ORIGINAL STUDIES. Keywords: Pulmonary rehabilitation; COPD; nutrition

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1 ORIGINAL STUDIES Efficacy and Costs of Nutritional Rehabilitation in Muscle-Wasted Patients With Chronic Obstructive Pulmonary Disease in a Community- Based Setting: A Prespecified Subgroup Analysis of the INTERCOM Trial Carel R. van Wetering, Martine Hoogendoorn, MSc, Roelinka Broekhuizen, PhD, Gonnie J. W. Geraerts-Keeris, Dirk R. A. J. De Munck, MD, Maureen P. M. H. Rutten-van Mölken, PhD, and Annemie M. W. J. Schols, PhD Rationale: Limited data are available on effectiveness and costs of nutritional rehabilitation for patients with COPD in community care. Methods: In a 2-year RCT, 199 COPD patients (FEV 1 %pred. 6% [SD 16%]) and impaired exercise capacity were randomized to the interdisciplinary community-based COPD management program (INTER- COM) or usual care (UC). A prescheduled subgroup analysis was performed on 39 of 199 patients who were muscle wasted and received UC or nutritional therapy in combination with exercise training. Body composition, muscle strength, and exercise capacity were assessed at baseline and 4, 12, and 24 months. Results: Between group differences after 4 months in favor of the intervention group: fat free mass index (FFMI.9 kg/m 2 [SE 5.2, P \.1]), body mass index (BMI 1. kg/m 2 [SE 5.4, P 5.9]), maximum inspiratory mouth pressure (Pimax 1.4 kpa [SE 5.5, P 5.11]), quadriceps average power (QAP 13.1 Watt [SE55.8, P 5.36]), 6-minute walking distance (6MWD 27 m, [SE , P 5.28]), cycle endurance time (CET 525 seconds [SE5195, P 5.13]), and peak exercise capacity (Wmax 12 Watt [SE 5 5, P 5.36]). Between group difference over 24 months in favor of the intervention group: Pimax 1.7 kpa (SE 5.53, P 5.4), QAP 19 Watt (SE 5 6, P 5.5), 6MWD 57 (SE 5 19, P 5.6), and CET 485 seconds (SE 5 159, P 5.6). After 4 months total costs were Euro 151 higher in the intervention group than in the UC group (P \.5), but not significantly different after 24 months. Hospital admission costs were significantly lower in the intervention group V 4724 (95% CI 774, 1734). Conclusion: This study in muscle-wasted COPD patients with moderate airflow obstruction shows a prolonged positive response to nutritional support integrated in a community-based rehabilitation program. Clinical trial.gov: NCT (J Am Med Dir Assoc 21; 11: ) Keywords: Pulmonary rehabilitation; COPD; nutrition Department of Respiratory Medicine, Máxima Medical Centre, Veldhoven, The Netherlands (C.R.vW., D.R.A.J.D.M.); Institute for Medical Technology Assessment (imta), Erasmus University/Erasmus Medical Centre, Rotterdam, The Netherlands (M.H., M.P.M.H.R.vM.); Department of Respiratory Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands (R.B., A.M.W.J.S.); Department of Dietetics, Máxima Medical Centre, Veldhoven, The Netherlands (G.J.W.G.K.). Funding for this study was provided by the Netherlands government: Clinical Trial registration number: NCT This study was financially supported by the Netherlands Asthma Foundation (NAF, ), the "Stichting Astma Bestrijding" (SAB), Nutricia Netherlands, Pfizer and Partners in Care Solutions (PICASSO) for COPD. Address correspondence to Annemie Schols, PhD, Department of Respiratory Medicine, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, PO Box 58, 622 AZ Maastricht, The Netherlands. a.schols@pul.unimaas.nl Copyright Ó21 American Medical Directors Association DOI:1.116/j.jamda ORIGINAL STUDIES van Wetering et al 179

2 The efficacy and feasibility of nutritional intervention in patients with chronic obstructive pulmonary disease (COPD) with weight loss or muscle wasting is still debated. According to the meta-analysis by Ferreira et al 1 nutritional therapy in stable COPD patients has no significant effect on anthropometric measures, lung function, or exercise capacity. However, Weekes et al 2 recently reported in a randomized controlled trial (RCT) in outpatients with COPD at risk for nutritional depletion that dietary counseling and food fortification resulted in weight gain both during and beyond the intervention period while the controls lost weight. No improvements in muscle mass and muscle function were observed. All sufficiently powered RCTs that investigated the effects of nutritional support as integrated part of a supervised in- or outpatient pulmonary rehabilitation program however reported positive effects on body mass, muscle function, and exercise performance. 3 5 Scarce data are available in literature about the rationale and effectiveness of nutritional rehabilitation in less advanced COPD. Furthermore, no data are available on the feasibility of nutritional rehabilitation in a community-based setting as well as on the long-term clinical outcomes and cost-effectiveness. To address these issues we conducted a 2-year RCT evaluating the effect of an INTERdisciplinary COMmunity-based COPD management program (INTERCOM) compared to usual care (UC). The INTERCOM program aimed to provide tailored care by physiotherapists, dieticians, and COPD nurses working outside but in collaboration with the hospital. All patients in the intervention group received exercise training and education. The smokers in the intervention group received smoking cessation support. The patients in the intervention group who were muscle wasted received additional nutritional intervention. A full description of the program and the clinical results of this trial have been reported elsewhere. 6,7 In brief, over the total 2-year period, there were significantly better effects in the INTERCOM group compared with the UC group in health status, exercise capacity, and perceived effectiveness but no differences were found for exacerbations, muscle function, and body composition. At the start of the trial, a subgroup analysis among the muscle-wasted patients was planned to study the relative effect of nutritional support on body composition and functional status assuming a prevalence of muscle wasting in the randomized group of 3%. Although the prevalence according to our criteria turned out to be lower we still found a significantly different weight response in the muscle-wasted intervention group compared with the UC group calling for more detailed analyses of this subgroup. METHODS Patients and Design The INTERCOM trial recruited patients with COPD according to European Respiratory Society/American Thoracic Society (ERS/ATS) criteria that were under supervision of the department of respiratory medicine of 2 general hospitals in the Netherlands. Patients were included if they had a forced expiratory volume in 1 second (FEV 1 ) % predicted below 8% and an impaired exercise capacity defined as peak exercise capacity (Wmax) during an incremental cycle ergo meter test of less than 7% of the predicted normal value. 8 Patients who had prior rehabilitation and patients with serious comorbidity that precluded exercise therapy were excluded. At inclusion, patients were judged to be clinically stable by their respiratory physician and pharmacotherapy had been optimized. All patients gave written informed consent for participation in the study. Ethical approval was granted by the Medical Ethics Committee from Máxima Medical Centre. Patients were randomized to the group receiving the IN- TERCOM program or UC using a computerized procedure with concealed patient allocation. Outcomes were assessed at baseline and 4, 12, and 24 months after the start of the trial, except for peak exercise capacity, which was measured at baseline and 4 months only. All measurements were assessed single-blinded. INTERCOM Program for Muscle-Wasted Patients The intervention consisted of an intensive 4-month, standardized, supervised rehabilitation phase and a 2-month active maintenance phase. Weight losing and muscle-wasted patients received scheduled counseling by a dietician and a standardized nutritional therapy during the supervised 4-month period to enhance the efficacy of rehabilitation. Muscle wasting was defined according to previously published criteria fat-free mass index (FFMI) # 15 (female) / # 16 (male) kg/m 2. 9 Involuntary weight loss was defined as weight loss of at least 5% in 1 month or at least 1% in 6 months prior to admission to the COPD management program while the body mass index (BMI) was at most 25 kg/m 2. Nutritional therapy consisted of 3 oral liquid (3 125 ml) supplements per 24 hours containing 564 kcal in total for a period of 4 months (Respifor, Nutricia, B.V. Zoetermeer, The Netherlands). For ease of presentation, the entire group of both weight-losing and muscle-wasted patients is referred to as muscle wasted because only 2 patients appeared to have suffered recent weight loss as outlined later in this article. The INTERCOM program was offered by local dieticians and physiotherapists in the proximity of the patient s home and by respiratory nurses from the hospital. The physiotherapists and dieticians were supervised by a physiotherapist and dietician from the general hospital. During the first 4 months, patients visited the physiotherapists twice a week (3 minutes per visit) for intensive supervised exercise training. The dietician was consulted at the start of the intervention and after 1, 2, and 4 months. All patients participated in an individualized education program and smokers were assigned to the respiratory nurse for standardized smoking cessation counseling according to the Minimal Intervention Strategy for Lung patients. During the 2-month maintenance phase, muscle-wasted patients visited the dietician 4 times, ie, after 6, 9, 12, and 24 months. In this period nutritional supplements were continued upon indication. Patients visited the physiotherapist once a month to monitor exercise capacity and adherence to the training and to provide encouragement to continue the exercise training at home. After a patient had 18 van Wetering et al JAMDA March 21

3 experienced an exacerbation, he or she was allowed to start 6 extra training sessions in 3 weeks at the physiotherapy practice. The visits to the respiratory nurse were scheduled upon indication or request. Usual Care The UC group received pharmacotherapy according to accepted guidelines, a short smoking cessation advice by their chest physician, and if they met the criteria for nutritional support, a verbal recommendation to improve dietary intake. Outcomes According to the study protocol, outcomes of the nutritional intervention were change from baseline in FFMI, body mass index (BMI), muscle function, and exercise performance as assessed by peak exercise capacity (Wmax), Cycle Endurance test (CET), and 6-minute walking distance (6MWD). Furthermore, differences in disease-specific quality of life (QOL), the total number of exacerbations (moderate plus severe), and the number of severe exacerbations were explored. Body composition was assessed using single-frequency (5 khz) bioelectrical impedance analysis (Bodystat 15, Bodystat Ltd. Douglas, Isle of Main, Britain). The FFMI was calculated as the fat-free mass divided by height 2 (kg/m 2 ). Body weight was measured using digital scales (Seca, Vogel Halke, Hamburg, Germany). Height was measured using a wall-mounted stadiometer with subjects standing barefoot. BMI was calculated as weight/height 2 (kg/m 2 ). Inspiratory muscle strength was assessed by measuring maximal inspiratory mouth pressure (Pi-max) according to the method of Black and Hyatt (Masterlab, Jaeger, Wurzburg, Germany). Quadriceps average power (QAP) was assessed during an isokinetic test at a speed of 18 /seconds during 1 contractions from until 9 knee flexion using a Biodex system 3 dynamometer (Biodex Corporation, Shirley, New York, NY). The CET started at 5% of the peak work rate (CET 5%) during a maximum of 1 minutes and continued thereafter at 7% of peak work rate (CET 7%) until exhaustion. The 6MWD measures the distance walked during 6 minutes in a 5-meter corridor in the hospital. The test was performed without encouragement. Peak exercise capacity (Wmax) was measured using an incremental cycle ergometer test (Corrival 1, Lode, Groningen, The Netherlands). FEV 1 was derived from the flow volume curve. Disease-specific quality of life was assessed with the St. George s Respiratory Questionnaire (SGRQ). A moderate exacerbation was defined as a visit to the general practitioner or respiratory physician in combination with a prescription of antibiotics and/or prednisolone or a visit to the emergency department or day care of a hospital, which according to the patient was related to a worsening of COPD symptoms. A severe exacerbation was defined as a hospitalization for a COPD exacerbation. Smoking status was assessed by self reporting. Resource Utilization and Unit Costs The cost analysis part of this study was performed from a societal perspective. All COPD- and non-copd-related health care costs, travel expenses, and cost of productivity losses were assessed. All costs related to conducting the trial and developing the intervention have been excluded. Patients recorded in cost booklets contacts with care professionals, over-the-counter medication, medical devices, hospital admissions, time lost from paid work, hours of (un)paid household assistance, travel expenses, and nutritional supplements. One booklet consisted of a period of 4 weeks. If indicated, patients were contacted by phone to clarify their answers. Data Table 1. Baseline Characteristics of the Randomized Study Population Randomized Patients (n 5 199) Nonwasted* Muscle Wasted P N 5 (M/F) 16 (117/43) 39 (24/15).171* INTERCOM/Usual Care 81/79 16/23.291* Smoking n 5 (no/yes) 117/33 18/21 \.1* Smoking (pack years) 38.5 (26.7) 32.2 (2.8).289 Age (y) 66.7 (8.9) 64. (8.7).81 Weight (kg) 79.9 (12.8) 62.6 (9.2) \.1 Body height (m) 1.69 (.8) 1.69 (.11).88 Body mass index (kg/m 2 ) 27.9 (4.2) 21.7 (4.2) \.1 Fat free mass (kg) 51.7 (7.) 43.2 (6.9) \.1 Fat free mass index (kg/m 2 ) 17.9 (1.6) 14.9 (1.4) \.1 % Fat mass (%) 35.1 (6.5) 3.8 (7.3).1 Quadriceps average power (W) 18 (37) 96(37).73 Pi max (mm Hg) 7. (2.5) 6.2 (2.3).62 6 MWD (m) 514 (98) 525 (94).785 W max (Watt) 86.9 (31.8) 79.4 (25.3).151 SGRQ total score 38.9 (15) 35.6 (14).233 DLco % pred 7 (21) 55 (16) \.1 FEV 1 % pred 6. (15.8) 54.7 (15.2).6 Data are n (%), or mean (SD). Pimax, maximal inspiratory mouth pressure; 6 MWD, 6-minute walking distance; Wmax, peak exercise capacity; SGRQ total, St. George s Respiratory Questionnaire total score; DLco % pred, diffusion capacity for carbon monoxide; FEV 1, forced expiratory volume in 1 second. * Chi square test Mann-Whitney U test, the difference in the other variables is tested using Independent Samples t test. ORIGINAL STUDIES van Wetering et al 181

4 Randomized 99 Wasted Non-wasted INTERCOM Usual Care INTERCOM Usual Care Inclusion 3 n=3 6 n=79 - drop-out 3 n=3 n=81 n=5 - drop-out 4 intervention Start - drop-out 1 n= 1 - died 6 - drop-out 2 n= 1 n=75 - drop-out 3 n=3 n=75 - drop-out 4 4 months 6 - died 4 - drop-out 2 n= 1 n=7 - drop-out 3 - died 3 n=73 - died 1 follow up yr 1 2 follow up n=61 n=64 2 yr drop-out 1 3 n=64 - drop-out 3 - died n=72 - drop-out 4 - died n=4 Fig. 1. Patient enrollment scheme. Reasons drop out: 1:wasted INTERCOM: started inpatient rehabilitation (), 2: wasted UC: started nutritional rehabilitation (), started INTERCOM intervention (),3: non wasted INTERCOM: co-morbidity (n=7), illness family member (), 4: non wasted UC: co-morbidity (n=4). on hospital admissions were also extracted from the electronic hospital records of the 2 hospitals involved in the study to avoid missing any hospital admissions. Outpatient medication was obtained from local pharmacies. Resource utilization and costs of productivity losses was valued using Dutch guideline prices updated to the year 27. Because of the limited study period, no discounting was applied to costs or effects. Statistical Analyses A per protocol analysis was performed. Differences in baseline characteristics between muscle-wasted and non musclewasted patients and the differences between the muscle-wasted patients in the INTERCOM group and the muscle-wasted patients in the UC group were statistically tested using independent sample t tests for continuous, normally distributed data; Mann-Whitney U tests for continuous, non-normally distributed data; and chi-square tests for categorical variables. The outcomes after 4 months of treatment were compared between groups by linear regression with baseline value of the parameter, treatment group, smoking status at baseline, FEV 1 % pred at baseline, the self-reported number of exacerbations during the 12 months preceding the trial, and gender as predictors. Within group changes in normally distributed parameters were compared with the paired Student t test and nonparametrically distributed parameters with the Wilcoxon signed rank test. These analyses were performed with SPSS version 13. (SPSS Inc., Chicago, IL). Repeated measurement analysis was performed to analyze the change over 24 months in all continuous outcome variables using the SAS procedure PROC MIXED with the covariance among repeated measures modeled as unstructured. The model included treatment, time (ie, the measurement at 4, 12, and 24 months), treatment by time interaction, muscle-wasted (y/n), and muscle-wasted treatment, baseline value of variable of interest, smoking status at baseline, FEV 1 % pred at baseline, the self-reported number of exacerbations during the 12 months preceding the trial, and gender. To account for data on costs and total and severe exacerbations that were missing after patients prematurely dropped out from the trial and the additional uncertainty that these missing values introduced, the multiple imputation technique based on the propensity score method was used. The 95% 182 van Wetering et al JAMDA March 21

5 Table 2. Change from Baseline in Health Outcomes over 24 Months Health Outcome Muscle Wasted Nonwasted P Value of Interaction* INTERCOM (n 5 16) Usual Care (n 5 14) INTERCOM (n 5 7) Usual Care (n 5 72) FFMI (kg/m 2 ) BMI (kg/m 2 ) Pimax (cm H 2 O) QAP (Watt) CET (sec) MWD (m) SGRQ total Total exack Severe exac FFMI, fat-free mass index; BMI, body mass index; CET, Cycle Endurance time; 6MWD, 6-minute walking distance; QAP, Quadriceps average power; Pimax, maximal inspiratory mouth pressure; SGRQ total, St. George s Respiratory Questionnaire total score; exac 5 exacerbations * Based on repeated measurement analyses with model: Change from baseline in variable of interest 5 treatment, time, treatment*time, depleted, depleted*treatment, baseline value of variable of interest, smoking at baseline, number of exacerbations 12 months before trial, FEV 1 % pred at baseline, and gender. P \.5. P \.1. P \.1. k Based on multiple imputation. Negative binomial regression, with treatment, smoking status at baseline, FEV1% pred. at baseline, muscle wasted at baseline, muscle wasted*treatment and the self-reported number of exacerbations during the 12 months preceding the trial as factors, and the natural logarithm of the length of the observation period as offset variable. confidence intervals (CI) around the estimates were obtained by nonparametric bootstrapping. The total number of exacerbations was compared between treatment groups using negative binomial regression, with treatment, smoking status at baseline, FEV1% pred at baseline, and the self-reported number of exacerbations during the12 months preceding the trial as factors, and the natural logarithm of the length of the observation period as offset variable. RESULTS Patients Between January 22 and December 24, 199 patients were enrolled in the trial of whom 39 (2%) patients were classified as muscle wasted at baseline; 23 were randomized into the INTERCOM group and 16 into the Usual Care group. Baseline characteristics of muscle-wasted and non muscle-wasted patients are presented in Table 1. Table 3. Effects after 4 Months of Intervention in Muscle-Wasted Patients Health Outcome Usual Care* INTERCOM* INTERCOM vs Usual Care Baseline (n 5 14) 4 Months (n 5 14) Baseline (n 5 16) 4 Months (n 5 16) Adjusted Difference FFMI (kg/m 2 ) 15. (1.) 14.8 (.9) 14.8 (1.) 15.4 (.9).9.2 BMI (kg/m 2 ) 21.8 (2.6) 21.4 (2.1) 22. (1.9) 22.7 (2.) 1..4 Pi max (kpa) 6.6 (2.7) 6.3 (2.1) 6.3 (2.1) 6.7 (2.3) QAP (Watt) 99.7 (33.8) 94.7 (32.8) 1.7 (41.8) 16.7 (36.5) Wmax (Watt) 86. (24.2) 8.6 (23.6) 83.3 (25.6) 85.9 (23.8) CET (sec) 62 ( ) 474 ( ) 71 ( ) 982 ( ) MWD (m) (15.7) (9.7) (87.2) (81.8) SGRQ Total 31.5 (16.) 37.1 (11.3) 33.9 (12.3) 32.7 (13.1) Total exac Sever exac FFM, fat-free mass; FFMI, fat-free mass index; BMI, body mass index; %FM, percentage fat mass; CET, Cycle Endurance test; 6 MWD, six minute walking distance; Wmax, peak exercise capacity; QPT, isometric quadriceps peak torque; Pimax, maximal inspiratory mouth pressure; SGRQ total, St. George s Respiratory Questionnaire total score. * Variables before and after intervention were compared within groups by the paired Student s t-test and represented as mean (SD) or mean (range) when nonparametrically distributed. The change in outcome of the variables after 4 months of intervention were compared between groups by linear regression with baseline value of the parameter, treatment group, smoking status at baseline, FEV1%predicted, number of exacerbations 12 months before trial and gender as predictors (P \.5). Values represent the unstandardized coefficient B. P \.1 within groups. P \.5 within groups. k P \.1 between groups. P \.5 between groups. SE ORIGINAL STUDIES van Wetering et al 183

6 Besides differences in body composition, the musclewasted subgroup was also characterized by a significantly higher proportion of smokers and a significantly lower diffusing capacity compared with non muscle-wasted patients. Characterization of the tissue-wasting pattern of the muscle-wasted patients at baseline revealed that a substantial proportion (58%) of patients with muscle wasting had a normal weight ( sarcopenic phenotype ). Only 2 patients reported recent weight loss but these patients were not suffering from more advanced airflow obstruction; their mean FEV 1 % pred (SD) was 57% (7). Besides pack years (39.3 [22.4] versus 23.3 [14.9] years; P 5.16), gender (48% male versus 81% male; P 5.49), and body height (1.66 versus 1.74; P 5.22) there were no other significant differences between patients in the muscle-wasted INTERCOM and musclewasted UC group. The patient disposition and the reasons for drop out are described in Figure 1. Two patients from the UC group were advised by their chest physicians to discontinue participation in the study and received nutritional intervention. These patients were excluded from the current analyses, as were 2 patients who started inpatient rehabilitation. Table 2 shows there is a significant interaction between the effect of the INTERCOM program in terms of FFMI, BMI, and weight and being muscle wasted or not. Over a period of 24 months the improvement was significantly greater in the muscle-wasted patients, justifying detailed comparison of the muscle-wasted INTERCOM group and the muscle-wasted Usual Care group. Effects of the Intervention after 4 Months During the 4 months of supervised exercise training and nutritional intervention, the majority of patients in the muscle-wasted INTERCOM group gained at least 5% in weight (56%) and fat-free mass (FFM) (63%). In contrast, a substantial proportion of patients in the muscle-wasted Usual Care group lost at least 5% in weight (28%) and FFM (42%). After 4 months, a significant between-group difference was found in FFMI (.9 kg/m 2 [SE 5.2, P \.1]), BMI 1. kg/m 2 (SE 5.4, P 5.9), Pimax 1.4 kpa (SE 5.5, P 5.11), and QAP 13 Watt (SE 5 5.8, P 5.36) (Table 3). A significant between-group difference in 6MWD of 27 m (SE , P 5.28), CET 525 seconds (SE 5 195, P 5.13), and Wmax 12 Watt (SE 5 5, P 5.36) was observed after 4 months. Effects of the Intervention over 24 Months In Table 2 and Figures 2 and 3 the effects over 24 months are shown. Over 24 months the muscle-wasted INTERCOM patients showed significant improvements in body composition (FFMI.53 kg/m 2 (SE 5.17, P 5.6), BMI 1.1 (SE 5.37, P 5.9), respiratory mouth pressure (Pimax 1.1 kpa (SE 5.35, P 5.4), and limb muscle function (QAP) 12 Watt, SE 5 3.9, P 5.6) compared with baseline. No significant changes compared to baseline were found in the muscle-wasted UC group. Between-group comparison over 24 months showed that in the muscle-wasted INTER- COM group inspiratory mouth pressure (Pimax 1.7 kpa [SE A (kg) Change from baseline in weight B in FFM (kg) Change from baseline Usual Care muscle wasted INTERCOM muscle wasted Usual Care non-muscle wasted INTERCOM non-muscle wasted Fig. 2. Change from baseline over 24 months in weight (A) and Fat Free Mass (B). 5.53, P 5.4]) and limb muscle function (QAP 19 Watt [SE 5 6, P 5.5]) were significantly improved. Compared to baseline, the muscle-wasted INTERCOM group remained stable. However, the muscle-wasted UC group showed a significant deterioration in CET ( 352 seconds [SE 5 115, P 5.6]), 6MWD ( 57 m [SE 5 13, P 5.3]), and disease-specific quality of life (5.4 [SE 5 2.4, P 5.4). This resulted in significant between-group differences for 6MWD (57 m [SE 5 19, P 5.6) and CET (485 seconds (SE 5 159, P 5.6). We observed no significant difference between the 2 groups in the total number of exacerbations but the number of severe exacerbations per patient was significantly lower in the muscle-wasted INTER- COM group compared to the muscle-wasted UC group (.51 [95% CI:.94;.14]). Four patients in the muscle-wasted INTERCOM group and 2 patients in the muscle-wasted UC group stopped smoking. The differences in quit rate and the percentage of smokers after 24 months were not statistically significant. One patient in the muscle-wasted INTERCOM group restarted smoking during the 2-year study period. In 69% of the muscle-wasted patients in the INTERCOM group nutritional supplements 184 van Wetering et al JAMDA March 21

7 A B Change from baseline in average power (W) C hange from baseline in Pi Max (cm H 2 O ) C Change from baseline in 6MWD (m) Usual Care muscle wasted INTERCOM muscle wasted Usual Care non-muscle wasted INTERCOM non-muscle wasted Fig. 3. Change from baseline over 24 months in Quadriceps average power (A), Pimax (B), and 6MWD (C) over 24 months. were also administered after 4 months (mean intake 4.2 packages/week). Costs After 4 months, mean total costs per patient were V287 for the muscle-wasted INTERCOM group and V1368 for the muscle-wasted UC group, resulting in a between-group difference of V151 (95% CI: 165; 2669). The intervention costs, calculated as the 4-month difference in costs for the physiotherapist, dietician, respiratory nurse, and diet nutrition between the 2 groups, were V1284 per patient. The costs related to the nutritional intervention were V694, consisting of V99 for nutritional counseling and V595 for nutritional supplements. The mean 2-year total costs per patient were V12,83 for the muscle-wasted INTERCOM group and V14,25 for the muscle-wasted Usual Care group, resulting in a nonsignificant cost saving of V1195 (95% CI: 795; 5759). Based on the study protocol the 2-year intervention costs amount to a total of V274 per patient for visiting the physiotherapists (V194 [95% CI: 87; 1297]), the respiratory nurse (V147 [95% CI: 116; 178]), dietary counseling (V239 [95% CI: 191; 28]), and nutritional supplements (V126 [95% CI: 621; 1986). However, the costs related to hospital admissions were significantly lower in the muscle-wasted INTERCOM group V4724 (95% CI: 774; 1734) compared with the musclewasted Usual Care group and even with the non musclewasted INTERCOM group ( % CI: 3767; 22) (Figure 4). In the muscle-wasted INTERCOM group, 2 (13%) patients were hospitalized 3 times for an average period of 12 days while in the muscle-wasted UC group 1 (71%) patients were hospitalized 21 times for an average period of 1 days. DISCUSSION The present study reports a subgroup analysis of patients in the INTERCOM trial, which gives it an exploratory and hypothesis generating nature. This per-protocol analysis is nevertheless interesting because we know little about longterm effect of nutritional interventions (either as part of a pulmonary rehabilitation program or on its own) in less advanced COPD. Hence, the prolonged positive response to nutritional rehabilitation as found in our analysis is intriguing. In the muscle-wasted intervention group body ORIGINAL STUDIES van Wetering et al 185

8 14, 12, 1, 8, 6, 4, 2, * * hospital admissions nutritional intervention rehabilitation medication other costs muscle wasted INTERCOM (6) muscle wasted usual care (4) non muscle wasted INTERCOM (n=7) * Significant difference in hospital admissions costs compared with muscle wasted INTERCOM Fig. 4. Mean total 2-year costs per patient for different categories of resource use. composition and muscle function improved significantly over 2 years and exercise capacity and quality of life maintained stable. In contrast, exercise capacity and quality of life significantly decreased in the muscle-wasted control group. Despite additional costs of nutritional intervention, total costs were not significantly different from the muscle-wasted patients receiving Usual Care nor the non muscle-wasted patients in the intervention group. This was due to a significant reduction in costs of hospital admissions. Short-term effects of nutritional rehabilitation in advanced COPD have been reported previously. Creutzberg et al 1 concluded that nutritional supplementation therapy implemented in an 8-week inpatient pulmonary rehabilitation program showed improved body composition and exercise performance in muscle-wasted patients with severe COPD. Steiner et al 4 showed in advanced COPD that 7 weeks of endurance exercise training (merely consisting of walking exercises) resulted in a negative energy balance that could be overcome by supplementation using the same nutritional intervention regimen as in the present study. The nutritional rehabilitation strategy of the INTERCOM program was similar to previous studies by the Maastricht group in advanced disease in a clinical setting but relative exercise intensity in the current study was lower. Despite a less controllable community-based setting, the proportion of patients with a positive weight response on nutritional intervention was very high (. 5% weight gain in 56% of the patients). This could be related to a milder degree of lung function impairment or comorbidity, possibly linked to a lower level of systemic inflammation. In advanced COPD we previously showed in a clinically controlled setting that nonresponders were characterized by more pronounced systemic inflammation. 11 Unfortunately we did not take blood samples in the current study to analyze the systemic inflammatory profile. Another explanation for the relatively high proportion of responders to the nutritional intervention could be related to differences in muscle-wasting pattern among the patients in different studies. Nearly all musclewasted patients in the current study were weight stable and 58% were characterized by muscle wasting with a relative preservation of fat mass. In addition to a lower prevalence of recent weight loss in the current study group, 2 other factors could explain the good treatment response. Engelen et al 12 recently showed in muscle-wasted COPD patients with less advanced airflow obstruction that the anabolic response to a meal was more efficient than in healthy age matched control subjects. In advanced COPD, not only muscle wasting is prevalent, but these patients are often also characterized by a decreased oxidative phenotype that may affect insulin sensitivity and limit the anabolic response to nutritional modulation. 13 There is yet no data on muscle oxidative phenotype in less advanced COPD patients. The costs of nutritional intervention in the first 4 months were primarily driven by the relatively high costs of the nutritional supplements, which are much higher than the costs of nutritional counseling. If the cost analysis would have been performed from a healthcare perspective instead of a societal perspective, the unit costs of the nutritional supplement Respifor would be about 25-3% lower because the price of Respifor for those entitled to reimbursement is lower. However, because the nutritional intervention was associated with a significant reduction in costs of hospital admissions, total costs after 24 months tended to be lower in the muscle-wasted patients receiving the intervention than in the muscle-wasted patients receiving Usual Care. In line with the reduction of severe exacerbations requiring hospital admissions we and others indeed showed in a previous paper that not only in severe and very severe COPD 14 but also in moderate COPD, skeletal muscle weakness is a significant determinant of hospitalization risk. 15 In this study we could not disentangle the relative contribution of nutritional intervention from the contribution of the exercise training. Otherwise in muscle-wasted patients with advanced COPD whole body exercise training alone did not increase body weight and even tended to decrease fat-free mass. 3 In conclusion, this subgroup analysis of the INTER- COM trial demonstrated the feasibility of nutritional support as integrated part of a community-based COPD management program in muscle-wasted COPD patients. It also provided indications for the efficacy of this approach. Nutritional rehabilitation improved body composition and muscle function, prevented deterioration of 6MWD and quality of life, and even reduced costs related to severe exacerbations. 186 van Wetering et al JAMDA March 21

9 ACKNOWLEDGMENTS The authors acknowledge the team of local dieticians and physiotherapists and the respiratory nurses and chest physicians of the coordinating hospitals who carefully delivered the intervention to the participating patients. REFERENCES 1. Ferreira I, Brooks D, Lacasse Y, et al. Nutritional supplementation for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev 25 (2):CD Weekes CE, Emery PW, Elia M. Dietary counselling and food fortification in stable COPD: A randomised trial. Thorax 29;64: Schols AM, Soeters PB, Mostert R, et al. Physiologic effects of nutritional support and anabolic steroids in patients with chronic obstructive pulmonary disease. A placebo-controlled randomized trial. Am J Respir Crit Care Med 1995;152: Steiner MC, Barton RL, Singh SJ, Morgan MD. Nutritional enhancement of exercise performance in chronic obstructive pulmonary disease: A randomised controlled trial. Thorax 23;58: Broekhuizen R, Wouters EF, Creutzberg EC, et al. Polyunsaturated fatty acids improve exercise capacity in chronic obstructive pulmonary disease. Thorax 25;6: Wetering CR, Hoogendoorn M, Mol SJ, et al. Short- and long-term efficacy of a community-based COPD management program in less advanced COPD: a randomised controlled trial. Thorax 21;65: Hoogendoorn M, Wetering CR, Schols AM, et al. Is INTERdisicplinary COMmunity-based COPD management (INTERCOM) cost-effective? Eur Respir J 21;35: Jones NL, Makrides L, Hitchcock C, et al. Normal standards for an incremental progressive cycle ergometer test. Am Rev Respir Dis 1985;131: Vermeeren MA, Creutzberg EC, Schols AM, et al. Prevalence of nutritional depletion in a large out-patient population of patients with COPD; COSMIC Study Group. Respir Med 26;1: Creutzberg EC, Wouters EF, Mostert R, et al. Efficacy of nutritional supplementation therapy in depleted patients with chronic obstructive pulmonary disease. Nutrition 23;19: Creutzberg EC, Schols AM, Weling-Scheepers, et al. Characterization of nonresponse to high caloric oral nutritional therapy in depleted patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2;161: Engelen MP, Rutten EP, De Castro CL, et al. Supplementation of soy protein with branched-chain amino acids alters protein metabolism in healthy elderly and even more in patients with chronic obstructive pulmonary disease. Am J Clin Nutr 27;85: Gosker HR, Zeegers M, Wouters FM, Schols AMWJ. Muscle fibre type shifting in the vastus lateralis of patients with COPD is associated with disease severity: A systematic review and meta-analysis. Thorax 27;62: Decramer M, Gosselink R, Troosters T, et al. Muscle weakness is related to utilization of health care resources in COPD patients. Eur Respir J 1997;1: Van Wetering CR, Van Nooten FE, Mol SJM, et al. Systemic impairment in relation to disease burden in patients with moderate COPD eligible for a lifestyle program. Int J Chron Obstruct Pulmon Dis 28; 3: ORIGINAL STUDIES van Wetering et al 187