exercise testsand walking tests [29,30] like the 6MWT and the Shuttlewalk test [31] in COPD patients, and reduced maximal andfunctional exercise tests are both related to reducedventilatory capacity.

Methodological considerations

The Bergen COPD-cohort study excluded patients with in-flammatory disorders like rheumatoid arthritis, while pa-tients with common chronic diseases with knowninflammatory components like chronic heart disease, dia-betes and hypertension were included in the study. Thecomorbidity could be thought to influence the longitudinalchange in 6MWD. However, comorbidity was not a predictorof change in 6MWD. In a general COPD population, espe-cially among patients in GOLD stages III or IV, other chronicdiseases are common. We assume that our study populationis representative for the common COPD patients met inoutpatient clinics or in hospitals.

Table 3 Unadjusted and adjusted yearly change in 6-min walk distance (6MWD) for baseline predictor variables,estimated by general estimating equations (GEE) analysis.

Predictors atbaseline

Unadjusted Adjusted*

Yearlychangein 6MWD

p-Value Yearlychangein 6MWD

p-Value

SexWomen �14.3 �13.1Men �9.6 0.316 �15.8 0.694

Ageat 64 years �12.7 �13.1per 10 yearsincrease

�5.3 0.042 �0.6 0.816

GOLD stageII �45.5III �14.1 0.048IV �34.7 0.006

FEV1

at 1.5 l �11.7 �13.1per literincrease

14.8 <0.001 12.4 0.019

FVCat 3.3 l �11.8 �13.1per literincrease

7.3 0.001 0.2 0.957

FFMIat 17.0 kg/m2 �11.7 �13.1per kg/m2

increase1.4 0.046 0.4 0.692

FMIat 8.4 kg/m2 �11.9 �13.1per kg/m2

increase0.11 0.886 0.1 0.881

Pack yearsat 40.9 years �11.5 �13.1per 10 yearsincrease

0.4 0.620 0.2 0.844

Exacerbations last yeara

0e1 �9.8 �13.12� �18.2 0.159 �14.6 0.772

Charlson comorbidity index1 �9.9 �13.12 �17.4 0.180 �21.7 0.0703 �6.0 0.538 �6.3 0.2144 �20.3 0.282 �19.2 0.423

Hard physical activityNo activity �22.5 0.002 �13.1Hard activity �6.1 3.9 0.001

Light physical activityNo activity �16.2 0.564 �13.1Light activity �11.1 �21.1 0.348

*In the adjusted GEE analysis all the predictor variables, timeand the interaction terms between the variable and time wereincluded in the analysis. FEV1: forced expiratory volume in onesecond; FVC: forced vital capacity; FFMI: fat free mass index;FMI: fat mass index.a Exacerbations requiring either hospitalization with oral an-

tibiotics or oral steroids last year prior to inclusion.

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Because of limited resources, 6MWT was only per-formed once on each occasion in our study, even thoughtwo tests are recommended according to ATS guidelines[3]. The learning effect is a bias in the 6MWT and to reduceit, two tests are preferred [3]. In the study of Hernandeset al. [32] the learning effect between first and secondtest resulted in an increase in 6MWD of 27 m. The testswere performed on two consecutive days. Our subjectsincreased their 6MWD from baseline to 1 year. It is possiblethat a learning effect could hide a natural decline in the6MWD over this period, but it is more unlikely that theeffect could last for 3 years. The changes in SpO2, HR andBorg score were not different from baseline to 1 year orfrom baseline to 3 years for any GOLD stages. This couldindicate that the patients’ effort was the same at base-line, 1-year and 3 years follow-up.

Study population

Among patients included in the study, the distribution ac-cording to GOLD stages were 179 patients in GOLD stage II,169 in stage III and 41 in stage IV. There were fewer patientswith more serious disease state as represented by GOLDstage IV. The explanation might be that the most severelyill patients were not able to participate in the studybecause of limited functional capacity. This finding issimilar to other studies [8,10]. However, the majority of ourpatients were in GOLD stages III and IV. The dropout ratefrom baseline to 3 years was 32%. The patients were lost tofollow-up mostly because of death or increased diseaseseverity. Kapella et al. [8] and Spruit et al. [10] also had astudy period of 3 years and the dropout rates in thesestudies were 31%. Casanova et al. [7] had a follow-up periodof 5 years, and the dropouts during the study period was34%. COPD is a progressive disease and in long-term studies,an increasing dropout rate is unavoidable. In this respect,our results are in accordance with previous studies. Thedropout rate was higher in those who did not participate inpulmonary rehabilitation. The explanation is probably thatthe most severely ill patients were not able to participatein pulmonary rehabilitation.

Conclusion

Our findings demonstrated that patients in GOLD stage IImaintained their functional capacity assessed by 6MWDover 3 years, while it was significantly reduced for patientsin GOLD stages III and IV. Level of habitual physical activityand FEV1 were predictors for longitudinal change in func-tional capacity. The level of physical activity was higher atthree years in subjects who had participated in a rehabili-tation program during the observation period. The pre-vention of further reduction in lung function, if possible,and implementation of physical training programs seem tobe important for maintaining functional capacity over timein COPD patients.

Conflicts of interest

None of the authors have any competing interests.

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