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Lancet. 2009 Oct 3;374(9696):1171-8. doi: 10.1016/S0140-6736(09)61298-8. Epub 2009 Aug 27.

Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial.

Collaborators (501)

Schiavi E, Casas JC, Rhodius E, Gené R, Sáenz CB, Giugno E, Di Bartolo C, De Salvo MC, Abbate E, López AM, Steinfort C, Peters M, Carroll P, Simpson G, Freiberg D, Fogarty P, Watts R, Wheatley J, Vetter N, Burghuber O, Hesse C, Flicker M, Kähler C, Bral G, Carron K, Coolen D, De Backer W, De Beukelaar T, Decramer M, Deman R, Dewispelaere B, Driesen P, Elinck W, Mentens Y, Vandeurzen K, Van Renterghem D, Van Zandweghe L, Verhaeghe W, Vincken W, Delaunois L, Duchatelet P, Noseda A, Nuttin G, Rodenstein D, Thibaut-Baudrez A, Vandermoten G, Wackenier-Genard P, Baldassarre S, Schlesser M, Barreto SS, Corrêa JC, da Silva LC, Fiss E, Chibante AM, de Mattos WL, Fritscher CC, de Oliveira JA, Pizzichini E, Neves M, Cruz A, Pereira CA, Cukier A, Stirbulov R, Jardim JR, Kalandrova K, Novakova M, Hartman P, Jensovsky V, Vacek J, Kasak V, Erban J, Kalina P, Chlumsky J, Musil J, Hojka I, Havlikova A, Mares J, Klenha K, Vondra V, Havlik M, Parakova Z, Vlcek J, Dvorakova J, Mazacova H, Velart D, Pospisil L, Zajicova O, Kolman P, Binková I, Fratrik J, Lange P, Backer V, Dahl R, Harving H, Tønnesen P, Munch E, Rasmussen OB, Tougaard L, Egede F, Hansen NC, Høegholm A, Rasmussen FV, Jakobsen KS, Wessels J, Frandsen JL, Evald T, Hilskov J, Garsdal P, Nielsen C, Haahr S, Korsgaard J, Revsbeck PA, Hansen JG, Soerensen T, Arnved JR, Møller A, Enevoldsen H, Døssing M, Christensen P, Christensen KD, Frølund L, Venho K, Pietiläinen M, Saarelainen P, Kotaniemi J, Männistö J, Aubier M, Pigearias B, Malaquin F, Grunchec N, Bernabeu L, Carme B, Prud'homme A, Bonte F, Boz D, Meunier R, Rasolojaona MT, Apprill M, Fargeon R, Bernard P, Tirouvanziam F, Legendre M, Jasnot JY, Barczok M, Becker JC, Pilz M, Grimm-Sachs V, Jahn M, Kemmerich B, Vorderstrasse W, Klein G, Kroemer B, Lehnert J, Redlich R, Schmidtmann S, Schultz T, Weber HH, Siafakas N, Anagnostopoulou O, Toubis M, Gourgoulianis K, Sichletides L, Kakoura M, Christaki P, Lychros I, Spiropoulos K, Bousmoukilia S, Hui DS, Yu WC, Chan HS, Wong ML, Baliko Z, Bisits M, Böszörményi G, Marton M, Fonay K, Györi Z, Hajdu L, Lukács J, Kovacs G, Magyar P, Nagy G, Namenyi M, Meszaros E, Petö L, Somfay A, Kiraly Z, Strausz J, Szalai Z, Szilasi M, Szima B, Sztancsik Z, Costello R, Burke C, Paggiaro PL, Mazzocchi P, Cattaneo C, Peccini F, Dottorini M, Dottorini M, Tazza R, Pirina P, Ginesu F, Ortu R, Sugamiele M, Mastroberardino M, Anzalone G, Canonica GW, De Benedetto F, Falcone F, Greco P, Papi A, Ciaccia A, Vincenti R, Parentini G, Tubaldi A, De Rose V, Ferretti G, Gasparini S, Legnani D, Ligia GP, Padua V, Santelli G, Mazza F, Boccieri MG, Cogo R, Pegna AL, Pistolesi M, Colorizio V, Zanon P, Nishimura M, Yamauchi K, Ogawa H, Hattori T, Ichinose M, Kimura K, Kaneko N, Seyama K, Fukuchi Y, Kubo K, Taniguchi H, Hirata K, Tohda Y, Aizawa H, Matsumoto S, Sakalauskas R, Bagdonas A, Nargela RV, Mahayiddin AA, Harun R, Liam CK, Peregrina JR, Castañón JJ, Valay RP, Martínez RH, Peregrina AD, van Noord J, Aalbers R, Creemers JP, Dalinghaus WH, Eland ME, Pannekoek BJ, Pasma HR, Rudolphus A, Damsté HE, Evers WB, Gans SJ, Timmer H, Westbroek J, Black P, Epton M, Dahle R, Eivindson A, Asmervik J, Lier PA, Cañizares-Fernandez L, Guzman-Banzon A, Aquino T, Sy-Naval S, Trinidad T, Gorecka D, Plusa TP, Pisarczyk-Bogacka E, Gorski P, Kozielski J, Pierzchala W, Szczeklik A, Kuna P, Slominksi JM, Almeida J, Sá R, Bárbara C, Pato R, Moita J, Cardoso J, Chuchalin AG, Ovtcharenko S, Nonikov V, Ilkovich M, Tsoi A, Wang YT, Lo C, Lim TK, Kristufek P, Chovan L, Rozborilova E, Salat D, Plutinsky J, Suskovic S, Kosnik M, Turel M, Rezar L, Ulcar-Kostic S, Ras GJ, Du Toit JJ, Herbst L, van der Linden M, Nel AM, Jansen JJ, Bester FC, Colyn HJ, Abdullah I, Abdullah IA, Bateman E, Heredia Budó JL, Pardo JM, Miravitlles M, Alonso JL, Val Adán P, Morera J, Ferrer J, Alvarez-Sala JL, Francés JF, Otero FF, Alvarez MJ, Hernando HV, Pérez AM, Flix SH, Bendito AS, Gimeno RB, Montemayor T, Fernández-Montes CV, Vazquez SN, Peña VS, Goday MR, Villar AB, Olivas RB, Candeira SR, Agustí A, Ancochea J, Trigo JM, González-Moro JM, Brotons B, Merino J, Tordera MP, Ruiz FO, Encuentra AL, Batista JJ, Pinilla FJ, Agüero R, Russi E, Solèr M, Tamm M, Bräendli O, Pons M, Tschopp JM, Hess T, Kuo HP, Shiao GM, Pothirat C, Wongtim S, Kiatboonsri S, Dejsomritrutai W, Boonsawat W, Erk M, Tuncay E, Celikel T, Caglayan B, Tabak L, Cöplü L, Ardiç S, Ucar N, Mirici A, Kocabas A, Erginel S, Cimrin AH, Mansur A, Bucknall C, Griffiths P, Halpin D, Morgan M, Morice A, Anderson P, Plant P, Britton M, Harrison T, Crooks S, Shales D, Douglas G, Gravil J, Altose MD, Amgott T, Andrews CP, Cote C, Averill F, Bailey W, Bensch G, Bleecker ER, Koh D, Block M, Braman S, Brannen AL, Brazinsky SA, Bruya T, Callahan D, Celli B, Condemi JJ, Corser B, Osmanski J, Craig T, Degraff A, Doherty DE, Anderson M, Doner M, Donohue J, Eichenhorn M, Ettinger N, Govert J, Folz R, Lasky J, Kovitz K, Friedman M, Giessel G, Pomerantz R, Castillo G, Greenwald GI, Hanania N, Hautamaki RD, Henderson W 4th, Heyder A, Hyers T, Ilowite J, Janes M, Kahn R, Harder R, Kaiser H, Kanner RE, Kaye M, Kreitzer S, Lawlor D, Leech I, Levine B, Littner M, Jarmukli N, Liu J, Lorch DG, Mahler D, Make B, Mandel M, Mathur P, Meyer DH, Milam MG, Mohsenifar Z, Moriarty T, Otoshi J, Patel R, Pratt A, Prenner B, Rehm J, Repsher L, Ries A, Rock KB, Sharafkhaneh A, San Pedro G, Scanlon PD, Scheinberg P, Schelbar EJ, Schul J, Fine J, Segall N, Seibert A, Serfillipi GL, Spirn I, Sussman R, Tashkin D, Wachtel A, Westerman J, Wise RA, Zielinski R, ZuWallack R, Ferguson G, Gelb A, Kuschner W, Mahutte K, Martinez F, Plautz M, Rochester C, Schilero G, Tino G, Turino G, Keppel J.

Abstract

BACKGROUND:

The beneficial effects of pharmacotherapy for chronic obstructive pulmonary disease (COPD) are well established. However, there are few data for treatment in the early stages of the disease. We examined the effect of tiotropium on outcomes in a large subgroup of patients with moderate COPD.

METHODS:

The Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) study was a randomised, double-blind, placebo-controlled trial undertaken in 487 centres in 37 countries. 5993 patients aged 40 years or more with COPD were randomly assigned to receive 4 years of treatment with either once daily tiotropium (18 microg; n=2987) or matching placebo (n=3006), delivered by an inhalation device. Randomisation was by computer-generated blocks of four, with stratification according to study site. In a prespecified subgroup analysis, we investigated the effects of tiotropium in patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II disease. Primary endpoints were the yearly rates of decline in prebronchodilator forced expiratory volume in 1 s (FEV(1)) and in postbronchodilator FEV(1), beginning on day 30 until completion of double-blind treatment. The analysis included all patients who had at least three measurements of pulmonary function. This study is registered with ClinicalTrials.gov, number NCT00144339.

FINDINGS:

2739 participants (mean age 64 years [SD 9]) had GOLD stage II disease at randomisation (tiotropium, n=1384; control, n=1355), with a mean postbronchodilator FEV(1) of 1.63 L (SD 0.37; 59% of predicted value). 1218 patients in the tiotropium group and 1157 in the control group had three or more measurements of postbronchodilator pulmonary function after day 30 and were included in the analysis. The rate of decline of mean postbronchodilator FEV(1) was lower in the tiotropium group than in the control group (43 mL per year [SE 2] vs 49 mL per year [SE 2], p=0.024). For prebronchodilator pulmonary function, 1221 patients in the tiotropium group and 1158 in the control group had three or more measurements and were included in the analysis. The rate of decline of mean prebronchodilator FEV(1) did not differ between groups (35 mL per year [SE 2] vs 37 mL per year [SE 2]; p=0.38). Health status, measured with the St George's Respiratory Questionnaire, was better at all timepoints in the tiotropium group than in the control group (p</=0.006 for all timepoints). Time to first exacerbation and time to exacerbation resulting in hospital admission were also longer in the tiotropium group than in the control group (hazard ratio 0.82, 95% CI 0.75-0.90, and 0.74, 0.62-0.88, respectively).

INTERPRETATION:

Tiotropium seemed to reduce the rate of decline of postbronchodilator FEV(1) in patients with GOLD stage II COPD. This finding and the other improvements in outcomes suggest that treatment of COPD should begin at an early stage of the disease.

FUNDING:

Boehringer Ingelheim and Pfizer Pharmaceuticals.

PMID:
19716598
DOI:
10.1016/S0140-6736(09)61298-8
[Indexed for MEDLINE]

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