Supplementary Appendix

Transcript

Supplementary Appendix
This appendix has been provided by the authors to give readers additional information about their work.
Supplement to: Wise RA, Anzueto A, Cotton D, et al. Tiotropium Respimat inhaler and the risk of death in COPD.
N Engl J Med 2013. DOI: 10.1056/NEJMoa1303342
Contents
Appendix 1
TIOSPIR investigators
3
Appendix 2
Committees
Scientific Steering Committee
13
Data Monitoring Committee
13
Mortality Adjudication Committee
13
Appendix 3
Mortality Adjudication Committee—Principles of Operation
14
Appendix 4
Figure S1. Participant Disposition
17
Appendix 5
Kaplan-Meier Plots
Figure S2. Time to Premature Discontinuation
18
Figure S3. Time to First Severe Exacerbation
19
Figure S4. Time to MACE
20
Figure S5. Time to Death (Including Vital Status Follow-up)—Tiotropium Respimat 5
µg Versus Tiotropium HandiHaler 18 µg
21
Figure S6. Time to Onset of Fatal Event (On treatment only)—Tiotropium Respimat
5 µg versus tiotropium HandiHaler 18 µg
22
Figure S7. Time to First Exacerbation—Tiotropium Respimat 5 µg Versus
Tiotropium HandiHaler 18 µg
23
Appendix 6
Figure S8. Spirometry Substudy: Trough FEV1
24
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Appendix 7
Figure S9. Predefined Subgroup Analyses of Mortality—Tiotropium Respimat 5 µg
Versus Tiotropium HandiHaler 18 µg (Vital Status Follow up)
25
Figure S10. Predefined Subgroup Analyses of Mortality—Tiotropium Respimat 2.5 µg
Versus Tiotropium HandiHaler 18 µg (Vital Status Follow up)
27
Figure S11. Predefined Subgroup Analyses of COPD Exacerbations—Tiotropium
Respimat 5 µg Versus Tiotropium HandiHaler 18 µg
29
Figure S12. Subgroup Analyses of COPD Exacerbations: Tiotropium Respimat 2.5 µg
Versus Tiotropium HandiHaler 18 µg
31
Appendix 8
Table S1. Baseline Characteristics of the Participants
33
Appendix 9
Table S2. Adjudicated Primary Causes of Death (“Other” Category in Table 2)
36
Table S3. Adjudicated Primary Causes of Death (“Other Cardiovascular” Category in
Table 2)
38
Table S4. Serious Adverse Events
39
Table S5. Adverse Events Leading to Discontinuation
50
Table S6 Adverse Events Related to Study Treatment
53
Appendix 10
Table S7. Mortality Rates in Four Pooled Tiotropium Respimat Trials 205.254, 205.255,
205.372, 1205.14 (A) and in UPLIFT (B)
55
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Appendix 1: TIOSPIR investigators
Argentina
X. Bocca; J. Casas; H. Defranchi; P. Elias; M. Fernández; S. Figueroa; E. Giugno; S.
Mannarino; L. Marzoratti; A. Medina; J. Nogueira; R. Olmo; A. Rodriguez; R. Rojas; M. Salvo; L.
Wehbe; A. Yañez;
Australia
P. Fogarty; M. Holmes; D. Langton; M. Phillips; A. Southcott; A. Veale; Austria: O. Ablinger; M.
Sweilem; R. Voves;
Belgium
Y. Balthazar; M. Beutels; M. De Meulemeester; M. Decramer; Y. Devresse; T. Eykerman; O.
Maury; G. Vereecken; J. Weckx;
Brazil
R. Adalberto; R. Dias; E. Fiss; J. Jardim; F. Lastebasse; L. Losso; F. Lundgren; B. Maranhao;
D. Mello; E. Pizzichini; F. Studart; L. Waldo;
Bulgaria
A. Dancheva; V. Dimitrov; R. Dimitrova; D. Dimova; V. Hodzhev; K. Kostov; D. Osmanliev; K.
Palaveev; D. Popov; M. Simeonova; B. Stefanova; V. Youroukova;
Canada
E. Amer; A. Bailey; K. Bayly; A. Bell; J. Bouchard; P. Boucher; J. Braidy; G. Cox; B. Craig; D.
Dattani; A. Dhar; A. Dowell; F. Ervin; T. Fera; S. Field; M. FitzGerald; G. Fox; J. Gauthier; R.
Goldstein; S. Goulet; R. Hart; S. Henein; K. Ho; R. Hodder; L. Homik; P. Houle; D. Kanawaty; A.
Kaplan; A. Kelly; K. Killian; P. Killorn; P. Lachance; S. Lam; D. Landry; B. Lasko; J. Leech; R.
Luton; D. Marciniuk; I. Mayers; R. Michael; A. Nayar; D. O'Donnell; D. O'Keefe; M. O'Mahony;
W. O'Mahony; M. Palayew; S. Ralph; W. Ramesh; Q. Rizvi; D. Rolf; A. Sharma; R. Tytus; B.
Zidel;
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China
C. Bai; S. Cai; G. Chen; P. Chen; P. Chen; S. Cui; Z. Gao; G. Ge; C. Hu; J. Huang; M. Huang;
W. Huang; Y. Huang; H. Jiang; J. Li; Y. Li; Y. Lin; C. Liu; J. Liu; Y. Liu; Z. Luo; X. Sun; Y. Tang;
H. Wan; H. Wang; Z. Wen; C. Wu; Y. Wu; Z. Xiao; J. Xin; J. Yang; K. Ying; W. Yu; J. Zhang; L.
Zhao; Z. Zhao; X. Zhong; J. Zhou; X. Zhou;
Colombia
G. Cardona; H. Giraldo; D. Isaza; C. Matiz; C. Tirado;
Croatia
L. Bulat; L. Glad; T. Gluncic; P. Gordana; I. Gudelj; M. Horvat; A. Markovic; K. Mise; F. Pavicic;
M. Samarzija; S. Skrinjaric-Cincar; G. Stjepanovic; N. Tudoric; Z. Vrbica;
Denmark
V. Backer; K. Brockelmann; R. Dahl; M. Dolberg; V. Dzajic; V. Dzajic; B. Enk; S. Garne; M.
Hansen; G. Jensen; C. Johnsen; S. Kindt; B. Lavik; A. Møller; C. Nielsen; S. Nielsen; T.
Sørensen; I. Titlestad;
Finland
H. Ekroos; J. Elo; A. Hakulinen; J. Kotaniemi; L. Pusa; T. Rantala; I. Strander;
France
N. Abenhaim; J. Aroun; P. Auré; C. Baranes; P. Bayle; C. Beaurain; A. Bellessort; P. Bellvert; A.
Bettendorf; D. Beuzelin; D. Biquet; O. Bisch; P. Blouin; L. Boisseau; D. Bonneau; C. Bortolotti;
L. Boucher; M. Boukhana; P. Bourcq; A. Boye; P. Boyer; N. Breton; B. Buffard; D. Cadinot; A.
Campagne; B. Ceccarelli; G. Chaigneau; Y. Couffin; L. Coutrey; B. Daguzan; G. Delamare; D.
Delsart; M. Delvallez; J. Dillinger; A. Ducolone; G. Durel; D. Dusser; R. Ferrier; C. Fivel; T.
Frappé; E. Garrel; A. Goby; P. Hasselmann; M. Herent; B. Hersen; T. Humbert; N. Jude; E.
Kellou; F. Lacoin; G. Lalanne; M. Larrousse; B. Lauer; M. Legendre; D. Lejay; B. Lemarie; P.
Leprince; A. Lion; J. Lopez; C. Lousqui; B. Mannessier; D. Marin; M. Marlier; P. Marmor; G.
Martocq; B. Meme; P. Mercier; P. Michellier; D. Milosevic; J. Molinier; J. Moreul; Y. Mostefai; S.
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Mouel; M. Moulla; D. Parent; C. Perrin; D. Petit; E. Peyre; E. Pierot; C. Pinet; M. Pouget; P.
Remaud; D. Richter; J. Roger; P. Rolle; T. Schaupp; A. Sebbah; L. Specht; D. Taminau; P.
Tardif; P. Touzet; P. Triot; J. Troussier; J. Troussier; J. Unal; P. Verdavoine; J. Vogel; J. Wurtz;
D. Zimmermann;
Georgia
V. Chumburidze; M. Gotua; V. Katsarava; I. Khintibidze; B. Kobulia; T. Maglakelidze; K.
Vacharadze;
Germany
H. Alakmeh; G. Althammer; A. Babyesiza; E. Beck; A. Benedix; P. Berg; F. Berger; F. Bert; U.
Bettig; U. Botzen; C. Büttner; R. Deckelmann; E. Degtyareva; R. Dichmann; W. Dorsch; J.
Eckhard; A. Eilers; P. Entzian; W. Erdle; J. Feimer; F. Feldmeyer; W. Feußner; K. Förster; K.
Franz; H. Frick; A. Fritzsche; W. Gams; U. Gehling; C. Geßner; T. Ginko; D. Glatzel; D. Grill; V.
Grimm-Sachs; W. Gröschel; B. Groß; W. Großkopf; G. Groth; J. Groth; A. Gummert; K.
Günsberg; H. Hector; G. Heinz; R. Hennig; H. Hering; P. Hofbauer; M. Hoffmann; S. Hofmann;
G. Hoheisel; S. Höltz; G. Hoppe; R. Hüting; B. Jasch; M. Jezek; J. Junggeburth; J.
Kampschulte; F. Kannieß; F. Käßner; S. Kehm; O. Kestermann; J. Kirschner; U. Kleinecke-Pohl;
R. Knorr; M. Krüll; P. Kühne; C. Kuschel; G. Lammert-Hünger; T. Lienert; A. Linnhoff; M.
Luttermann; D. Mahlo; M. Malek; C. Mallinckrodt; I. Marten; H. Martin; S. Mindt; H. Mueller; I.
Naudts; A. Nieß; D. Patzer; H. Pfeuffer; M. Pilz; K. Pumpe; J. Purgaj; B. Raack; W. Rau; R.
Redlich; J. Reichhardt; V. Richter; P. Riegel; M. Rolke; P. Salbach; R. Sauer; O. Schmidt; S.
Schmidtmann; B. Schmorell; H. Schneider; W. Schröder-Babo; W. Schürmann; M. Sebert; V.
Seiz; H. Steffen; I. Steinebach; G. Stöckle; E. Streck; K. Stuff; P. Stutz; F. Talkner; H. Trauth; P.
Van Bodegom; W. Venske; W. Vorderstrasse; M. Waltert; H. Weber; S. Wehgartner-Winkler; A.
Weihrich; C. Welss; M. Werner; U. Westerhausen; K. Weyland; C. Wiederhold; S. Wiemer; E.
Winkelmann; J. Winkler; K. Zemke;
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Great Britain
P. Ainsworth; M. Blagden; B. Bodalia; M. Britton; T. Cahill; A. Ellery; T. Gooding; D. Halpin; A.
Middleton; M. Nordstrom; W. Turner;
Greece
A. Antoniadis; S. Bousmoukilia; M. Christodoulou; M. Gaga; L. Ganavias; E. GeorgatouPapageorgiou; M. Kakoura; K. Kallergis; K. Katsoulis; F. Kokkinis; V. Salesiotou; N. Siafakas; G.
Tatsis; E. Vlachogianni;
Guatemala
O. Diaz; E. Echeverria; A. Ferriño; J. López; J. Moralejo; G. Morales; E. Yoc;
Hungary
Z. Andrasofszky; B. Balint; A. Banvolgyi; A. Bartha; M. Borhy; I. Breining; Z. Csontos; K. Czebe;
M. Czompo; K. Farago; Z. Györi; M. Jedlinszki; Z. Kiraly; N. Kosztyu; Z. Kuberka; K. Major; A.
Nagy; V. Obbagy; M. Rakvács; A. Somfay; Z. Szalai; G. Szantai; I. Szarka; M. Szentesi; E.
Szolnoki; G. Tamas; A. Varga; A. Varga; A. Varga; I. Vekony; K. Visy;
India
A. Balki; K. Jagannath; N. Khippal; A. Malpani; K. Manish; V. Nandagopal; W. Pradyut; N.
Promod; G. Raj; R. Ravindra; P. Rhijwani; K. Srikanth; R. Swarnakar; J. Whig;
Ireland
J. Healy; S. Lane; G. McElvaney; G. McLaughlin; E. Mulloy; A. O'Brien; D. O'Brien; B.
O'Doherty;
Israel
Y. Adir; R. Breuer; G. Fink; M. Kramer; D. Lieberman; Y. Schwarz; D. Shitrit; Z. Weiler;
Italy
G. Anzalone; F. Benedetto; D. Berra; M. Bonavia; C. Calabrese; S. Carlone; A. Casalini; M.
Donno; M. Dottorini; G. Ferrara; C. Gulotta; G. Ligia; E. Marassi; S. Marsico; R. Maselli; M.
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Mastroberardino; R. Ottanelli; F. Pasqua; R. Pela; R. Perra; A. Pesci; M. Pistolesi; S. Salis; G.
Santelli; G. Steinhilber; G. Tassi; R. Torchio; S. Valente; P. Zanon; L. Zucchi;
Republic of Korea
B. Choi; H. Chung; K. In; S. Jeong; K. Kim; S. Kim; Y. Kim; H. Lee; J. Lee; K. Lee; S. Lee; Y.
Lee; S. Lim; H. Moon; Y. Oh; C. Park; Y. Rhee; J. Shim; K. Shin; C. Son; C. Yoo; H. Yum;
Latvia
A. Babjoniseva; M. Bukovskis; A. Gersamija; D. Harasimjukas; R. Iesalniece; N. Kakurina; A.
Krams; Z. Lapkovska; V. Lozovskis; A. Petersone;
Lithuania
I. Davoliene; V. Griskeviciene; A. Kiziela; V. Matukiene; S. Naudziunas; D. Susinskiene; D.
Vaicius; L. Valius; T. Volosevic;
Malaysia
R. Harun; S. How; T. Ismail; K. Khaira; A. Mahayiddin; Y. Pang; N. Razali; N. Tarekh;
Mexico
D. Alcalá; J. Castañón; U. Chavarria; M. Corona; R. Posadas; A. Ramirez; A. Servin-Diaz;
Netherlands
M. Alhakim; A. Amin; P. Coenen; W. Feis; A. Jong; H. van Mierlo; J. van Soest; W. van Erp; V.
Van de Walle;
New Zealand
B. Brockway; M. Epton; J. Gillies; D. Quinn; D. Taylor; E. Walford;
Norway
J. Ahlqvist; S. Arora; O. Brunstad; R. Dahle; B. Ghezai; J. Gronert; S. Henrichsen; S. Jørstad; T.
Karlsson; T. Kristiansen; P. Lier; L. Myhr; T. Tomala;
Panama
E. Guevara; M. Lopez; L. Noriega; Peru: J. Antunez; F. Chariarse; A. Guerreros; D. Ore; R.
Ortega; M. Tsukayama; R. Viladegut;
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Philippines
A. Balgos; M. Bernardo; G. Carlos; M. Ferrer; A. Germar; M. Isidro; M. Jorge; C. Roa;
Poland
W. Andrzejewski; B. Asankowicz-Bargiel; H. Batura-Gabryel; J. Bortkiewicz; K. Brzecki; M.
Cieslak; A. Czerwinska; M. Dabrowska; A. Dargiewicz; M. Dobryniewska; K. Filipek; B. Firek; A.
Gawron; P. Gorski; I. Grzelewska-Rzymowska; R. Harat; G. Jasieniak-Pinis; E. Jassem; J.
Kalamarz; G. Kania; E. Karasek; K. Komnata; A. Kot; V. Labij; E. Laczynska; K. Lis; A. Madej;
D. Madra-Rogacka; D. Malosek; R. Mordaka; R. Mroz; P. Nalepa; P. Napora; D. Pasternak; W.
Pierzchala; P. Piskorz; G. Pulka; I. Rajtar; C. Rybacki; A. Sawicki; A. Senderska; A. SidorowiczBialynicka; H. Szelerska-Twardosz; J. Szymkowiak; E. Trawinska; M. Wlodarczyk; M.
Zurowska-Gebala;
Portugal
A. Almeida; C. Bárbara; C. Bárbara; R. Costa; M. Guimarães; J. Moita; M. Póvoa; A. Reis; P.
Simão;
Romania
T. Alexandru; L. Andrei; G. Apti; I. Copaci; E. Ibraim; P. Leru; F. Nitu; A. Savu; R. Stoenescu; C.
Toma; A. Trailescu;
Russia
E. Alekseeva; V. Arkhipovsky; O. Barbarash; A. Bezlepko; M. Boyarkin; E. Bukreeva; B.
Chernyak; A. Emelyanov; V. Esip; R. Fassakhov; O. Fedorova; N. Galvas; E. Gaydar; M.
Goldin; E. Idrisova; G. Ignatova; M. Ilkovich; A. Ivleva; L. Khaisheva; R. Khamitov; G. Komarov;
O. Korovina; V. Kostin; A. Krivosheev; L. Kukol; E. Lashina; I. Leshchenko; T. Martynenko; V.
Martynenko; I. Motylev; B. Nemtsov; V. Nonikov; L. Ogorodova; V. Oleynikov; M. Osipenko; S.
Ovcharenko; S. Palyutin; S. Pavlishchuk; T. Pistraya; V. Podzolkov; G. Polevtsova; V. Popova;
N. Raspopina; N. Romaschok; I. Ryzhova; G. Shestakova; E. Shmelev; E. Shuganov; Y.
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Shvarts; I. Sidorenko; L. Sidorova; V. Simanenkov; K. Soloviev; I. Stitsenko; V. Trofimov; S.
Ushakova; A. Vizel; V. Zadionchenko; A. Zhestkov;
Serbia
Z. Lazic; M. Milikic; P. Rebic; G. Sovljanski; I. Stankovic; P. Svorcan; B. Zvezdin;
Slovakia
L. Frajtova; A. Golubov; S. Hrebenar; P. Jurco; D. Kavkova; H. Lescisinova; V. Mikova; J.
Plutinsky; E. Pribulova; E. Rozborilova; K. Sarkanova; M. Szarazova; R. Timurova-Zambova;
South Africa
S. Abdool-Gaffar; A. Abdullah; I. Abdullah; E. Bateman; F. Bester; A. Bruning; C. Duvenage; J.
Jansen; J. Joubert; J. O'Brien; G. Ras; J. Richards; D. Richter; H. Van Rensburg;
Spain
R. Agüero; F. Álvarez; B. Barreiro; J. Budó; E. Esplá; A. Fernández; A. Ferrer; A. González; M.
Herero; I. Inchaurraga; J. Lara; L. Llano; E. Macías; J. Manzano; E. Martinez; E. Martínez; J.
Merino; M. Mezquita; J. Morera; R. Olivas; S. Pérez; F. Río; J. Signes-Costa; J. Sustaeta; M.
Terns; J. Trigo; D. Villegas; J. Vizuete;
Sweden
E. Angesjö; I. Barrehag-Vinge; E. Bonnevier; D. Curiac; A. Elfstrand; P. Fardelin; R.
Gunnarsson; P. Lagerbäck; M. Lundgren; L. Paulsson; B. Polhem; K. Romberg;
Switzerland
H. Bettschen; T. Brack; M. Brutsche; G. Domenighetti; E. Köhler; U. Lagler; H. Martin; P.
Matthias; A. Paky; M. Pons; K. Remund; E. Russi; M. Tamm;
Taiwan
S. Cheng; L. Hang; T. Hsiue; J. Hsu; M. Huang; P. Kuo; C. Lin; M. Lin; W. Perng; Y. Tsai; T.
Tsao; C. Wang; Y. Wei; C. Wu;
Thailand
K. Bangpattanasiri; W. Boonsawat; W. Keeratichananont; W. Kositsakulchai; K. Suntrapiwat;
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Tunisia
M. Beji; R. Charfi; I. Drira; H. Ghedira; H. Ghrairi; A. Kamel; A. Kheder; J. Knani; S. Maalej; C.
Rezaiek; F. Tritar;
Turkey
S. Ardic; C. Babayigit; B. Caglayan; A. Cilli; M. Dereli; I. Firat; A. Gorguner; S. Guclu; O.
Hatipoglu; A. Kocabas; F. Kosar; B. Kurt; R. Ozacar; M. Polatli; S. Saryal; C. Sevinc; F. Talay;
H. Turker; O. Yetkin;
Ukraine
L. Amer; V. Blazhko; O. Dyadyk; O. Dzyublyk; Y. Feshchenko; V. Gavrysyuk; O. Godlevska; M.
Iabluchanskyi; L. Iashyna; I. Klyaritskaya; O. Korzh; O. Kovalyova; V. Melnyk; N. Monogarova;
Y. Mostovoiy; M. Ostrovskyy; S. Panina; T. Pertseva; G. Popik; V. Rodionova; V. Savchenko; N.
Shvets; O. Smolyanyy; S. Soldatchenko; V. Sushko; V. Vizir; O. Voloshyna;
United States of America
W. Abel; K. Adams; M. Ali; M. Ali; S. Alkins; G. Allen, Jr.; D. Altamirano; L. Alwine; S. Amar; C.
Andrews; S. Apaliski; J. Arana; N. Arcuri-Kimzey; C. Arena; E. Armas; S. Arora; A. Axelrod; M.
Axler; K. Bailey; S. Barag; M. Barber; B. Barker; M. Baron; P. Barrington; A. Bartkowiak, Jr.; S.
Basheda; P. Bass III; T. Bauch; M. Beacom; R. Beasley; J. Beavins; W. Beliveau; R. Benkert; T.
Bennett; J. Bernstein; S. Bhuchar; V. Bland; K. Blaze; B. Block; J. Boeren; J. Boscia III; B.
Bowling; D. Brautigam; W. Bray; M. Brewer; C. Bricker; J. Brodnan; C. Brown; T. Bruya; J. Burk;
W. Byars; J. Castilleja; C. Cauthen; M. Chen; W. Chi; K. Chinsky; T. Christensen; F. Civitarese;
M. Cohen; S. Cohen; J. Cohn; B. Cole; J. Cole; D. Colvin; J. Condemi; M. Conway; C. Corder;
H. Covelli; M. Cromer; H. Cruz; M. Czarnecki; T. Dao; M. Davis; J. Delgado; D. DeSantis; J.
Dexter; R. Dobrusin; G. Doering; J. Donohue; M. Dransfield; R. Dua; L. Dubois; A. Dulgeroff; L.
Dunn; J. Earl; L. Edmonds; M. Eichenhorn; J. Elacion; S. ElBayadi; D. Elias; M. Ellis; H. Ellison;
P. Emmans, Jr.; D. Erb; N. Ettinger; F. Fakih; R. Fei; G. Feldman; R. Fernandez-Medero; D.
Fitz-Patrick; H. Fleming; C. Fogarty; L. Ford; J. Forman; W. Fowler; N. Fraser; P. Friedman; S.
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Fritz; K. Gallagher; A. Garner; D. Goodman; A. Gorin; J. Graif; D. Grant; J. Gregory; S. Grubb;
P. Grumley; J. Gutmann; G. Hammond; F. Hampel, Jr.; N. Hanania; J. Hansbrough; P. Hartley;
L. Hazan; W. Head; M. Heitbrink; S. Hellems; W. Henderson IV; E. Hendrix; J. Henkle; A.
Heyder; D. Hill; R. Hippert; J. Hoekstra; J. Hoodin; B. House; J. Hoyt; R. Huling; T. Hyers; R.
Ison; T. Jackson; J. Jacobs; L. Jagminas; M. Janes; M. Jardula; D. Jasper; P. Jederlinic; D.
Jenks; A. Jimenez; F. Jimenez; L. Johnson; D. Jones IV; T. Kaelin; F. Kahn; R. Kahn; H. Kaiser;
R. Kalhan; M. Karetzky; J. Karpel; S. Kemp; J. Kessel; M. Khan; J. Kingsley; E. Kleerup; A.
Knight; T. Knutson; A. Koser; S. Kulback; S. Kureishy; J. Labuda II; C. LaForce; A. Laliotis; P.
Laman; C. Landolt; R. Lapidus; M. Lasala; D. Lawlor; D. Layish; H. Le; D. Ledford; D. Lee; H.
Lee; M. Lee; W. Leeds; T. Lemire; D. Levinsky; C. Lichty II; J. Lochner; K. Longshaw; W. Lucht;
L. Lynn; L. Madsen; D. Mahler; S. Makam; L. Maletz; J. Mann; H. Marcelin; J. Mariglio; A.
Marinelli, Jr.; S. Marks; R. Marple; K. Maynard; F. Mazdisnian; E. McCarthy; M. McCartney; J.
McGettigan, Jr.; M. McGuire; D. McNeil; R. McNeill; D. McNicol; K. Mehta; I. Melendez-Rivera;
J. Meli, Jr.; G. Meyers; P. Meyers; M. Milam; M. Millard; R. Miller, Jr.; D. Minnick; S. Minton; V.
Mirkil; E. Moon; M. Moon; J. Morales-Ramirez; J. Moran; T. Moriarty; S. Morin; F. Morris; A.
Murray; H. Murthy; M. Nassery; A. Nayak; B. Nevins; R. Nielsen; J. Nissim; T. Nussdorfer; D.
Oelberg; T. O'Reilly; R. Orr; H. Paez; B. Palchick; G. Parides; J. Parrinello; R. Paster; B. Patel;
N. Patel; W. Patton; J. Pearle; P. Pearlstein; J. Perez; R. Perry; D. Phillips; M. Pieretti; B.
Pogue; R. Pohil; S. Pollard; K. Popovich; J. Porcelli; B. Preston; K. Pritchett; K. Pudi; R.
Purighalla; J. Quigley; S. Radow; M. Raikhel; J. Ramsdell; P. Rastogi; D. Reddy; R. Reddy; A.
Reichman; L. Rice, Jr.; R. Richwine; L. Riffel; E. Riffer; T. Riske; A. Rizzo; E. Robinette; S.
Ross; L. Rudolph; G. Ruoff; P. Sachs; M. Samson; S. Samudrala; J. Sandberg; W. Sargeant; K.
Saxman; P. Scanlon; E. Schachter; E. Schelbar; E. Schramm; R. Schreiman; C. Schroeder; J.
Schul; M. Schwartz; A. Seibert; J. Sensenbrenner; P. Sepulveda; L. Shandilya; P. Shapero; J.
Shea; D. Short; J. Sibille; T. Siler; H. Silverboard; A. Silverthorn; H. Simon; S. Simon; J. Singh;
J. Sippel; C. Smith; K. Smith; R. Solano; L. Somerville; W. Soong; J. Southard; J. Spainhour,
Page 11 of 57
Jr.; J. Speer; W. Spencer; M. Spuza-Milord; D. Steigman; G. Stewart III; C. Straughn; B. Streit;
C. Strumillo; R. Surowitz; G. Tarleton; G. Tarshis; J. Taylor; M. Teltser; J. Tita; R. Topkis; D.
Torres II; M. Turner; J. Updegrove; R. Vaela; S. Verma; E. Viera; M. Villareal; K. Voelker; W.
Walthall; A. Wanderer; J. Wayne; P. Weinberg; R. Weiss; L. Wheatley; J. White; P. Whitten; H.
Wilson, Jr.; O. Wiltz; J. Winder; A. Wine; D. Winslow; R. Wise; J. Wood; K. Wood; S. Yarows; B.
Yergin; T. Yunger; D. Zawadski; R. ZuWallack; K. Zuzarte
Page 12 of 57
Appendix 2: Committees
Scientific Steering Committee:
Antonio Anzueto, USA
Peter Calverley, UK
Ronald Dahl, Denmark
Daniel Dusser, France
Gordon Pledger, USA
Robert Wise, USA (chair)
Data Monitoring Committee:
Paul Corris, UK
Michael Rudolf, UK
Neil Schluger, USA (chair)
Bruce Turnbull, USA
Frans Van de Werf, Belgium
Nicole LaVallee, USA (nonvoting independent statistician)
Mortality Adjudication Committee:
Stefan Anker, Germany
Raymond Browne, USA
Sanford Kempin, USA
Peter Kowey, USA
Lorcan McGarvey, UK (chair)
Sheldon Magder, Canada
Dennis Niewoehner, USA
Claus Vogelmeier, Germany
Page 13 of 57
Appendix 3
TIOSPIR (Protocol 205.452)
Mortality Adjudication Committee—Principles of Operation
Assignment of Primary Cause of Death
The Mortality Adjudication Committee (MAC) will designate probable primary cause of death
when there is disagreement with the principal investigator’s assessment of the primary cause of
death.
The general principles and methods used in the classification are listed below:
1. In cases where the information is incomplete, consideration will be given to the
circumstances of the death and the specificity and source of the available information. A
cause of death will be adjudicated as “unknown cause of death” only if the following criteria
are met:
 If, after relevant clinical information has been requested and all voting MAC members still
feel they are unable to determine the cause of death, the case will be adjudicated as
“unknown cause of death” by Panel Committee determination only.
2. In general, the primary cause of death should be attributed to the disorder that causes the
patient to present for medical treatment. This should be distinguished from terminal events
that are the immediate cause of death.
 For example, if a patient is admitted to the hospital with a chronic obstructive pulmonary
disease (COPD) exacerbation, from which they do not fully recover, and the patient
subsequently develops complications such as pneumonia, respiratory failure, renal failure,
sepsis, or myocardial infarction, the primary cause of death will be attributed to COPD.
 For example, if a patient undergoes surgery for cancer and dies from complications of the
surgery or during the immediate postoperative period, the primary cause of death will be
attributed to cancer, even if the cancer was potentially curable by the surgery.
Page 14 of 57
 All diagnoses of cancer should be based on summary information obtained from the
primary medical record as noted in the documentation provided to the MAC. If available,
documentation should include results from imaging studies, histologic diagnoses,
operative or procedure notes, and records of treatment. Patients who die with an uncured
cancer (which is likely to result in the patient's death in short to medium term) will be
designated as dying from that cancer.
 For example, a patient with documented gastric cancer who dies of gastrointestinal
hemorrhage will be classified to have died from gastric cancer.
 A patient who dies from sepsis resulting from profound neutropenia while undergoing
chemotherapy for lymphoma will be classified as dying from lymphoma.
 If a patient has multiple predisposing conditions upon presenting for medical treatment
that ultimately leads to death, the MAC must select the predisposing condition that is most
likely the cause for death.
3. A COPD exacerbation will be defined (per clinical trial protocol section 5.1.1) as typical
symptoms and clinical signs coupled with standard treatment measures. Diagnosis of
pneumonia in the presence of an exacerbation of COPD should preferably be accompanied
by radiological findings. However, the MAC must select the primary cause of death as either
COPD or pneumonia in the case where there is diagnosis of pneumonia in the presence of
an exacerbation of COPD.
4. In circumstances where a patient presents in their final medical illness with progressive
respiratory symptoms and signs (eg, dyspnea, tachypnea, hypoxemia, hypercapnia) and
bilateral ankle swelling and in the absence of documentary evidence to support an alternative
diagnosis (eg, right and/or left ventricular failure) the primary cause of death will be attributed
to COPD. The attribution to COPD should only be considered in those patients with Global
Page 15 of 57
Initiative for Chronic Obstructive Lung Disease (GOLD) Stage III or IV disease and, if known,
co-existent chronic hypoxemia and hypercapnia.
5. Sudden cardiac death will be recorded as follows: Death occurring within 1 hour of an abrupt
change of a person's clinical state without other obvious noncardiac cause.
6. Sudden death will be recorded as follows: Death occurring more than 1 hour and less than
24 hours of last being observed alive and without evidence of a deteriorating medical
condition.
 The MAC is aware that the Food and Drug Administration (FDA) draft cardiovascular end
point definition document defines sudden cardiac death as a death within 24 hours.
Additionally, the MAC is aware that sudden death is used as a component of major
cardiovascular adverse event (MACE) and will be included in analyses. Due to the fact
that this study population is at high risk for rapid death from pulmonary causes, the MAC
does not feel that it would be appropriate to classify all deaths within 24 hours as cardiac.
Therefore, the MAC will continue to classify deaths as sudden cardiac if they occur within
1 hour, and as sudden death if after 1 hour but within 24 hours of witnessed vitality.
 When was the person last known to be alive?
 When was the person found to be deceased?
 What were the events surrounding the death?
 Did the decedent have any symptoms or change in health status that preceded the death?
Special mention should be made to symptoms such as dyspnea, febrile illnesses, chest
pain, abdominal pain, syncope, seizures, paralysis, and change in mental status.
 Were there recent medical visits or recent changes in medication?
 Was an autopsy performed?
Page 16 of 57
Appendix 4
Figure S1: Participant disposition
Of 17,183 participants randomized, 17,135 received treatment and formed the “modified intent to treat
analysis set”. The modified intent to treat analysis set was analyzed for the primary end point of time to
mortality. Data irregularities were observed at two investigational sites; the 19 participants from these
sites were not included in other analyses (all other safety end points and efficacy end points, including
Page 17 of 57
second primary end point of time to first exacerbation). The remaining 17,116 participants formed the
“treated set”.
Page 18 of 57
Appendix 5: Kaplan-Meier Plots
Figure S2. Time to Premature Discontinuation*
*Treatment discontinuation (premature discontinuation or death) before participants started study closeout after day 660.
Patients who died while still on study medication were censored.
Page 19 of 57
Figure S3. Time to First Severe Exacerbation
On treatment only, treated set.
Page 20 of 57
Figure S4. Time to MACE*
*Fatal or nonfatal MACE. On treatment only, treated set.
MACE denotes major adverse cardiovascular event.
Page 21 of 57
Figure S5. Time to Death (Including Vital Status Follow-up): Tiotropium Respimat 5 µg Versus Tiotropium HandiHaler 18 µg
Page 22 of 57
Figure S6. Time to Onset of Fatal Event (On treatment Only)—Tiotropium Respimat 5 µg Versus Tiotropium HandiHaler 18
µg
Page 23 of 57
Figure S7. Time to First Exacerbation—Tiotropium Respimat 5 µg Versus Tiotropium HandiHaler 18 µg
Page 24 of 57
Appendix 6
Figure S8. Spirometry Substudy—Trough FEV1
MMRM model analyzes trough FEV1 through week 120 using a repeated measures approach. Analyses included the fixed terms for treatment,
investigative site, visit, treatment-by-visit interaction, baseline FEV1, and baseline FEV1-by-visit interaction, and a random term for
patient. Noninferiority was evaluated for treatment main effects using a noninferiority delta of 50 ml. The adjusted mean trough FEV1: absolute
values are as follows: 1.258 L, 1.285 L, and 1.295 for tiotropium Respimat 2.5 µg, Respimat 5 µg, and HandiHaler 18 µg, respectively (average 24
to 120 weeks).
Page 25 of 57
Appendix 7
Figure S9. Predefined Subgroup Analyses of Mortality—Tiotropium Respimat 5 µg Versus Tiotropium HandiHaler 18 µg
(Vital Status Follow up)
A
Page 26 of 57
B
All subgroup variables refer to baseline.
History of cardiac disorder is defined as history of at least one of myocardial infarction, cardiac arrhythmia, New York Heart Association heart
failure Class I–IV, or ischemic heart disease/coronary artery disease.
Exacerbation episode in the last year is defined as the investigator-reported number of chronic obstructive pulmonary disease exacerbations or
worsening episodes in the last year which have been treated with steroids and/or antibiotics.
Page 27 of 57
Figure S10. Predefined Subgroup Analyses of Mortality—Tiotropium Respimat 2.5 µg Versus Tiotropium HandiHaler 18 µg
(Vital Status Follow up)
A
Page 28 of 57
B
Page 29 of 57
Figure S11. Predefined Subgroup Analyses of COPD Exacerbations—Tiotropium Respimat 5 µg Versus Tiotropium
HandiHaler 18 µg
A
Page 30 of 57
B
Page 31 of 57
Figure S12. Subgroup Analyses of Exacerbations—Tiotropium Respimat 2.5 µg Versus Tiotropium HandiHaler 18 µg
A
Page 32 of 57
B
worsening episodes in the last year which have been treated with steroids and/or antibiotics..
Page 33 of 57
Appendix 8
Table S1: Baseline Characteristics of the Participants
Characteristic
Tiotropium
Tiotropium
Tiotropium
Respimat
Respimat 5 µg
HandiHaler 18 µg
2.5 µg
(N=5705)
(N=5687)
71.1
72.5
71.0
Age—year
65.1±9.1
64.9±9.1
65.0±9.0
Body mass index
26.2±5.7
26.2±5.7
26.2±5.7
37.9
38.7
37.7
43.6±24.6
44.1±25.0
43.7±24.7
7.4±6.1
7.4±6.2
7.5±6.2
Europe/Africa/Australia/New Zealand
55.9
56.8
56.2
Latin America
5.8
5.7
6.0
North America
24.5
23.9
23.8
Asia
13.8
13.6
14.0
White
81.8
81.5
81.4
Black
1.3
1.6
1.5
Asian
14.2
14.1
14.3
1.328±0.481
1.352±0.481
1.338±0.473
48.0±13.9
48.5±13.8
48.4±13.9
FVC—liters
2.696±0.848
2.726±0.843
2.716±0.843
Ratio of FEV1 to FVC
0.498±0.115
0.501±0.114
0.498±0.114
(N=5724)
Male sex—%
Smoking status
Current smoker—%
Smoking history—pack-year
Duration of COPD—year
Geographic region—%
Race—%*
Spirometry—postbronchodilation
FEV1—liters Ӂ
FEV1—% of predicted value
Page 34 of 57
GOLD stage—%†
FEV1 ≥80%
0.2
0.3
0.2
50% ≤FEV1 <80%
46.8
48.1
48.0
30% ≤FEV1 <50%
40.2
40.1
39.7
FEV1 <30%
11.4
10.0
10.9
10.6
10.8
10.7
None
91.8
92.2
92.3
Class I
3.3
3.2
2.7
Class II
3.9
4.0
4.3
Class III
0.8
0.5
0.6
Class IV
0.0
0.0
0.1
Myocardial infarction
5.9
5.9
6.1
Stroke
2.2
2.4
2.2
Ischemic heart disease/coronary artery
14.8
15.0
15.7
90.8
90.3
90.7
Short-acting‡
17.3
17.5
17.1
Long-acting
46.5
46.8
47.3
Short-acting
54.4
53.1
53.3
Long-acting‡
61.9
61.2
62.3
Inhaled‡
58.9
58.8
59.4
Oral
5.0
4.3
4.7
History of cardiac disorder—%
Cardiac arrhythmia
Heart failure class
disease
Respiratory medication—%
Any
Inhaled anticholinergics
Inhaled β-agonists
Corticosteroids
Page 35 of 57
Leukotriene receptor antagonists
2.6
2.5
2.6
Mucolytics
7.1
7.2
7.4
Supplemental oxygen
4.2
3.9
4.2
Xanthines
15.9
15.4
15.5
Phosphodiesterase 4 inhibitor
0.1
0.3
0.3
51.7
50.9
50.8
β-blockers
14.5
14.1
14.6
Calcium channel blockers
17.9
18.1
17.2
Angiotensin-converting enzyme
20.9
21.0
20.2
Angiotensin II receptor blockers
11.6
11.6
11.1
Nitrates
3.9
4.2
4.2
Acetylsalicylic acid
18.9
19.2
19.7
Cardiovascular medication—%
Any
inhibitors
Data are for the treated set (total N=17,116).
Plus-minus values are means ±SD. The body mass index is the weight in kilograms divided by the square
of the height in meters.
COPD denotes chronic obstructive pulmonary disease; FEV1 is forced expiratory volume in 1 second,
FVC is forced vital capacity, GOLD is Global Initiative for Chronic Obstructive Lung Disease.
*Race was not collected in France, thus 468 participants (2.7%) have race missing.
†Data were missing for 43 participants in this category, 193 participants had FEV1/FVC at least 70% and
are therefore not categorized here.
‡Used either alone or as a fixed combination.
Ӂ P-value <0.05 for baseline FEV1 (liters); P-values are based on F-tests for the continuous variables
and on Chi-Squared tests for the categorical variables.
Page 36 of 57
Appendix 9
Table S2. Adjudicated Primary Causes of Death (“Other” Category in Table 2)
Tiotropium
Tiotropium
Tiotropium
Respimat 2.5 µg
Respimat 5 µg
HandiHaler 18 µg
(N=5730)
(N=5711)
(N=5694)
33 (0.6)
35 (0.6)
51 (0.9)
Hepatobiliary disorders
3 (0.1)
1 (0.0)
2 (0.0)
Infections and infestations
7 (0.1)
9 (0.2)
9 (0.2)
Psychiatric disorders
1 (0.0)
2 (0.0)
4 (0.1)
Gastrointestinal disorders
6 (0.1)
10 (0.2)
16 (0.3)
Nervous system disorders
3 (0.1)
2 (0.0)
2 (0.0)
General disorders and administration site conditions
0 (0.0)
0 (0.0)
2 (0.0)
Injury, poisoning, and procedural complications
11 (0.2)
11 (0.2)
16 (0.3)
Musculoskeletal and connective tissue disorders
1 (0.0)
0 (0.0)
0 (0.0)
Renal and urinary disorders
1 (0.0)
0 (0.0)
0 (0.0)
System organ class
Other causes of death not included in Table 2, N (%)
Page 37 of 57
Table S3. Adjudicated Primary Causes of Death (“Other Cardiovascular” Category in Table 2)
Tiotropium
Tiotropium
Tiotropium
Respimat 2.5 µg
Respimat 5 µg
HandiHaler 18 µg
(N=5730)
(N=5711)
(N=5694)
17 (0.3)
21 (0.4)
19 (0.3)
Cardiac death
0 (0.0)
2 (0.0)
0 (0.0)
Cardiac failure
1 (0.0)
5 (0.1)
3 (0.1)
Cardiac failure congestive
5 (0.1)
3 (0.1)
4 (0.1)
Aortic valve stenosis
1 (0.0)
0 (0.0)
1 (0.0)
Cardiac arrest
2 (0.0)
1 (0.0)
1 (0.0)
Cardiac failure acute
0 (0.0)
1 (0.0)
1 (0.0)
Cardiac failure chronic
0 (0.0)
1 (0.0)
1 (0.0)
Cardiac valve disease
0 (0.0)
1 (0.0)
0 (0.0)
Congestive cardiomyopathy
0 (0.0)
0 (0.0)
1 (0.0)
Cor pulmonale
1 (0.0)
1 (0.0)
1 (0.0)
Coronary artery disease
0 (0.0)
1 (0.0)
1 (0.0)
Coronary artery insufficiency
0 (0.0)
2 (0.0)
0 (0.0)
Ischemic cardiomyopathy
1 (0.0)
0 (0.0)
0 (0.0)
Myocardial ischemia
1 (0.0)
0 (0.0)
0 (0.0)
Aortic aneurysm
2 (0.0)
0 (0.0)
2 (0.0)
Preferred term
Other cardiovascular not included in Table 2, N (%)
Page 38 of 57
Aortic aneurysm rupture
1 (0.0)
0 (0.0)
1 (0.0)
Aortic dissection
1 (0.0)
0 (0.0)
1 (0.0)
Aortic rupture
1 (0.0)
0 (0.0)
0 (0.0)
Aortic stenosis
0 (0.0)
1 (0.0)
0 (0.0)
Arteriosclerosis
0 (0.0)
1 (0.0)
0 (0.0)
Peripheral ischemia
0 (0.0)
0 (0.0)
1 (0.0)
Peripheral vascular disorder
0 (0.0)
1 (0.0)
0 (0.0)
Page 39 of 57
Table S4. Serious Adverse Events*
System organ class/preferred term
Tiotropium Respimat
Tiotropium Respimat
Tiotropium HandiHaler
2.5 µg
5 µg
18 µg
N
(%)
N
(%)
N
(%)
Number of patients
5724
(100.0)
5705
(100.0)
5687
(100.0)
Total with serious adverse events
1937
(33.8)
1846
(32.4)
1842
(32.4)
Respiratory, thoracic, and mediastinal disorders
1017
(17.8)
957
(16.8)
964
(17.0)
895
(15.6)
868
(15.2)
851
(15.0)
Respiratory failure
42
(0.7)
40
(0.7)
35
(0.6)
Acute respiratory failure
30
(0.5)
32
(0.6)
28
(0.5)
Pulmonary embolism
28
(0.5)
28
(0.5)
24
(0.4)
Dyspnea
24
(0.4)
17
(0.3)
21
(0.4)
Pneumothorax
25
(0.4)
25
(0.4)
21
(0.4)
Hemoptysis
10
(0.2)
8
(0.1)
13
(0.2)
Bronchospasm
2
(0.0)
4
(0.1)
7
(0.1)
Epistaxis
6
(0.1)
1
(0.0)
4
(0.1)
Hypoxia
3
(0.1)
8
(0.1)
8
(0.1)
Pleural effusion
6
(0.1)
8
(0.1)
10
(0.2)
Pneumonia aspiration
7
(0.1)
3
(0.1)
4
(0.1)
Pulmonary mass
5
(0.1)
4
(0.1)
10
(0.2)
Chronic obstructive pulmonary disease
Page 40 of 57
Respiratory distress
Tiotropium Respimat
Tiotropium Respimat
2.5 µg
5 µg
18 µg
N
(%)
N
(%)
N
(%)
7
(0.1)
1
(0.0)
1
(0.0)
497
(8.7)
502
(8.8)
495
(8.7)
339
(5.9)
344
(6.0)
340
(6.0)
Lobar pneumonia
16
(0.3)
15
(0.3)
12
(0.2)
Sepsis
18
(0.3)
22
(0.4)
16
(0.3)
Bronchitis
16
(0.3)
9
(0.2)
11
(0.2)
6
(0.1)
14
(0.2)
14
(0.2)
16
(0.3)
8
(0.1)
8
(0.1)
Urinary tract infection
9
(0.2)
22
(0.4)
6
(0.1)
Appendicitis
7
(0.1)
6
(0.1)
7
(0.1)
Bronchopneumonia
4
(0.1)
3
(0.1)
4
(0.1)
Cystitis
2
(0.0)
3
(0.1)
4
(0.1)
Diverticulitis
9
(0.2)
6
(0.1)
6
(0.1)
11
(0.2)
5
(0.1)
8
(0.1)
Influenza
4
(0.1)
6
(0.1)
2
(0.0)
Pyelonephritis
6
(0.1)
6
(0.1)
2
(0.0)
Respiratory tract infection
3
(0.1)
7
(0.1)
3
(0.1)
Pneumonia
Cellulitis
Infective exacerbation of chronic obstructive airways disease
Gastroenteritis
Page 41 of 57
Tiotropium Respimat
Tiotropium Respimat
2.5 µg
5 µg
18 µg
N
(%)
N
(%)
N
(%)
Septic shock
6
(0.1)
6
(0.1)
12
(0.2)
Upper respiratory tract infection
4
(0.1)
5
(0.1)
3
(0.1)
Urosepsis
7
(0.1)
2
(0.0)
4
(0.1)
293
(5.1)
273
(4.8)
270
(4.7)
53
(0.9)
45
(0.8)
39
(0.7)
Atrial fibrillation
41
(0.7)
37
(0.6)
32
(0.6)
Angina pectoris
20
(0.3)
28
(0.5)
22
(0.4)
Cardiac failure
30
(0.5)
23
(0.4)
24
(0.4)
Cardiac failure congestive
26
(0.5)
22
(0.4)
29
(0.5)
Coronary artery disease
18
(0.3)
25
(0.4)
23
(0.4)
Acute myocardial infarction
21
(0.4)
21
(0.4)
13
(0.2)
Angina unstable
10
(0.2)
19
(0.3)
10
(0.2)
Cardiac arrest
12
(0.2)
7
(0.1)
9
(0.2)
Cardiopulmonary failure
9
(0.2)
11
(0.2)
9
(0.2)
Acute coronary syndrome
4
(0.1)
3
(0.1)
9
(0.2)
Arrhythmia
5
(0.1)
8
(0.1)
7
(0.1)
Atrial flutter
10
(0.2)
6
(0.1)
4
(0.1)
Cardiac disorders
Page 42 of 57
Tiotropium Respimat
Tiotropium Respimat
2.5 µg
5 µg
18 µg
N
(%)
N
(%)
N
(%)
Cardiac failure acute
4
(0.1)
4
(0.1)
6
(0.1)
Cardiorespiratory arrest
9
(0.2)
5
(0.1)
8
(0.1)
Cardiomyopathy
3
(0.1)
4
(0.1)
3
(0.1)
Cor pulmonale
4
(0.1)
4
(0.1)
6
(0.1)
Cor pulmonale chronic
3
(0.1)
2
(0.0)
4
(0.1)
Coronary artery stenosis
6
(0.1)
2
(0.0)
3
(0.1)
Myocardial ischemia
7
(0.1)
7
(0.1)
11
(0.2)
Supraventricular tachycardia
1
(0.0)
3
(0.1)
6
(0.1)
279
(4.9)
274
(4.8)
250
(4.4)
Lung neoplasm malignant
52
(0.9)
60
(1.1)
48
(0.8)
Basal cell carcinoma
17
(0.3)
26
(0.5)
15
(0.3)
Prostate cancer
17
(0.3)
17
(0.3)
14
(0.2)
Bladder cancer
13
(0.2)
10
(0.2)
4
(0.1)
Colon cancer
13
(0.2)
4
(0.1)
10
(0.2)
Squamous cell carcinoma
9
(0.2)
12
(0.2)
19
(0.3)
Bladder neoplasm
5
(0.1)
1
(0.0)
4
(0.1)
Neoplasms benign, malignant, and unspecified (including cysts and
polyps)
Page 43 of 57
Tiotropium Respimat
Tiotropium Respimat
2.5 µg
5 µg
18 µg
N
(%)
N
(%)
N
(%)
Breast cancer
8
(0.1)
8
(0.1)
4
(0.1)
Bronchial carcinoma
8
(0.1)
7
(0.1)
4
(0.1)
Gastric cancer
6
(0.1)
3
(0.1)
4
(0.1)
Lung adenocarcinoma
10
(0.2)
9
(0.2)
6
(0.1)
Lung cancer metastatic
3
(0.1)
7
(0.1)
9
(0.2)
Lung neoplasm
6
(0.1)
7
(0.1)
5
(0.1)
Malignant melanoma
2
(0.0)
3
(0.1)
4
(0.1)
Metastases to central nervous system
9
(0.2)
0
(0.0)
2
(0.0)
Metastases to liver
6
(0.1)
3
(0.1)
3
(0.1)
Nonsmall cell lung cancer
6
(0.1)
5
(0.1)
5
(0.1)
Pancreatic carcinoma
6
(0.1)
6
(0.1)
7
(0.1)
Small cell lung cancer
3
(0.1)
5
(0.1)
4
(0.1)
Squamous cell carcinoma of lung
6
(0.1)
6
(0.1)
6
(0.1)
Transitional cell carcinoma
4
(0.1)
5
(0.1)
1
(0.0)
152
(2.7)
148
(2.6)
140
(2.5)
Gastrointestinal hemorrhage
11
(0.2)
12
(0.2)
8
(0.1)
Inguinal hernia
10
(0.2)
16
(0.3)
15
(0.3)
Page 44 of 57
Tiotropium Respimat
Tiotropium Respimat
2.5 µg
5 µg
18 µg
N
(%)
N
(%)
N
(%)
Abdominal pain
4
(0.1)
13
(0.2)
4
(0.1)
Constipation
3
(0.1)
3
(0.1)
4
(0.1)
Diarrhea
7
(0.1)
4
(0.1)
7
(0.1)
Duodenal ulcer
6
(0.1)
2
(0.0)
2
(0.0)
Gastric ulcer
4
(0.1)
1
(0.0)
4
(0.1)
Gastritis
7
(0.1)
6
(0.1)
4
(0.1)
Gastroesophageal reflux disease
7
(0.1)
3
(0.1)
3
(0.1)
Ileus
2
(0.0)
3
(0.1)
8
(0.1)
Intestinal obstruction
9
(0.2)
6
(0.1)
7
(0.1)
Nausea
2
(0.0)
2
(0.0)
6
(0.1)
Pancreatitis
9
(0.2)
3
(0.1)
4
(0.1)
Pancreatitis acute
5
(0.1)
3
(0.1)
4
(0.1)
Small intestinal obstruction
6
(0.1)
7
(0.1)
4
(0.1)
Upper gastrointestinal hemorrhage
5
(0.1)
3
(0.1)
3
(0.1)
Vomiting
4
(0.1)
3
(0.1)
3
(0.1)
136
(2.4)
138
(2.4)
121
(2.1)
35
(0.6)
38
(0.7)
35
(0.6)
Cerebrovascular accident
Page 45 of 57
Tiotropium Respimat
Tiotropium Respimat
2.5 µg
5 µg
18 µg
N
(%)
N
(%)
N
(%)
Syncope
14
(0.2)
17
(0.3)
15
(0.3)
Transient ischemic attack
18
(0.3)
23
(0.4)
14
(0.2)
Carotid artery stenosis
4
(0.1)
8
(0.1)
7
(0.1)
Cerebral hemorrhage
4
(0.1)
4
(0.1)
2
(0.0)
Convulsion
3
(0.1)
2
(0.0)
5
(0.1)
Dizziness
6
(0.1)
5
(0.1)
3
(0.1)
Epilepsy
2
(0.0)
4
(0.1)
3
(0.1)
Ischemic stroke
5
(0.1)
3
(0.1)
7
(0.1)
108
(1.9)
99
(1.7)
111
(2.0)
Death
28
(0.5)
21
(0.4)
13
(0.2)
Noncardiac chest pain
19
(0.3)
23
(0.4)
22
(0.4)
Sudden death
27
(0.5)
13
(0.2)
18
(0.3)
Asthenia
8
(0.1)
3
(0.1)
3
(0.1)
Chest pain
4
(0.1)
8
(0.1)
6
(0.1)
Hernia
3
(0.1)
3
(0.1)
4
(0.1)
Multi-organ failure
2
(0.0)
3
(0.1)
7
(0.1)
Pyrexia
1
(0.0)
3
(0.1)
5
(0.1)
Page 46 of 57
Sudden cardiac death
Tiotropium Respimat
Tiotropium Respimat
2.5 µg
5 µg
18 µg
N
(%)
N
(%)
N
(%)
3
(0.1)
9
(0.2)
6
(0.1)
116
(2.0)
93
(1.6)
97
(1.7)
8
(0.1)
19
(0.3)
4
(0.1)
11
(0.2)
5
(0.1)
11
(0.2)
Femoral neck fracture
1
(0.0)
3
(0.1)
5
(0.1)
Femur fracture
5
(0.1)
5
(0.1)
4
(0.1)
10
(0.2)
9
(0.2)
5
(0.1)
Road traffic accident
2
(0.0)
3
(0.1)
5
(0.1)
Spinal compression fracture
4
(0.1)
2
(0.0)
4
(0.1)
Spinal fracture
6
(0.1)
1
(0.0)
2
(0.0)
Subdural hematoma
2
(0.0)
2
(0.0)
5
(0.1)
Upper limb fracture
6
(0.1)
3
(0.1)
0
(0.0)
Vascular disorders
91
(1.6)
92
(1.6)
91
(1.6)
Aortic aneurysm
8
(0.1)
15
(0.3)
12
(0.2)
Hypertension
8
(0.1)
8
(0.1)
12
(0.2)
Arteriosclerosis
5
(0.1)
6
(0.1)
4
(0.1)
Deep vein thrombosis
5
(0.1)
11
(0.2)
6
(0.1)
Fall
Hip fracture
Rib fracture
Page 47 of 57
Tiotropium Respimat
Tiotropium Respimat
2.5 µg
5 µg
18 µg
N
(%)
N
(%)
N
(%)
Hypotension
0
(0.0)
6
(0.1)
9
(0.2)
Intermittent claudication
4
(0.1)
2
(0.0)
3
(0.1)
Peripheral arterial occlusive disease
7
(0.1)
8
(0.1)
10
(0.2)
Peripheral ischemia
4
(0.1)
5
(0.1)
3
(0.1)
80
(1.4)
63
(1.1)
82
(1.4)
Osteoarthritis
10
(0.2)
12
(0.2)
23
(0.4)
Intervertebral disc protrusion
10
(0.2)
6
(0.1)
10
(0.2)
Arthralgia
6
(0.1)
1
(0.0)
5
(0.1)
Arthritis
5
(0.1)
8
(0.1)
2
(0.0)
11
(0.2)
3
(0.1)
6
(0.1)
Spinal column stenosis
6
(0.1)
1
(0.0)
2
(0.0)
Spinal osteoarthritis
4
(0.1)
4
(0.1)
6
(0.1)
48
(0.8)
65
(1.1)
59
(1.0)
17
(0.3)
14
(0.2)
24
(0.4)
Hematuria
3
(0.1)
9
(0.2)
4
(0.1)
Nephrolithiasis
4
(0.1)
8
(0.1)
4
(0.1)
Renal failure
9
(0.2)
8
(0.1)
5
(0.1)
Back pain
Renal failure acute
Page 48 of 57
Urinary retention
Tiotropium Respimat
Tiotropium Respimat
2.5 µg
5 µg
18 µg
N
(%)
N
(%)
N
(%)
5
(0.1)
9
(0.2)
9
(0.2)
49
(0.9)
47
(0.8)
48
(0.8)
Cholecystectomy
5
(0.1)
5
(0.1)
1
(0.0)
Knee arthroplasty
3
(0.1)
6
(0.1)
4
(0.1)
Hepatobiliary disorders
48
(0.8)
28
(0.5)
26
(0.5)
Cholelithiasis
12
(0.2)
12
(0.2)
4
(0.1)
Cholecystitis
11
(0.2)
7
(0.1)
6
(0.1)
Cholecystitis acute
10
(0.2)
2
(0.0)
10
(0.2)
33
(0.6)
40
(0.7)
31
(0.5)
Dehydration
8
(0.1)
8
(0.1)
5
(0.1)
Hyponatremia
8
(0.1)
4
(0.1)
5
(0.1)
22
(0.4)
16
(0.3)
29
(0.5)
10
(0.2)
10
(0.2)
13
(0.2)
20
(0.3)
31
(0.5)
21
(0.4)
Anxiety
2
(0.0)
5
(0.1)
2
(0.0)
Depression
7
(0.1)
7
(0.1)
5
(0.1)
Eye disorders
16
(0.3)
21
(0.4)
19
(0.3)
Surgical and medical procedures
Metabolism and nutrition disorders
Blood and lymphatic system disorders
Anemia
Page 49 of 57
Cataract
Reproductive system and breast disorders
Benign prostatic hyperplasia
Ear and labyrinth disorders
Vertigo
Tiotropium Respimat
Tiotropium Respimat
2.5 µg
5 µg
18 µg
N
(%)
N
(%)
N
(%)
13
(0.2)
10
(0.2)
14
(0.2)
20
(0.3)
17
(0.3)
14
(0.2)
8
(0.1)
14
(0.2)
4
(0.1)
7
(0.1)
2
(0.0)
2
(0.0)
6
(0.1)
1
(0.0)
2
(0.0)
*Frequency [N (%)] of patients with serious adverse events as determined by investigator occurring in ≥9 participants (≥0.1%) of total population at
the preferred term level by treatment, primary system organ class, and preferred term. Treated set (on treatment plus 30-day follow-up).
Page 50 of 57
Table S5. Adverse Events Leading to Discontinuation*
Number of patients
Tiotropium Respimat
Tiotropium Respimat
2.5 µg
5 µg
18 µg
N
(%)
N
(%)
N
(%)
5724
(100.0)
5705
(100.0)
5687
(100.0)
Total with adverse events leading to permanent discontinuation
448
(7.8)
468
(8.2)
498
(8.8)
163
(2.8)
175
(3.1)
198
(3.5)
104
(1.8)
98
(1.7)
103
(1.8)
Dyspnea
15
(0.3)
26
(0.5)
24
(0.4)
Cough
15
(0.3)
15
(0.3)
19
(0.3)
Acute respiratory failure
7
(0.1)
7
(0.1)
10
(0.2)
Oropharyngeal pain
4
(0.1)
0
(0.0)
6
(0.1)
Pulmonary embolism
4
(0.1)
3
(0.1)
3
(0.1)
Respiratory failure
8
(0.1)
4
(0.1)
12
(0.2)
88
(1.5)
65
(1.1)
79
(1.4)
27
(0.5)
18
(0.3)
19
(0.3)
Lung adenocarcinoma
7
(0.1)
2
(0.0)
4
(0.1)
Lung cancer metastatic
3
(0.1)
3
(0.1)
6
(0.1)
Nonsmall cell lung cancer
5
(0.1)
1
(0.0)
3
(0.1)
Chronic obstructive pulmonary disease
polyps)
Lung neoplasm malignant
Page 51 of 57
Tiotropium Respimat
Tiotropium Respimat
2.5 µg
5 µg
18 µg
N
(%)
N
(%)
N
(%)
Pancreatic carcinoma
2
(0.0)
3
(0.1)
5
(0.1)
46
(0.8)
53
(0.9)
51
(0.9)
27
(0.5)
33
(0.6)
35
(0.6)
1
(0.0)
6
(0.1)
4
(0.1)
42
(0.7)
40
(0.7)
40
(0.7)
Cardiac failure
2
(0.0)
6
(0.1)
2
(0.0)
7
(0.1)
7
(0.1)
3
(0.1)
Palpitations
5
(0.1)
4
(0.1)
4
(0.1)
Tachycardia
6
(0.1)
1
(0.0)
2
(0.0)
39
(0.7)
39
(0.7)
31
(0.5)
Dry mouth
9
(0.2)
16
(0.3)
14
(0.2)
Nausea
3
(0.1)
5
(0.1)
2
(0.0)
34
(0.6)
35
(0.6)
24
(0.4)
12
(0.2)
7
(0.1)
6
(0.1)
Dizziness
6
(0.1)
7
(0.1)
3
(0.1)
Headache
5
(0.1)
8
(0.1)
6
(0.1)
12
(0.2)
21
(0.4)
27
(0.5)
Pneumonia
Sepsis
Cardiac disorders
Cerebrovascular accident
Page 52 of 57
Chest discomfort
Urinary retention
Benign prostatic hyperplasia
Tiotropium Respimat
Tiotropium Respimat
2.5 µg
5 µg
18 µg
N
(%)
N
(%)
N
(%)
3
(0.1)
3
(0.1)
5
(0.1)
13
(0.2)
9
(0.2)
12
(0.2)
1
(0.0)
5
(0.1)
5
(0.1)
1
(0.0)
5
(0.1)
4
(0.1)
1
(0.0)
4
(0.1)
4
(0.1)
*Frequency [N (%)] of patients with adverse events as determined by investigator leading to permanent discontinuation occurring in ≥9 participants
(≥0.1%) of total population at the preferred term level by treatment, primary system organ class, and preferred term. Treated set (on treatment plus
30-day follow-up).
Page 53 of 57
Table S6. Adverse Events Related to Study Treatment*
System organ class
Tiotropium Respimat
Tiotropium Respimat
2.5 µg
5 µg
18 µg
N
(%)
N
(%)
N
(%)
5724
(100.0)
5705
(100.0)
5687
(100.0)
369
(6.4)
374
(6.6)
374
(6.6)
26
(0.5)
21
(0.4)
24
(0.4)
1
(0.0)
0
(0.0)
0
(0.0)
Blood and lymphatic system disorders
1
(0.0)
0
(0.0)
0
(0.0)
Immune system disorders
2
(0.0)
4
(0.1)
1
(0.0)
Metabolism and nutrition disorders
0
(0.0)
2
(0.0)
3
(0.1)
6
(0.1)
9
(0.2)
6
(0.1)
38
(0.7)
30
(0.5)
28
(0.5)
Eye disorders
13
(0.2)
14
(0.2)
22
(0.4)
4
(0.1)
2
(0.0)
0
(0.0)
Cardiac disorders
24
(0.4)
23
(0.4)
23
(0.4)
Vascular disorders
4
(0.1)
4
(0.1)
2
(0.0)
180
(3.1)
165
(2.9)
161
(2.8)
102
(1.8)
123
(2.2)
129
(2.3)
Number of patients
Total with related adverse events
polyps)
Ear and labyrinth disorders
Page 54 of 57
System organ class
Skin and subcutaneous tissue disorders
Tiotropium Respimat
Tiotropium Respimat
2.5 µg
5 µg
18 µg
N
(%)
N
(%)
N
(%)
13
(0.2)
13
(0.2)
21
(0.4)
4
(0.1)
4
(0.1)
7
(0.1)
14
(0.2)
17
(0.3)
20
(0.4)
8
(0.1)
8
(0.1)
8
(0.1)
16
(0.3)
29
(0.5)
21
(0.4)
Investigations
2
(0.0)
1
(0.0)
2
(0.0)
0
(0.0)
1
(0.0)
1
(0.0)
*Frequency [N (%)] of participants with investigator-determined related adverse events by treatment and primary system organ class. Treated set
(on treatment plus 30-day follow-up).
Page 55 of 57
Appendix 10
Table S7. Mortality Rates in Four Pooled Tiotropium Respimat Trials 205.254, 205.255, 205.372, 1205.14 (A) and in
UPLIFT (B)
A
Tiotropium
Tiotropium Respimat
Placebo
Rate Ratio
Respimat
5 µg (N=3049)
(N=3047)
(Tiotropium/Placebo)
(4 trials)—cut-
N (%) with
Time at risk
Rate/100
N (%) with
Time at risk
Rate/100
off at day 337*
event
(patient-yrs)
patient-yrs
event
(patient-yrs)
patient-yrs
68 (2.2)
2574
2.64
51 (1.7)
2571
1.98
Total with fatal
Estimate
95% CI
1.33
0.93, 1.92
AEs
* Cut-off at day 169 for trial 1205.14
Fatal events are counted if AE onset is after drug start and death occurred within 337 (or 169 for 1205.14) days after drug start.
For patients with certain fatal AE who died within 337/169 days after drug start, time at risk = death date − drug start date + 1. For all other
patients, time at risk = min (last date known alive − drug start date + 1, 337/169 days).
The rate is number of patients with events per 100 patient-years at risk.
The estimates and CIs for rate ratios are based on a Cochran-Mantel-Haenszel test stratified by trial. AE denotes adverse event; CI is confidence
interval.
Page 56 of 57
B
UPLIFT—cut-off
Placebo
Rate Ratio
at day 1440
18 µg (N=2986)
(N=3006)
(Tiotropium/Placebo)
Total with fatal
N (%) with
Time at risk
Rate/100
N (%) with
Time at risk
Rate/100
event
(patient-yrs)
patient-yrs
event
(patient-yrs)
patient-yrs
430 (14.4)
10927
3.94
491 (16.3)
10872
4.52
Estimate
95% CI
0.87
0.77, 0.99
AEs
Fatal events are counted if AE onset is after drug start and death occurred within 1440 days after drug start.
For patients with certain fatal AE who died within 1440 days after drug start, time at risk = death date − drug start date + 1. For all other patients,
time at risk = min (last date known alive − drug start date + 1, 1440 days).
The rate is number of patients with events per 100 patient-years at risk.
The estimates and CIs for rate ratios are based on a Cochran-Mantel-Haenszel test. AE denotes adverse event; CI is confidence interval.
Page 57 of 57

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