Longitudinal inspiratory capacity changes in chronic obstructive pulmonary disease

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1 Celli et l. Respirtory Reserch 2012, 13:66 RESEARCH Open Access Longitudinl inspirtory cpcity chnges in chronic ostructive pulmonry disese Brtolome R Celli 1*, Mrc Decrmer 2, Theodore Lystig 3, Steven Kesten 3 nd Donld P Tshkin 4 Astrct Bckground: The chnges in inspirtory cpcity (IC) over time in chronic ostructive pulmonry disese (COPD) ptients re unknown. The Understnding Potentil Long-term Impcts on Function with (UPLIFT W ) tril included IC mesurements. Methods: IC nlysis from UPLIFT W (N = 5992) ws performed t 1 nd 6 months, nd every 6 months through 4 yers. Annulized rte of decline in pre- nd post-ronchodiltor IC nd men differences t ech time point were nlyzed y mixed-effects models. The reltionships etween seline IC nd excertion rte nd mortlity were explored using Cox regression nlysis. Results: Bseline chrcteristics: ge, 65 yers; 75% men; post-ronchodiltor forced expirtory volume in 1 second, 1.32 L (48% predicted); pre- nd post-ronchodiltor IC, 2.03 nd 2.33 L. Men IC rte of decline (ml/yer) ws 34 ± 2 (1.7% of seline) nd 50 ± 3 (2.1% of seline) pre- nd post-ronchodiltor, respectively, without significnt etween-group differences. Morning pre-ronchodiltor (trough) IC improved with tiotropium versus plceo: 124 ml (1 month), 103 ml (1 yer), 107 ml (2 yers), 98 ml (3 yers), nd 97 ml (4 yers) (ll p < 0.001). Postronchodiltor improvements were similr etween tretment groups. Lower seline IC vlues were ssocited with reduced time to first excertion. For the lowest qurtile (n = 1413) the vlues in months were 14.3 ( ) for tiotropium nd 10.3 ( ) for controls (p < 0.01). Conclusion: IC declines from pproximtely 34 to 50 ml/yer in ptients with stge II to IV COPD. tretment does not chnge the IC decline rte ut provides 24-hour improvements in IC sustined over the long term. Trough IC differences suggest tht tiotropium provides sustined decrese in end-expirtory lung volume. Keywords: COPD, Inspirtory Cpcity, Bckground It hs een incresingly recognized tht lung volumes hve n independent importnt ssocition with symptom limittions nd outcomes, including survivl, in ptients with chronic ostructive pulmonry disese (COPD) [1-5]. As the disese progresses, ir trpping nd hyperinfltion develop, which worsen during physicl ctivity nd excertions. Increses in inspirtory cpcity (IC) re positively ssocited with exercise durtion nd decresed rethlessness during ctivity [2-4]. The ssocition ppers to e stronger thn the ssocition of forced expirtory volume in 1 second (FEV 1 ) with these outcomes nd therefore represents n * Correspondence: celli@copdnet.org 1 Pulmonry Division, Brighm nd Women s Hospitl, Boston, MA, USA Full list of uthor informtion is ville t the end of the rticle importnt surrogte of the functionl impct of COPD on ptient-reported outcomes. While the nnulized rte of decline in FEV 1 hs een well studied, there is no informtion regrding the rte of chnge in IC in ptients with COPD [6-14]. Few studies hve incorported long-term evlutions of lung function eyond FEV 1 nd forced vitl cpcity (FVC) nd none hve reported on the rte of decline in IC. The Understnding Potentil Long-term Impcts on Function with (UPLIFT W ) tril is 4-yer, rndomized, doule-lind, plceo-controlled tril of tiotropium 18 μg dily in ptients with COPD who were permitted to use ll respirtory medictions throughout the tril, other thn inhled nticholinergics [13]. In UPLIFT W, the IC ws mesured during the pre- nd post-ronchodiltor slow vitl cpcity (SVC) mneuvers 2012 Celli et l.; licensee BioMed Centrl Ltd. This is n Open Access rticle distriuted under the terms of the Cretive Commons Attriution License ( which permits unrestricted use, distriution, nd reproduction in ny medium, provided the originl work is properly cited.

2 Celli et l. Respirtory Reserch 2012, 13:66 Pge 2 of 8 using stndrdized spirometric technique. We conducted the following nlyses on the UPLIFT W dt: first, we investigted chnges in IC over time in ptients with COPD; second, we evluted the effect of tiotropium (compred with control) on trough nd postronchodiltor IC over 4 yers; third, we determined the chnges in SVC nd forced expirtory volume in 6 seconds (FEV 6 ); finlly, we explored the reltionship etween IC t seline nd time to first excertion, s well s mortlity. Methods Study design The study design detils from the UPLIFT W tril hve een pulished previously [12,13]. UPLIFT W ws rndomized, doule-lind, plceo-controlled clinicl tril evluting tiotropium 18 μg dily over 4 yers in ptients with COPD. The rtes of decline in pre- nd postronchodiltor FEV 1 were the primry endpoints. Asolute vlues for spirometry over 4 yers, excertions, helth-relted qulity of life (ccording to St George s Respirtory Questionnire [SGRQ]) [15]; only seline dt reported here), nd mortlity vriles were secondry outcomes. All mintennce respirtory medictions, except for inhled nticholinergics, were permitted. The study hd Institutionl Review Bord pprovl nd ll ptients gve written informed consent. The study ws conducted in ccordnce with the Declrtion of Helsinki. Ptients Ptients were included sed on clinicl dignosis of COPD, post-ronchodiltor FEV 1 70% of predicted, FEV 1 /FVC 0.70, ged 40 yers, nd smoking history of 10 pck-yers. The mjor exclusion criteri were s follows: history of sthm, COPD excertion within 4 weeks of screening, prior pulmonry resection, nd supplementl oxygen use > 12 hours per dy. Lung function outcomes Spirometry ws performed ccording to Americn Thorcic Society (ATS) criteri [16] t seline, t 30 dys post-rndomiztion, t every 6 months postrndomiztion, nd t 30 dys following the lst dose of study mediction. Spirometry ws conducted efore nd fter short-cting ronchodiltors (iprtropium 80 μg, then luterol 400 μg 60 minutes lter). Following rndomiztion, study drug ws dministered immeditely prior to short-cting ronchodiltors. Spirometry ws performed with the sme equipment t ech site using tril-specific customized softwre. Results were trnsmitted for centrlized qulity ssurnce ssessment (Quntum Reserch Inc, Louisville, Colordo, USA). SVC y slow exhltion mneuver ws performed first, followed y the FVC mneuver. Both mneuvers were performed three times with up to five forced expirtory mneuvers permitted in order to otin three cceptle efforts. The highest cceptle FEV 1 nd the highest FVC otined on ny of the three cceptle efforts were recorded. IC ws mesured in mneuvers used to generte the SVC. All investigtors were trined to collect IC nd SVC mesurements, nd the technique used ws stndrd nd supervised t ll centers. A computerized lgorithm helped stilize the end-expirtory signl nd prompted technicins to perform IC nd SVC mneuvers tht met ATS stndrds. All ptients were sitting nd continuous recording ws mde of the tidl volume. When ptients chieved tidl volume signl with stle end-expirtory volume, they were instructed to inspire s deeply s possile until no more ir could e inhled. At tht point, the ptient performed the SVC mneuver until residul volume ws reched. The mneuvers were repeted fter 5 minutes rest until three pproprite, reproducile trcings were otined. The est IC nd SVC were used for nlyses. Excertions, helth sttus, nd mortlity Excertion dt nd dverse events were collected t ech clinic visit. For the purpose of this nlysis, excertions were defined y episodes of shortness of reth nd chnge in the sputum tht merited course of corticosteroids or ntiiotics (or oth) nd/or required visit to n emergency room or dmission to hospitl. The SGRQ ws dministered t seline nd every 6 months. Mortlity ws determined up to Dy 1470 fter rndomiztion [13]. Sttisticl methods Dt from ll rndomized ptients with cceptle prend post-ronchodiltor mesurements t seline were included in this nlysis. A mixed-effects model with repeted mesurements nlysis of vrince ws utilized to determine the rte of chnge in spirometry vriles. Dt sets were restricted to ptients with 3 postrndomiztion spirometry test sets for clcultion of nnulized rte of decline in FEV 1, FVC, nd SVC, nd to ptients with 1 post-rndomiztion spirometry test set for clcultion of nnulized rte of decline in IC nd FEV 6. IC t seline ws divided into pproximte qurtiles using the cut points of 1.5, 2.0, nd 2.5 L. Hzrd rtios for the risk of n excertion nd for mortlity were clculted using Cox regression. Results Study popultion The demogrphics of the UPLIFT W popultion hve een previously descried nd re displyed in Tle 1

3 Celli et l. Respirtory Reserch 2012, 13:66 Pge 3 of 8 Tle 1 Bseline chrcteristics of ptients in the tiotropium nd control groups Chrcteristic (n = 2986) (n = 3006) Mle, % Age, yers 64.5 ± ± 8.5 Body mss index 26.0 ± ± 5.1 Smoking sttus Current smoker, % Smoking history, pck-yers 49.0 ± ± 27.9 SGRQ totl score, units 45.7 ± ± 17.2 Respirtory medictions, % Short-cting inhled nticholinergics Long-cting inhled nticholinergics Short-cting inhled β 2 -gonists Long-cting inhled β 2 -gonists Inhled corticosteroids Orl steroids Theophylline compounds Mucolytics Leukotriene receptor ntgonists Supplementl oxygen Men ± SD. Used lone or s fixed comintion. Arevition: SGRQ, St George s Respirtory Questionnire. [13]. Using the 2010 grding of irflow ostruction s chrcterized y the Glol Inititive for Chronic Ostructive Lung Disese (GOLD) [1], the men postronchodiltor FEV 1 ws 48 % predicted (Tle 2) with 46 %, 44 %, nd 9 % stge II, III, nd IV disese, respectively. Evlule mesurements of IC t seline were ville for 5992 ptients. IC nd SVC Improvements in morning pre-ronchodiltor IC were oserved throughout the tril, with the differences etween tiotropium nd control rnging from 94 to 125 ml (p < t ll time points) (Figure 1). Significnt improvements were lso oserved for preronchodiltor SVC (etween-tretment differences etween 150 nd 186 ml, p < t ll time points) (Figure 2), nd FEV 6 (etween-tretment differences etween 131 nd 161 ml, p < t ll time points) (Figure 3). Differences oserved for FVC were etween 170 nd 204 ml (p < 0.001) [13]. Pre-ronchodiltor IC declined from 32 to 36 ml/yer while post-ronchodiltor IC declined from 47 to 52 ml/yer, with no differences etween tretment groups (Tle 3). The corresponding rtes of decline for SVC were numericlly lrger, with pre-ronchodiltor vlues etween 41 nd 47 ml/yer nd postronchodiltor vlues etween 65 nd 66 ml/yer; corresponding vlues for FEV 6 were ml/yer nd 57 ml/yer, with no etween-tretment differences (Tle 3). The men rte of decline in pre-ronchodiltor IC ws similr for ptients t GOLD stge II (plceo group, 33 ml/yer; tiotropium group, 37 ml/yer), stge III (34 nd 37 ml/yer, respectively), nd stge IV (20 nd 34 ml/yer), ut incresed with the severity of irflow ostruction for post-ronchodiltor IC (GOLD stge II, 41 nd 44 ml/yer; stge III, 48 nd 56 ml/yer; stge IV, 57 nd 63 ml/yer for the plceo nd tiotropium groups, respectively). Tle 4 illustrtes the tretment group preronchodiltor differences t 1, 2, 3, nd 4 yers for IC, SVC, FEV 6, nd FVC. Tretment group differences in IC pper firly stle over 4 yers. SVC, FEV 6,ndFVC showed the lrgest decline in etween-group differences from Yer 3 to Yer 4, with minor declines in Yer 4. Associtions mong vlues were determined t individul time points. The correltions etween IC nd FEV 1 vried etween 0.51 nd 0.60 (pre-ronchodiltor) nd etween 0.45 nd 0.54 (post-ronchodiltor). The correltions etween IC nd FVC vried etween 0.57 nd 0.66 (pre-ronchodiltor) nd etween 0.55 nd 0.63 (post-ronchodiltor). The correltions etween IC Tle 2 Bseline spirometry (men ± SD) of ptients in the tiotropium nd control groups (n = 2986) (n = 3006) Pre-ronchodiltor FEV 1, L 1.10 ± ± 0.40 FEV 1, % predicted 39.5 ± ± 11.9 FVC, L 2.63 ± ± 0.83 FEV 1 /FVC 42.4 ± ± 10.5 SVC 2.80 ± ± 83 IC 2.04 ± ± 70 FEV ± ± 62 Postronchodiltor FEV 1, L 1.33 ± ± 0.44 FEV 1, % predicted 47.7 ± ± 12.6 FVC, L 3.09 ± ± 0.90 FEV 1 /FVC 43.6 ± ± 10.7 SVC 3.21 ± ± 90 IC 2.35 ± ± 77 FEV ± ± 66 Arevitions: FEV 1, forced expirtory volume in 1 second; FEV 6, forced expirtory volume in 6 seconds; FVC, forced vitl cpcity; IC, inspirtory cpcity; SD, stndrd devition; SVC, slow vitl cpcity.

4 Celli et l. Respirtory Reserch 2012, 13:66 Pge 4 of IC (L) Post-ronchodiltor difference: 1-30 ml 2.00 Pre-ronchodiltor difference: ml Dy 30 (Stedy Stte) Month Figure 1 Estimted men pre- nd post-ronchodiltor IC in the tiotropium nd control groups through 4 yers. Arevitions: IC, inspirtory cpcity. nd SVC vried etween 0.63 nd 0.74 (pre-ronchodiltor) nd etween 0.61 nd 0.70 (post-ronchodiltor). Reltionship of seline IC to excertions nd mortlity The men (rnge) of pre-ronchodiltor seline IC y qurtiles were: Q1, 1.15 ( ); Q2, 1.76 ( ); Q3, 2.25 ( ); Q4, 2.95 ( ). Lower qurtiles of IC were ssocited with fster time to first excertion within ech tretment group (Tle 5). ws ssocited with lower risk for n excertion within ech qurtile, lthough the upper limit of the 95% confidence intervl (CI) exceeded one for the third qurtile. Lower qurtiles of IC were ssocited with higher risk for ftl event within ech tretment group (Tle 6). While the risk for ftl event ws reduced with tiotropium in ech qurtile, in ll cses, the 95% CI included one, likely influenced y the reltively low numer of events within ech qurtile (Tle 6). Discussion This nlysis from the UPLIFT W study offered some novel findings. Firstly, the pre-ronchodiltor IC declined from 32 to 52 ml/yer in ptients with COPD included in the 4-yer tril. Secondly, the rte of decline ws similr in ptients tking tiotropium compred with ptients tking control plus regulr medictions, ut the morning IC (trough) ws significntly higher in ptients tking tiotropium throughout the study. Thirdly, the chnges in IC were mirrored y the chnges in SVC. Fourthly, lower vlues of IC t seline were ssocited with higher rtes of excertions nd deth SVC (L) Post-ronchodiltor difference: ml Pre-ronchodiltor difference: ml Dy 30 (Stedy Stte) Month Figure 2 Estimted men pre- nd post-ronchodiltor SVC in the tiotropium nd control groups through 4 yers. Arevitions: SVC, slow vitl cpcity.

5 Celli et l. Respirtory Reserch 2012, 13:66 Pge 5 of 8 FEV 6 (L) Post-ronchodiltor difference: ml Pre-ronchodiltor difference: ml Dy 30 (Stedy Stte) Month Figure 3 Estimted men pre- nd post-ronchodiltor FEV 6 in the tiotropium nd control groups through 4 yers. Arevitions: FEV 6, forced vitl cpcity in 6 seconds. A series of studies hs shown tht the end-expirtory lung volume (EELV) is n importnt determinnt of exercise limittion nd the rte of development of dyspne during exercise, s well s good predictor of survivl [2-5]. Improvement in cliniclly relevnt outcomes such s increses in exercise endurnce time nd decreses in dyspne hve een relted more strongly to chnges in EELV thn to chnges in FEV 1 [2-4,17,18]. Furthermore, dt from the Ntionl Emphysem Therpy Tril (NETT) hve shown improvements in survivl in selected ptients who underwent surgicl lung volume reduction compred with ptients rndomized to medicl therpy [19]. Tken together, these studies strongly support the concept tht EELV is n importnt determinnt of functionl cpcity nd outcome in ptients with COPD. The IC hs een shown to reflect EELV nd cn e mesured t rest using spirometer nd during exercise using reltively simple mneuvers [17,20,21]. Until now, there hs een no description of the ehvior of IC over long periods of time nd of the effect of phrmcologic therpy on those chnges. The mesurements of IC nd SVC t seline nd t ech of the susequent visits were incorported s prt of the stndrdized spirometry equipment nd softwre. Such dt were envisioned to help close gps in knowledge in this importnt re. On verge, the IC declines over time t rte tht is similr to the decline in FEV 1. This supports the clinicl oservtion tht, s disese progresses, mny ptients with COPD will develop hyperinfltion. Since the puliction of the study y Fletcher nd Peto, it hs een clssiclly stted tht the rte of decline of FEV 1 in ptients with COPD oscilltes round 60 ml/yer [6]. Evidence from the UPLIFT W nd Towrds Revolution in COPD Helth (TORCH) trils showed tht the ctul rte of decline is lower, eing on verge close to 40 ml/yer [13,14]. Furthermore, recent nlysis of the spirometric records of the second Frminghm cohort Tle 3 Annul rtes of decline in pre-/post-ronchodiltor IC, FEV 6, nd SVC over 4 yers (ml/yer) (ml/yer) Δ control p-vlue N Men (SE) N Men (SE) Men (SE) IC Pre-ronchodiltor (3) (3) 5 (5) 0.30 Post-ronchodiltor (4) (4) 6 (5) 0.28 FEV 6 Pre-ronchodiltor (2) (2) 2 (3) 0.39 Post-ronchodiltor (2) (2) 0 (3) 0.91 SVC Pre-ronchodiltor (3) (3) 6 (4) 0.11 Post-ronchodiltor (3) (3) 1 (4) 0.79 Dt from SVC previously pulished [13]. Arevitions: FEV 6, forced expirtory volume in 6 seconds; IC, inspirtory cpcity; SE, stndrd error; SVC, slow vitl cpcity.

6 Celli et l. Respirtory Reserch 2012, 13:66 Pge 6 of 8 Tle 4 Men etween-tretment differences up to 4 yers in pre-ronchodiltor IC, SVC, FEV 6, nd FVC 1 Yer 2 Yers 3 Yers 4 Yers IC (SE) 103 (17) 107 (18) 98 (19) 97 (20) SVC (SE) 176 (13) 167 (14) 166 (15) 150 (16) FEV 6 (SE) 159 (9) 149 (10) 161 (11) 131 (12) FVC (SE) 198 (13) 189 (14) 200 (15) 170 (16) Dt from FVC previously pulished [13]. Arevitions: FEV 6, forced expirtory volume in 6 seconds; FVC, forced vitl cpcity; IC, inspirtory cpcity; SE, stndrd error; SVC, slow vitl cpcity. y Kohnsl et l. [22] showed tht the norml rte of decline is pproximtely 19 ml/yer nd ml for smokers in tht sme popultion. It seems s if the rte of decline, t lest for FEV 1, hs decresed over the time tht hs elpsed since the report y Fletcher nd Peto [6]. It cnnot e determined whether this is due to chnges in therpy, the environment, or the nthropometric constitution of popultions, ut the consequence is tht ceiling effect my hve een reched, eyond which it will e very difficult to chnge the rte of decline ny further, other thn through smoking cesstion in ptients who continue to smoke. However, it is theoreticlly possile to ttempt to erse the dditionl reltively smll decline tht ptients with COPD hve compred with non-smoker controls. Interestingly, we found tht the rte of decline of post-ronchodiltor IC ws greter in ptients with more severe irflow ostruction (GOLD stge IV, compred with stges III or II). This finding differs from the pttern oserved for FEV 1 in the UPLIFT W nd TORCH studies, in which there ws greter decline over time in ptients with milder irflow limittion [13,14]. Even though the rte of decline of IC in UPLIFT W ws similr in ptients with tiotropium when compred with controls, trough IC ws lrger y pproximtely 100 ml in the tiotropium group. These results re consistent with shorter-term studies with tiotropium [17,18,20,23]. Although we did not mesure totl lung cpcity (TLC), evidence from shorter-term studies suggests tht this my decrese fter ronchodiltors, ut the decrese is reltively smll, so tht the rtio of IC/TLC is likely to hve improved in the ptients tking tiotropium Tle 5 Time to first excertion (men months nd HRs) (95 % CI) ccording to seline IC qurtiles IC qurtile (n = 2855) (n = 2881) HR (95 % CI) Q1 (n = 1413) 14.3 ( ) 10.3 ( ) 0.81 ( ) Q2 (n = 1427) 14.7 ( ) 10.5 ( ) 0.83 ( ) Q3 (n = 1450) 16.8 ( ) 14.8 ( ) 0.95 ( ) Q4 (n = 1446) 20.4 ( ) 15.8 ( ) 0.86 ( ) Arevitions: CI, confidence intervl; HR, hzrd rtio; IC, inspirtory cpcity. Tle 6 All-cuse mortlity (n [%]) (95 % CI) until Dy 1470 ccording to seline IC qurtiles IC qurtile (n = 2855) (n = 2881) HR (95 % CI) Q1 141/714 (19.7 %) 158/699 (22.6 %) 0.85 ( ) Q2 115/669 (17.2 %) 136/758 (17.9 %) 0.95 ( ) Q3 94/735 (12.8 %) 104/715 (14.5 %) 0.86 ( ) Q4 64/737 (8.7 %) 78/709 (11.0 %) 0.79 ( ) Arevitions: CI, confidence intervl; HR, hzrd rtio; IC, inspirtory cpcity. compred with those on control [17,20]. The 4-yer UPLIFT W tril sustntited previous reports from trils up to 1 yer in durtion, demonstrting tht tiotropium improves excertion rtes nd helth-relted qulity of life. In ddition, the UPLIFT W tril showed tht tiotropium could improve survivl [13,24]. Such impcts on the course of COPD re likely to e relted to, or t lest influenced y, the chnge in IC. The dt re insufficient to prove cuse-nd-effect reltionship, ut recent evidence descriing reltionship etween hyperinfltion nd crdic function, more specificlly left ventriculr stroke volume, supports this possile mechnism [25]. Indeed, the dt re consistent with eneficil effect on crdic moridity suggested y the results of the UPLIFT W nd TORCH trils [13,26]. More studies re needed to explore the impct of chnges in lung function on crdic physiology. Tht the IC findings re rel is supported y the mesurement of two other volume vriles, the FEV 6 nd, more importntly, the SVC. It is known tht, in ptients with COPD, there is difference in fvor of the vitl cpcity etween the vlue otined with the slow mneuver nd the vlue otined during the forced mneuver (i.e. FVC). The SVC in this study ws on verge 100 ml lrger thn the FVC in the sme ptients, confirming in lrge popultion wht ws lredy known from smller physiologic studies. Wht hd not een explored ws the reltionship etween IC nd SVC. In the current nlysis, there ws strong ssocition etween IC nd SVC, suggesting tht one could potentilly e used s surrogte mrker of the other. Since we mesured oth FEV 1 nd IC in UPLIFT W,we sought to determine if oth vriles chnged in tndem, in the sme ptients nd in the sme direction, nd whether oth vriles hd similr prognostic vlue for the ptient-reported outcomes studied in UPLIFT W. In reltion to the first ojective, we oserved close ssocition etween FEV 1 chnge nd IC chnge, lthough the ssocitions etween IC nd either SVC or FVC ppered to e stronger. Furthermore, the chnges occurred in the sme direction in the sme ptients, therey mking one vrile potentil surrogte mrker of the other. Given the similr strength of their

7 Celli et l. Respirtory Reserch 2012, 13:66 Pge 7 of 8 ssocition, it seems pproprite to use the FEV 1 s the single most stle physiologic vrile for the study of these outcomes. UPLIFT W ws not designed to nswer the question of the ssocition of IC with exercise cpcity nd, therefore, this remins to e determined. There were some limittions to this study. It is possile tht the longitudinl IC chnges my hve een ffected y the rte of discontinutions in UPLIFT W, which ws pproximtely 40% overll [13]. However, similr discontinution rtes hve een reported in other lrge-scle trils of respirtory mintennce therpies in COPD [12]. There ws no centrlized review of the qulity of the IC, lthough this ws undertken for ll slow nd forced expirtory mneuvers tht y definition included the IC. In ddition, the lrge numer of ptients nd the lrge numer of mneuvers incorported reduces the likelihood of vriility nd rndomness s n explntion for the results. There re no vlidted interntionl predicted vlues for IC, FEV 6, nd SVC, nd no informtion out the minimlly clinicl importnt difference, so we hd to limit the nlyses to chnges in solute vlues of these vriles. It is unlikely tht expressing these vriles s chnge in their predicted vlues or, in the cse of IC, s chnge in its rtio to TLC would hve improved the strength of the nlysis or its conclusions. Conclusions In summry, in ptients with GOLD stge II to IV COPD included in the UPLIFT W study, men pre- nd post-ronchodiltor IC declined from 32 to 36 ml per yer nd from 47 to 52 ml per yer, respectively. Tretment with tiotropium did not chnge the rte of decline of IC over time ut provided 24-hour improvements sustined over the long term. The difference in trough IC etween tiotropium nd control suggests tht tiotropium resulted in sustined decrese in EELV. Both IC nd SVC provided informtion tht relted to clinicl outcomes, ut the close ssocition etween chnges in these vriles nd chnges in FEV 1 indictes tht the FEV 1 remins relevnt physiologicl vrile of use in the study of ptients with COPD. Long-term studies of the chnges in lung volumes nd their reltion to exercise performnce nd mortlity should e undertken to clrify the role of IC nd other lung volumes in the routine mngement of ptients with COPD. Arevitions CI: confidence intervl; COPD: chronic ostructive pulmonry disese; EELV: end-expirtory lung volume; FEV 1 : forced expirtory volume in 1 second; FEV 6 : forced expirtory volume in 6 seconds; FVC: forced vitl cpcity; GOLD: Glol Inititive for Chronic Ostructive Lung Disese; IC: inspirtory cpcity; NETT: Ntionl Emphysem Therpy Tril; SGRQ: St George s Respirtory Questionnire; SVC: slow vitl cpcity; TLC: totl lung cpcity; TORCH: Towrds Revolution in COPD Helth; UPLIFT W : Understnding potentil long-term impcts on function with tiotropium. Competing interests Steven Kesten, MD, nd Theodore Lystig, PhD, were employees of Boehringer Ingelheim t the time the study ws conducted. Brtolome R Celli, MD, Mrc Decrmer, MD, nd Donld P Tshkin, MD, hve no conflicts of interest to disclose. Authors contriutions All uthors hd ccess to the dt nd hd role in writing the mnuscript. Funding This study ws funded y Boehringer Ingelheim nd Pfizer. Acknowledgments Mrc Decrmer, MD, Brtolome R Celli, MD, Steven Kesten, MD, nd Donld P Tshkin, MD, contriuted to the design nd conduct of the UPLIFT W tril. All uthors contriuted to dt nlyses nd interprettion nd were involved in the preprtion of the mnuscript nd the decision to sumit the pper for puliction. Dr Dcheng Liu (Boehringer Ingelheim) provided sttisticl support nd Ntlie Dennis of PAREXEL provided editoril ssistnce. Author detils 1 Pulmonry Division, Brighm nd Women s Hospitl, Boston, MA, USA. 2 Respirtory Division, University of Leuven, Leuven, Belgium. 3 Respirtory Deprtment, Boehringer Ingelheim, Phrmceuticls Inc, Ridgefield, Connecticut, USA. 4 Deprtment of Medicine, Dvid Geffen School of Medicine t UCLA, Los Angeles, CA, USA. Received: 27 April 2012 Accepted: 19 July 2012 Pulished: 6 August 2012 References 1. Glol Inititive for Chronic Ostructive Lung Disese: Glol strtegy for the dignosis, mngement nd prevention of chronic ostructive pulmonry disese: NHLBI/WHO workshop report. Bethesd: Ntionl Hert, Lung nd Blood Institute; O Donnell DE, We KA: Exertionl rethlessness in ptients with chronic irflow limittion. The role of hyperinfltion. Am Rev Resp Dis 1993, 148: O Donnell DE, Lm M, We KA: Mesurement of symptoms, lung hyperinfltion, nd endurnce during exercise in chronic ostructive pulmonry disese. Am J Respir Crit Cre Med 1998, 158: O Donnell DE, Revill SM, We KA: Dynmic hyperinfltion nd exercise intolernce in chronic ostructive pulmonry disese. Am J Respir Crit Cre Med 2001, 164: Csnov C, Cote C, de Torres JP, Aquirre-Jime A, Mrin JM, Pinto-Plt V, Celli BR: Inspirtory cpcity-to-totl lung cpcity rtio predicts mortlity in ptients with chronic ostructive pulmonry disese. Am J Resp Crit Cre Med 2005, 171: Fletcher C, Peto R: The nturl history of chronic irflow ostruction. Br Med J 1977, 1: Anthonisen NR, Connett JE, Kiley JP, Altose MD, Biley WC, Buist AS, Conwy WA Jr, Enright PL, Knner RE, O Hr P: Effects of smoking intervention nd the use of n inhled nticholinergic ronchodiltor on the rte of decline of FEV 1. The Lung Helth Study. J Am Med Assoc 1994, 272: The Lung Helth Study Reserch Group: Effect of inhled trimcinolone on the decline in pulmonry function in chronic ostructive pulmonry disese. N Engl J Med 2000, 343: Puwels RA, Löfdhl CG, Litinen LA, Schouten JP, Postm DS, Pride NB, Ohlsson SV: Long-term tretment with inhled udesonide in persons with mild chronic ostructive pulmonry disese who continue smoking. N Engl J Med 1999, 340: Burge PS, Clverley PM, Jones PW, Spencer S, Anderson JA, Mslen TK: Rndomised, doule lind plceo controlled study of fluticsone propionte in ptients with moderte to severe chronic ostructive pulmonry disese: the ISOLDE tril. Br Med J 2000, 320:

8 Celli et l. Respirtory Reserch 2012, 13:66 Pge 8 of Decrmer M, Rutten-vn Mölken M, Dekhuijzen PN, Troosters T, vn Herwrden C, Pellegrino R, vn Schyck CP, Olivieri D, Del Donno M, De Bcker W, Lnkhorst I, Ardi A: Effects of N-cetylcysteine on outcomes in chronic ostructive pulmonry disese (Bronchitis Rndomized on NAC Cost-Utility Study, BRONCUS): rndomized plceo-controlled tril. Lncet 2005, 365: Decrmer M, Celli B, Tshkin DP, Puwels RA, Burkhrd D, Cssino C, Kesten S: Clinicl tril design considertions in ssessing long-term functionl impcts of tiotropium in COPD: the UPLIFT W tril. J COPD 2004, 1: Tshkin DP, Celli B, Senn S, Burkhrt D, Kesten S, Menjoge S, Decrmer M: for the UPLIFT W Investigtors: A 4-yer tril of tiotropium in ptients with chronic ostructive pulmonry disese. N Engl J Med 2008, 359: Celli BR, Thoms NE, Anderson JA, Ferguson GT, Jenkins CR, Jones PW, Vesto J, Knoil K, Ytes JC, Clverley PM: Effect of phrmcotherpy on rte of decline of lung function in chronic ostructive pulmonry disese: results from the TORCH study. Am J Respir Crit Cre Med 2008, 178: Jones PW, Quirk FH, Bveystock CM, Littlejohns P: A self-complete mesure of helth sttus for chronic irflow limittion: the St. George s Respirtory Questionnire. Am Rev Respir Dis 1992, 145: Americn Thorcic Society: Stndrdiztion of spirometry, 1994 updte. Am J Respir Crit Cre Med 1995, 152: O Donnell D, Flüge T, Gerken F, Hmilton A, We K, Aguilniu B, Mke B, Mgnussen H: Effects of tiotropium on lung hyperinfltion, dyspnoe nd exercise tolernce in COPD. Eur Respir J 2004, 23: Verkindre C, Brt F, Aguilniu B, Fortin F, Guérin JC, Le Merre C, Icono P, Huchon G: The effect of tiotropium on hyperinfltion nd exercise cpcity in chronic ostructive pulmonry disese. Respirtion 2006, 73: Ntionl Emphysem Tretment Tril Reserch Group: A rndomized tril compring lung-volume reduction surgery with medicl therpy for severe emphysem. N Engl J Med 2003, 348: Mltis F, Hmilton A, Mrciniuk D, Hernndez P, Sciur FC, Richter K, Kesten S, O Donnell D: Improvements in symptom-limited exercise performnce over eight hours with once-dily tiotropium in ptients with COPD. Chest 2005, 128: O Donnell DE, Voduc N, Fitzptrick M, We KA: Effect of slmeterol on the ventiltory response to exercise in chronic ostructive pulmonry disese. Eur Respir J 2004, 24: Kohnsl R, Mtinez-Cmlor P, Agusti A, Buist AS, Mnnino DM, Sorino JB: The nturl history of chronic irflow ostruction revisited: n nlysis of the Frminghm offspring cohort. Am J Respir Crit Cre Med 2009, 180: Celli B, ZuWllck R, Wng S, Kesten S: Improvements in resting inspirtory cpcity nd hyperinfltion with tiotropium in COPD with incresed sttic lung volumes. Chest 2003, 124: Celli B, Decrmer M, Kesten S, Liu D, Mehr S, Tshkin DP: UPLIFT Study Investigtors: Mortlity in the 4-yer tril of tiotropium (UPLIFT W )in ptients with COPD. Am J Respir Crit Cre Med 2009, 180: Vssux C, Torre-Bouscoulet L, Zeineldine S, Cortopssi F, Pz-Diz H, Celli BR, Pinto-plt VM: Effects of hyperinfltion on the oxygen pulse s mrker of crdic performnce in COPD. Eur Respir J 2008, 32: Clverley P, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Ytes JC, Vesto J: TORCH investigtors: Slmeterol nd fluticsone propionte nd survivl in chronic ostructive pulmonry disese. N Eng J Med 2007, 356: doi: / Cite this rticle s: Celli et l.: Longitudinl inspirtory cpcity chnges in chronic ostructive pulmonry disese. Respirtory Reserch :66. Sumit your next mnuscript to BioMed Centrl nd tke full dvntge of: Convenient online sumission Thorough peer review No spce constrints or color figure chrges Immedite puliction on cceptnce Inclusion in PuMed, CAS, Scopus nd Google Scholr Reserch which is freely ville for redistriution Sumit your mnuscript t