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N Engl J Med. 2016 Dec 29;375(26):2519-29. doi: 10.1056/NEJMoa1611593. Epub 2016 Nov 13.

Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis.

Collaborators (1233)

Fleming TR, Brophy J, Crofford LJ, Peura DA, Kerr DR, Krum H, Anwaruddin S, Askari A, Baranowski B, Bashian G, Benjamin TA, Brener S, Cavender M, Chenier M, Chhatriwalla A, Coleman C, Cremer P, Downey R, Galla J, Jones B, Kanderian A, Kwon D, Lahoud R, Lappe J, Lau E, Lazar L, Meadows T, Shishehbor M, William AD, Wu W, Zardkoohi O, Gupta R, Sharma J, Shields R, Sila C, Sweeney P, Truong VV, Uchino K, Falk G, Kandiel A, Philpott J, Qadeer MA, Stevens T, Thota P, Vargo J, Wang YM, Akhtar M, Austin B, Cantillon D, Cauthen C, Cavalcante JL, Dahiya A, Goldberg A, Gorodeski E, Kaminski M, Lai JE, Tarakji K, Underwood D, Atanasovski I, Balog C, Bash D, Becker M, Brown K, Bruce A, Davey D, D’Angelo P, Fabry L, Gladish D, Hodge P, Klancar R, Lamovsky L, Moore B, Myers K, Pasca N, Pothier C, Prcela L, Rodriguez R, Scebbi T, Schnauffer M, Suchar L, Theodos G, Wang T, Ali-Akhtar S, Anderson T, Baker KC, Collins S, DeShields R, Fasano C, Fayyad R, Goldfarb H, Gomez M, Graham T, Guilds-Zamarka L, Herman V, Holmes D, Hua YL, Iorga D, Ivanac K, Krapf S, Liepins A, Marquino V, McDonagh T, Mihalik C, Miranda C, Nemeth MA, Nguyen H, Pagano M, Pressler ML, Ratigan MK, Shine E, Simpson T, Spolnik A, Sullivan B, Tantiongco ES, Tarakhonych OI, Wang X, Wilson D, Wisemandle W, Xia RF, Zhang R, Berger C, Brock A, Brink K, Byrd P, Cabrera D, Caleen R, Cavin S, Crutchfield J, Dallas B, Dawood S, Dey M, DiLiberti J, D’Souza S, Edwards C, Finn A, Gardiner S, Garrett A, Gauley J, Goldman B, Gross J, Hinnant K, Horwhat A, Houle P, Humphreys K, Iles J, Kimball M, Kisly M, Kopcha S, Krishnan S, Lloyd W, Lopez G, Lowe K, Machado A, Martin E, Martin J, Nene M, Oren M, Pompilio R, Schimmel J, Shah S, Simari L, Singh A, Steflik C, Thompson K, Toledo R, Welborne C, Whitt J, Williamson M, Wright EM, Zarate J, Zucker J, Bradick A, Bustamente LT, Harris K, Smith T, Bossingham D, Buchanan R, Colquhoun D, De Looze F, Karrasch J, Huttenmeister R, Day D, Healy B, Pryor P, Hall S, Littlejohn G, Russo M, Taylor A, Will R, Azevedo M, Baaklini C, Borba V, Brenol JC, Castro M, Castro F, Cavalcanti F, Helfenstein Fonseca FA, Gomes M, Guimaraes S, Keiserman M, Kochen J, Lanna C, Levy R, Lomonte A, Marcolino F, Eliaschewitz F, Melazzi AC, Moriguchi E, Marques Neto JF, Neto E, Pinto M, Provenza J, Radominski S, Roimicher L, Saraiva JF, Scotton A, Simon J, Sousa A, Sebba Barroso de Souza Souza WK, Ximenes A, Adachi J, Aggarwal N, Attie N, Baker M, Barkhuizen F, Kooy J, Bartlett J, Beauchesne A, Bernstein I, Bhamjee H, Bose S, Bowler W, Campbell I, Chaulk DR, Chouinard G, Collingwood J, Conter H, Corey J, Craig B, Dauth P, Dufresne M, Dzongowski P, Faraawi R, Filteau P, Garceau C, Gorfinkel I, Grant E, Hart R, Henein S, Hudon C, Fortin M, Jasey G, Kanani S, Keegan P, Kendler D, Khraishi M, O'Keefe D, Lasko B, Lavoie N, Karsh J, Li J, Lichtenstein T, Hudson N, Lowe D, Luterman M, Luton R, Maranda C, McCarthy T, Misik K, Morin F, Mutrie J, Taylor S, Nagpal R, O'Mahony W, O'Mahony M, Pesant Y, Rodrigues J, Salter T, Saunders K, Schacter G, Senaratne M, Skeith K, Sussman J, Syan S, Syan G, Thorne J, Tsoukas G, Velji A, Zidel B, Arango C, Gomez J, Jannaut M, Botero Lopez R, Pinto Penaranda L, Ramirez G, Molina Restrepo J, Badilla-Gomez A, Cespedes-Vargas J, Garzona-Meseguer F, Gutreiman-Goldberg M, Lainez-Ventosilla A, Monge-Zeledon P, Moya-Rodriguez J, Oeding-Bermudez O, Poveda-Fernandez J, Saenz-Castro R, Vinocour-Fornieri M, Lam YY, Wai-Kwok G, Lee S, Mok CC, Abud-Mendoza C, Avila Armengol H, Carmona-Furusho L, Enkerlin-Pauwells H, Garcia-De La Torre I, Garcia-Lopez R, Cardiel Rios M, Hernandez-Paz R, Martinez-Osuna P, Ochoa-Ortega L, Robles-San Roman M, Saldate-Alonso M, Guerra Bautista G, Trujillo R, Vega Espinoza L, Berrocal Kasay AE, Ravelo Hernandez J, Kuroiwa R, Leon-Portocarrero M, Morales Olazabal L, Eullaran R, Lanzon A, Lichauco JJ, Li-Yu J, Navarra S, Ramiterre E, Salido E, Tan P, Chen DY, Chen HC, Lai JH, Chen PC, Chen HA, Hsu PN, Lai NS, Lin HY, Luo SF, Tsai WC, Tsay G, Bula L, Danyliuk S, Lysenko G, Ignatenko G, Karpenko O, Kononenko L, Koshlia V, Kovalenko V, Kuryata O, Nikirenkov Y, Parkhomenko O, Petrov A, Shpyleva N, Svintsitskyy A, Tseluyko V, Tykhonova S, Vizir V, Voloshyn O, Yagensky A, Abalos-Galito M, Adams J, Adelizzi A, Adetola A, Adler P, Aelion J, Ahmed S, Akerson M, Akpunonu B, Aldrich J, Hernandez P, Allaw M, Alloway J, Alper J, Alvarado O, Alvarez G, Alwine L, Amador P, Anagnostis G, Anderson J, Anderson M, Andrawis N, Andron R, Apaliski S, Arora R, Asher R, Nielsen M, Ashley R, Atiee G, Awasty V, Ayesu K, Bacon J, Eaton G, Baer W, Bakdash WA, Baker J, Ballard T, Baraf H, Barber M, Bari A, Barkhuizen A, Barnes R, Baron S, Barringer T, Cromwell W, Wise D, Bays H, Beach J, Beasley R, Izzo M, Bedel G, Bedoya R, Bennett M, Berenguer R, Beretta J, Berkowitz R, Bhat A, Bhuchar S, Bland V, Blaze K, Blecker E, Geiger R, Block B, Bloom A, Boccalandro F, Bockow B, Bookbinder S, Borenstein D, Bowers B, Englebrecht J, Bowling B, Brabham D, Williams S, Brandon D, Brautigam D, Bredlau C, Hartman R, Brkic-Vukotic O, Brockmyre A, Brodsky A, Brogan TA, Broker R, Brooks M, Bruce T, Brunner R, Brus W, Brusky J, Bruya T, Burack D, Burchenal J, Buynak R, Caciolo B, Cader C, Campbell J, Rask P, Urbach D, Campolo M, Capo J, Cappleman J, Card J, Cardona J, Marquez F, Carr G, Carr A, Castro-Skoglund J, Chachar M, Chakerian M, Chandler J, Chappel C, Chen M, Cheung D, Chilka S, Chintanadilok J, Chodock A, Christensen T, Christina M, Chuang R, Clark L, Clower J, Clunn A, Cohen S, Cohen K, Cohen R, Collins P, Collins H, Connery L, McArthur R, Conte J, Cordero A, Lassiter J, Cornett G, Beavins J, Coulter F, Courtnage S, Cowen P, Cox W, Coy K, Margolis J, Creamer M, Cruz J, Cullen K, Benson D, Curtis J, Cyrus T, Chinn J, Nakhle S, Dahdul A, Daly E, Milton A, Dandillaya R, Davida A, Davis C, Dawes K, Rubeiz G, Burbano De Lara J, Dean J, Short W, Deane P, DeGarmo R, DeHart D, DeHaven R, Delgado J, Deluccia W, Dennis D, Maldonado-Garcia C, Sanchez S, Szczesny M, Vendetti G, Denny D, Desai V, DeSantis M, Desir D, Detweiler R, Diab I, Diaz J, Dice J, Elizalde A, Hosler M, Dietz F, DiGiovanna M, Dikranian A, Doris J, Downs B, Montgomery M, Doyle N, Dreyfus J, D'Souza V, Kaner D, Livingston D, Dua A, Dugano-Daphnis P, DuMontier G, Dunmyer S, Dunn M, Dunn L, Dunteman E, Dushkin H, Baron M, Kravitz A, Tresser N, Wine A, Eade J, East C, Eberly J, Corbett B, Eddy R, Edris M, Edwards J, Edwards W, Eider W, El Sayad N, Elasmar I, Elijah R, Ellison W, Engel E, Engel E, Yang CY, Erickson B, Ettlinger R, Evanko D, Evans P, O’Neill D, Everett C, Guerrero V, Eyzaguirre R, Fairfax M, Fallows C, Farag A, Farrington C, Fedor R, Feinberg H, Feldman G, Feldman B, Ashrafzadeh A, Feliciano E, DeWitt M, Fenton I, Fernando R, Firek A, Fiechtner J, Fiel T, Fields H, Fields C, Figueredo R, Fiorillo T, Fisher G, Fitz-Patrick D, Flatt J, Fleischer L, Flint K, Collins R, Flippo G, Savage P, Folkerth S, Ford TL, Forney B, Forstot J, Franco M, Francyk D, Fraser N, Fraser A, Freed R, Freiburger J, Fruchter G, Gabra N, Gamarra L, Gaona R, Garcia B, Casanova R, Garcia H, Gebhardt S, Iezzi A, Shepard R, Heiman D, George W, George A, Gerrish C, Gibbs R, Gillespie E, Gimbel J, Gladstein G, Glickfield W, Godbole N, Goldberg M, Goldberger E, Gonzalez E, Gonzalez M, Gopalani S, Gorman D, Grant D, Gray W, Greco G, Sissleman S, Greenberg J, Grena P, Gresh J, Griffin R, Schnitz W, Willis L, Griffin C, Griffin J, Grossman C, Grubb S, Gudipati R, Gupta R, Gupta R, Guskiewicz R, Hack T, Hackshaw K, Hall A, Hamilton M, Hamm D, Hare E, Harper W, Harris L, Harrison B, Hart T, Haskel E, Headley D, Hearne A, Heigerick G, Henry B, Herman L, Hermann M, Herring R, Herrod J, Hershberger V, Herzog W, Hill J, Hilliard G, Hochman E, Hole S, Holgado M, Aiken R, Holkesvik R, Holt P, Horn C, Horner S, House A, Howard T, Howell M, Howell J, Hufman S, Hughes W, Hunter R, Diener C, Slaski A, Hussain M, Hymowitz R, Igleburger J, Ince C, Ismail Y, Jackson T, Jacobs W, Goldman B, Jaffe K, Jakes J, Janovitz R, Jauch W, Jenkins J, Johnson C, Johnson C, Jonas B, Jones R, Jordan R, Kabour A, Kades W, Kaell A, Kafka S, Kalen V, Kamdar B, Kantaros L, Jafar M, Kapil S, Karras D, Hutchins R, Kashif A, Kashou H, Katz A, Kaufmann R, Conlin M, Kay J, Kaye W, Levin R, Kelly R, Kempf K, Burch F, Kennedy A, Kenney H, Kenton D, Kerzner B, Kesselbrenner M, Khalifa A, Abuerreish M, Khan S, Khan J, Khan B, Khetan S, Kilpatrick F, Kutz D, Kim A, Kimelheim R, King C, Kinnaman S, Kirby W, Kirstein J, Kistler C, Kivitz A, Klein S, Kliger M, Kluge R, Knapp W, Lucas M, Knee C, Kneller G, Kobylinski S, Risser J, Kolba K, Korff G, Kosinski E, Krichmar P, Krumian R, Portnoy E, Kumar M, Fellows C, Kumar U, Kohli N, Kwon E, Ladner T, Lambert J, Lamothe M, Lang R, Laramee C, Larrain G, Lawson J, Leach C, Lee T, Leggett R, Lenzmeier T, Leung L, Levinsky D, Levinson L, Lewis D, Lidman R, Lieberman D, Lim E, Parikh N, Wyatt D, Linden D, Littlefield R, Long J, Long W, Longshaw K, Lorraine R, Losoya G, Lowe J, Lozman P, Lubin B, Ludivico C, Lunseth P, Paraskevopoulos N, Rusterholtz LA, Lutz K, Lynch M, MacCarter D, MacGillivray B, Madsen L, Maduakolam C, Magargle R, Maggiacomo F, Makarowski W, Mandel D, Manlove-Simmons K, Hodge R, Manning D, Marcadis A, Marino L, Marks S, O’Reilly T, Martin K, Martinez J, Marwah R, Matar F, Mathews S, Mathur R, Mazzone F, McCormick B, McCurley L, McDermott E, McDonald D, McElya M, McFarland M, McGrew F, McIntosh M, McKenzie W, McLaurin B, McLean B, McRae J, Surratt D, Mefford I, Mehta D, Mehta P, Mehta C, Meka A, Meli J, Merritt B, Michlin B, Mihills C, Mikhail M, Milas J, Miller J, Miller S, Miller J, Miller G, Miller D, Miller P, Mills R, Minkowitz H, Miranda F, Mizutani W, Modiano M, Modugu S, Moidel R, Mollen A, Molter D, Morcos C, Morelli J, Moretti J, Morgan A, Morgan C, Morin D, Miller J, Morris D, Surbeck W, Morris W, Davis K, Morrison B, Mortensen S, Lies R, Mossberg J, Moya-Hechevarria J, Mugmon M, Meilman H, Murillo A, Myerson G, Naini G, Nalamachu S, Neal J, Neal N, Neidorf D, Neutel J, Neuwelt C, Nguyen T, Nielsen R, Norwood P, Novak H, Nualart M, Ares-Romero P, Columbie A, Nwabara O, Nwaneri U, O'Barr T, Oberoi M, Ocampo A, Oftadeh L, Azurin E, Ogden P, Old W, Olds S, Martin F, Ong S, Oppy J, Otah K, Uzoaga E, Pace M, Paez H, Rousseau R, Palmer W, Pamfilis S, Pando J, Gomez J, Paraboschi C, Pasya SK, Shamim T, Patron A, Patton C, Colvin D, Pavon H, Payne D, Pearlstein P, Peck B, Peller J, Peniston J, Pepine C, Perez J, Perry R, Peters L, Peterson D, Pharr W, Anderson A, Philander P, Pish R, Plancher K, Plasner S, Pattanayak M, Poludniak J, Pomposini D, Popeil L, Porges A, Porter C, Porter A, Porterfield J, Poss G, Post G, Potts J, Pounds K, Prelutsky D, Prentiss A, Prieto B, Pritchett K, Promin R, Pruitt R, Prupas H, Quartner J, Raad G, Radin D, Raja N, Ramstad D, Ranasinghe E, Randall W, Rapo S, Rapoport R, Raupp M, Recknor C, Reddy R, McNeff J, Renzi M, Reynolds A, Rhodes R, Riaz M, Ricca A, Riccardi P, Ricci D, Rice D, Richwine R, Rico A, Rictor K, Riegel B, Corbelli J, Riley S, Reilly W, Rivas D, Rizzo W, Roberts D, Robins G, McDavid R, Robinson J, Jones C, Rodriguez H, Rodriguez I, Rogers B, Rogusky E, Rohr C, Baumbach R, Rosen R, Rosenblum G, Rosenfeld J, Seidner M, Rosenthal A, Almassi G, Ross S, Ryan W, Saifi A, Saikali W, Sakiewicz A, Sakornbut E, Salazar J, Salmon J, Sandberg J, Saniuk R, Santhanam S, Tengco R, Santoscoy R, Nikas A, Saponaro J, Sauter M, Berger M, Sayeed S, Schechtman J, Schenk A, Scherbarth K, Schiffman L, Schmedtje J, Schneider R, Schock J, Schramm E, Schwartz K, Schwartz S, Schwartzenberg J, Schwarz E, Scott D, Seals A, Meiners R, Seaton B, Sebai M, Boling E, Sebba A, Seco G, Segal S, Seidmeyer V, Selsky E, Jerome S, Sensenbrenner J, Shah S, Shah A, James E, Shah D, Shah M, Shah G, Shammas N, Duke S, Shams F, Shandilya L, Shemonsky N, Shergy W, Sherman H, Khan R, Shockey G, Shusman R, Siegel E, Sikes D, Silverfield J, Simon R, Singhal A, Sklaver N, Skyhar M, Slabic S, Sligh T, Smith L, Smith S, Snyder B, Solano R, Solinsky K, Solomon S, Som D, Sonel E, Sonel A, Sosenko M, Sotolongo R, Sousa D, Ali M, Spivack E, Sprague A, Srivastava S, Bilazarian S, Livson A, Portnay G, Stack M, Staub J, Stearns P, Stedman M, Steffens R, Stegemoller R, Steinberg P, Stephens M, Stephens L, Stern R, Stevens J, Collins B, Stoltz S, Trevino J, Stone W, Lesh K, Stout R, Rasheed M, Strain R, Straniero N, Studeny M, Stupi A, Shook B, Tyma T, Subich D, Suiter D, Suley E, Corst I, Sulich A, Sullivan N, Sutherland J, Ulven M, Swift D, Szewczak S, Bock B, Tamayo R, Tan E, Taunton O, Tavel E, Tawney K, Silverblatt J, Taylor P, Tidmore W, Titus J, Woodruff M, Trapp R, Trevino M, Trivedi K, Alexander A, Troum O, Tsai Y, Turner M, Turner M, Tyndall W, Underwood P, Valerio D, van Cleeff M, Vanderlaan R, Vargo J, Varma S, Vaughn M, Victoria R, Wadsworth L, Wagner S, Wallner H, Walter N, Ward S, Warfield D, Waxman J, Wayne J, Weaver C, Moore C, Wei N, Weinstein D, Weiss R, Weitz M, Wenocur H, Wentworth R, Weprin S, Wiesenhutter C, Wieskopf B, Wild J, Williams D, Williams T, Conard S, Wilmer C, Wilson J, Wilson S, Winkler A, Wood J, Woods B, Yakubov S, Yamada H, Yang M, Yataco A, Yates S, Yazdani S, Ylisastigui P, Yoachim R, Smith D, Yood R, Young C, Young D, Yuen J, Zaheer A, Zaidi F, Zakko S.

Abstract

BACKGROUND:

The cardiovascular safety of celecoxib, as compared with nonselective nonsteroidal antiinflammatory drugs (NSAIDs), remains uncertain.

METHODS:

Patients who required NSAIDs for osteoarthritis or rheumatoid arthritis and were at increased cardiovascular risk were randomly assigned to receive celecoxib, ibuprofen, or naproxen. The goal of the trial was to assess the noninferiority of celecoxib with regard to the primary composite outcome of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke. Noninferiority required a hazard ratio of 1.12 or lower, as well as an upper 97.5% confidence limit of 1.33 or lower in the intention-to-treat population and of 1.40 or lower in the on-treatment population. Gastrointestinal and renal outcomes were also adjudicated.

RESULTS:

A total of 24,081 patients were randomly assigned to the celecoxib group (mean [±SD] daily dose, 209±37 mg), the naproxen group (852±103 mg), or the ibuprofen group (2045±246 mg) for a mean treatment duration of 20.3±16.0 months and a mean follow-up period of 34.1±13.4 months. During the trial, 68.8% of the patients stopped taking the study drug, and 27.4% of the patients discontinued follow-up. In the intention-to-treat analyses, a primary outcome event occurred in 188 patients in the celecoxib group (2.3%), 201 patients in the naproxen group (2.5%), and 218 patients in the ibuprofen group (2.7%) (hazard ratio for celecoxib vs. naproxen, 0.93; 95% confidence interval [CI], 0.76 to 1.13; hazard ratio for celecoxib vs. ibuprofen, 0.85; 95% CI, 0.70 to 1.04; P<0.001 for noninferiority in both comparisons). In the on-treatment analysis, a primary outcome event occurred in 134 patients in the celecoxib group (1.7%), 144 patients in the naproxen group (1.8%), and 155 patients in the ibuprofen group (1.9%) (hazard ratio for celecoxib vs. naproxen, 0.90; 95% CI, 0.71 to 1.15; hazard ratio for celecoxib vs. ibuprofen, 0.81; 95% CI, 0.65 to 1.02; P<0.001 for noninferiority in both comparisons). The risk of gastrointestinal events was significantly lower with celecoxib than with naproxen (P=0.01) or ibuprofen (P=0.002); the risk of renal events was significantly lower with celecoxib than with ibuprofen (P=0.004) but was not significantly lower with celecoxib than with naproxen (P=0.19).

CONCLUSIONS:

At moderate doses, celecoxib was found to be noninferior to ibuprofen or naproxen with regard to cardiovascular safety. (Funded by Pfizer; ClinicalTrials.gov number, NCT00346216 .).

PMID:
27959716
DOI:
10.1056/NEJMoa1611593
[Indexed for MEDLINE]
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