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N Engl J Med. 2010 Nov 11;363(20):1909-17. doi: 10.1056/NEJMoa1007964. Epub 2010 Oct 6.

Clopidogrel with or without omeprazole in coronary artery disease.

Collaborators (405)

Bhatt DL, Cryer BL, Cohen M, Lanas A, Schnitzer TJ, Giugliano R, deFeyter PJ, Fennerty MB, Triadafilopoulis G, Makuch RW, Skene A, Laine L, Jamidar P, Upchurch B, Scirica BM, Joyner C, Karsch K, Amerena J, Hammett C, Jeffery I, Kanna R, Kiat H, Ganeva N, Georgiev B, Ginkova J, Goudev A, Hergeldjieva V, Krastev A, Mihov A, Mincheva V, Penchev K, Petrov I, Ramshev K, Tisheva S, Tokmakova M, Bertrand O, Cha J, Dion D, Ducas J, Gin K, Klinke P, Kouz S, Lefkowitz C, Maranda C, O'Keefe D, Pandey S, Rupka D, Sluzar V, Tremblay B, Araneda G, Díaz R, Lanas F, León L, Potthoff S, Raffo C, Vejar M, Villavicencio M, Yañez M, Kucera D, Čihalík Č, Dunaj M, Hraboš V, Monhart Z, Štípal R, Vojácek J, Vojtíšek P, Galinier M, Al-Zoebi A, Axthelm C, Bauknecht C, Behrens S, Berger HJ, Boscher D, Claus G, Dänschel W, Darius H, Dempfle CE, Dorsel T, Gawaz MP, Genth-Zotz S, Grönefeld G, Guelker H, Hahnefeld C, Heuer H, Horacek T, Klingenheben T, Kohler B, Kolditz J, Krämer A, Krause K, Lange R, Lawall H, Oeff M, Omran H, Proskynitopoulos N, Richard F, Schreckenberg A, Schröder T, Schuler G, Schulze HO, Schwencke C, Stangl V, Stumpf J, Taggeselle J, Uebel P, vom Dahl J, von Hodenberg E, Weil J, Weissbrodt M, Kerekes C, Kollár Á, Kovács Z, Lupkovics G, Regos L, Vértes A, Herczeg B, Tomcsányi J, Belli G, Brunelli C, De Luca G, Musumeci G, Gamba MA, Ruíz RA, Pons JL, Esperón GL, Martínez UR, Villeda Espinosa E, Biedrzycka M, Boruczkowska-Kaszkowiak A, Bronisz M, Bujak K, Derlaga B, Drzewiecki A, Gieroba A, Hiczkiewicz J, Hoffmann A, Jankowski M, Jaworska K, Jazwinska-Tarnawska E, Kaczmarek B, Kania G, Karczmarc A, Karpiński J, Karpiński M, Kawka-Urbanek T, Kołodziej P, Korzeniak R, Kosior J, Krynicki R, Kubica J, Kucharski L, Kurek P, Kustrzycka-Kratochwil D, Kuzniar J, Miękus P, Mirek-Bryniarska E, Monies F, Mrówczyńska A, Ogórek M, Ogórek M, Okopień B, Oręziak A, Pasierski T, Piepiorka M, Pluta W, Podogrodzka B, Polonski L, Rogacka D, Rozycka-Grudniewicz M, Ruszkowski P, Ściborski R, Stańczak-Krop A, Szełemej R, Szwed H, Tarchalski J, Targoński R, Ujda M, Wilczewski P, Wojciechowski D, Zarębiński M, Tatu-Chitoiu GP, Iosipescu L, Melicovici N, Militaru C, Mot S, Popescu E, Sipciu D, Tatu-Chitoiu GP, Tudoran M, Ungureanu G, Duris T, Mičko K, Pella D, Džupina A, Kolíková V, Nedelová I, Oriesek R, Škubová K, Stevlik J, Straňanková D, Koval O, Parkhomenko O, Shershnyova O, Sirenko Y, Skrutov A, Vakaliuk I, Vykhovanyuk I, Abbott JD, Agah R, Ahmed A, Albirini A, Alfieri A, Alkotob ML, Anagnostis G, Anderson MW, Arora V, Banerjee S, Barag S, Bedel G, Belber A, Benton R, Berlin H, Bolster DE, Brachfeld C, Brett CM, Brown C, Brown C, Canaday D, Canosa RP, Capó JP Jr, Carlson R, Carr K, Cartaya M, Chandna H, Chandra R, Chang MA, Charney R, Chiong R, Cohen J, Collins J, Connelly T, Corbelli JC, Cospolich B, Dadourian B, Dahiya R, Daigneault A, Dalton RP, Darrah S, Desai V, Detwiler J, Dhar S, Diaz PJ, Donovan D, El Hafi S, Elkin G, Ellis G Jr, Fabre C, Fahrenbach M, Figueredo V, First B, Fischell T, Flores EA, Foster RE, Frais M, French WJ, Frey A, Gaither N, Garcia LM, Garibian G, Gelernt M, Gilchrist I, Gillespie E, Gogia H, Goodman H, Gottlieb D, Goyal L, Graves MW, Grena P, Guerra O, Gupta A, Haideri H, Hamroff GS, Hassel D, Hassinger N, Haught HW, Herrod JN, Herzog E, Hirsch C, Holmberg MJ, Horton KB, Jan MA, Jinich D, Johnson C, Johnson D, Jones A, Kabour A, Kenton DM, Kindman A, Klugherz B, Kodali VP, Koren MJ, Kosinski E, Kramer J, Krishnaswami A, Kutner M, Lau T, Lee CW, Lins J, Little T, Lloret R, Lo E, Lui HK, Maggiacomo F, Malik A, Mason P, Mattichak S, Mattson E, Mayer N, McGuire D, McKenzie ME, McLean RA, Mercando A, Miller G, Moloney P, Nadar V, Nallasivan M, Noble G, Oderinde JB, Pamfilis S, Parris C, Patel D, Pellizzon G, Perlman R, Pessanha B, Peter A, Peter A, Phillips RT 3rd, Polk DM, Popov D, Promisloff S, Raad G, Rabinowitz AC, Raveendran G, Rouch C, Ryder R, Salha H, Sandberg JH, Sandhu JS, Sanz M, Savani D, Schlau A, Schwartz S, Seaworth JF, Shah P, Shah A, Shah R, Shammas NW, Shanes J, Sharma P, Sharpe CR, Shavelle D, Siegel RM, Simmons J, Simon HJ, Sotolongo RP, Speer JF, Srivastava S, Stahl L, Staniloae C, Stegeman DM, Stegemoller R, Stein B, Stoltz S, Stuver T, Sultan PK, Suresh DP, Sutherland JE, Taghizadeh B, Tauth J, Thew S, Thomas GS, Tinker W, Tretter J, Turk S, Turns J, Tuten CJ, Ugol L, Van De Graaff E, Vazquez-Tanus J, Verzosa S, Vogel C, Vora KN, Voyce SJ, Wainwright W, Waldo D, Wassmer P, Weiss RJ, Weiss RJ, Wertheimer J, Williams D, Williams G, Wood DM, Yiachos G, Zacharias C, Zakrzewski M.

Author information

  • 1Veterans AffairsBoston Healthcare System, Brigham and Women's Hospital, Boston, MA 02132, USA. dlbhattmd@post.harvard.edu

Abstract

BACKGROUND:

Gastrointestinal complications are an important problem of antithrombotic therapy. Proton-pump inhibitors (PPIs) are believed to decrease the risk of such complications, though no randomized trial has proved this in patients receiving dual antiplatelet therapy. Recently, concerns have been raised about the potential for PPIs to blunt the efficacy of clopidogrel.

METHODS:

We randomly assigned patients with an indication for dual antiplatelet therapy to receive clopidogrel in combination with either omeprazole or placebo, in addition to aspirin. The primary gastrointestinal end point was a composite of overt or occult bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction, or perforation. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, revascularization, or stroke. The trial was terminated prematurely when the sponsor lost financing.

RESULTS:

We planned to enroll about 5000 patients; a total of 3873 were randomly assigned and 3761 were included in analyses. In all, 51 patients had a gastrointestinal event; the event rate was 1.1% with omeprazole and 2.9% with placebo at 180 days (hazard ratio with omeprazole, 0.34, 95% confidence interval [CI], 0.18 to 0.63; P<0.001). The rate of overt upper gastrointestinal bleeding was also reduced with omeprazole as compared with placebo (hazard ratio, 0.13; 95% CI, 0.03 to 0.56; P = 0.001). A total of 109 patients had a cardiovascular event, with event rates of 4.9% with omeprazole and 5.7% with placebo (hazard ratio with omeprazole, 0.99; 95% CI, 0.68 to 1.44; P = 0.96); high-risk subgroups did not show significant heterogeneity. The two groups did not differ significantly in the rate of serious adverse events, though the risk of diarrhea was increased with omeprazole.

CONCLUSIONS:

Among patients receiving aspirin and clopidogrel, prophylactic use of a PPI reduced the rate of upper gastrointestinal bleeding. There was no apparent cardiovascular interaction between clopidogrel and omeprazole, but our results do not rule out a clinically meaningful difference in cardiovascular events due to use of a PPI. (Funded by Cogentus Pharmaceuticals; ClinicalTrials.gov number, NCT00557921.).

Comment in

PMID:
20925534
[PubMed - indexed for MEDLINE]
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