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N Engl J Med. 2019 Feb 21;380(8):752-762. doi: 10.1056/NEJMoa1809798. Epub 2018 Nov 10.

Low-Dose Methotrexate for the Prevention of Atherosclerotic Events.

Collaborators (878)

Ridker P, Glynn R, Everett B, Paynter N, Pradhan A, MacFadyen J, Zaharris E, Hasan A, Cunniff E, Sanchez M, Mam V, Samuelson H, Nestor S, Thompson A, Rosenberg Y, Iturriaga E, Cooper L, Leifer E, Chen J, Waclawiw M, Gordon D, Olive M, Shurin S, Brasile Mejac AM, Solomon D, Libby P, Clearfield M, Verma S, Gupta M, Buring J, Bohula E, Lawler P, Rost N, Singhal A, Barbhaiya M, Rao D, Ritter S, Sparks J, Tedeschi S, Harrington R, Bailey K, Ballantyne C, Ellenberg S, Fox D, Francis C, Gersh B, Lipman H, Tracy R, Weintraub W, Wilson P, Addamo C, Barrett L, Battis K, Bryce E, Cahill C, Calabrese S, Carpenedo J, Carrier R, Cassesso R, Chen L, Choi P, Danning R, Doroshevich M, Duran C, Fullerton E, Gonzalez-Park N, Grossbard J, Hall S, Hisoler F, Jean S, Jolicoeur P, Kennedy E, Khudaynazar N, Knuff E, Kostandy G, Krishnaswamy A, Krugolets G, Kuney S, Lema-Driscoll J, Lucci M, McDonough G, Mgarry R, Paik HI, Palmer E, Pasciak W, Peterkin N, Rieu-Werden M, Schlossberg A, Shapiro I, Smith C, Sylvain S, Teutsch G, Thomas C, Thomson A, Warny A, Wright C, Abidi M, Amaza H, Aboufakher R, Vold D, Acebo W, Acebo D, Adegbamigbe T, Adetunji B, Adiraju R, Issac J, Agarwal A, Brunetti N, Aggarwala G, Terry K, Ahlers K, Workman A, Ahmad Z, Ahmed H, Rowney V, Ahmed M, Ghouse A, Ahmed K, Elassad A, Ahsan S, Gikas H, Alani F, Ostrander A, Alderson L, Lesko M, Alegret R, Palacio J, Allison M, Lazaro L, Allison D, Richardson M, Alpert D, Kinsley M, Alvarado O, Parks R, Ambrose J, Garcia S, Anderson D, Bernard T, Andrawis N, Manalo J, Sandil J, Ansari S, Khan T, Anwar N, Ali U, Aponte L, Agosto M, Arif A, Zinn C, Arora R, Arora M, Arora R, Todela T, Aslam A, Morrison J, Aswani M, Chang SJ, Atieh M, Jackson R, Averbach M, Christ E, Averill F, Covington K, Awan M, Tuner E, Azizad M, Brown M, Baez-Suarez J, Santiago J, Bains S, Quiroz S, Baker J, Cox S, Banish D, Reams C, Bank A, Boben L, Barclay S, Strain R, Bari B, Kapil K, Barnes B, Brown D, Barnum O, Barnum M, Baruchin M, Vinas R, Baum S, Mattone A, Bays H, Nockerts N, Beau S, Anazawa F, Beaudry P, Reyes V, Beaudry Y, Viau C, Beaulieu E, Mcghee C, Bender K, Apelbaum M, Benzaquen L, Marre M, Bertrand O, Jadin M, Blanco A, Block L, Skinner S, Boghara H, Cooper Z, Bortnick A, Polanco D, Bouza M, Sanchez M, Brown G, Atkinson J, Brown C, Thomas L, Bryant J, Moore D, Buchbinder M, Price M, Burbano J, Fuentes G, Butman S, Bigelow A, Campbell W, Hickey T, Carbajal E, Chase M, Castriz J, Southard R, Cauthen B, Francis C, Cha J, Otis J, Chadderdon S, Naher A, Chehayeb R, Chen J, Lambuth K, Chen J, Bryant N, Cheng W, Oud J, Cheung D, Nieves S, Chodnicki D, Shearer S, Chouinard G, Boivin MC, Chouinard M, McMartin D, Cieza-Lara T, Lavoie N, Clay A, McClelland M, Johnson L, Cohen M, Glasgow B, Cohen S, Gawron H, Cone C, McLeod D, Conrad G, Seto S, Conway J, Hitchcock S, Cronin J, Laranjo M, Cruz J, Speerbrecker M, D'Alessandro F, Mcphail D, Danciu S, Zull L, Daniels D, Buchanan T, Danzig M, Barr M, Davidson E, Thearp H, Del Core M, Butkus E, DeLeon J, Drewes W, DeMaria A, Davila W, Diamantouros P, Carr S, Dieck J, Vallejo A, DiGiovanna M, Azeem F, Dobies D, Williamson V, Dong SJ, Gehin B, Doyle N, Hales S, Draper T, Rybicki M, Eaton C, Valiente J, Eaves W, Moore M, Edwards T, Edwards G, Eid F, Davis J, Eisen H, Matthews J, Erickson B, Dahl P, Farkouh M, Lan J, Farough A, Willis G, Fernando R, Simpson V, First B, Alcantar C, Focil A, Martinez P, Forman S, Ronquillo R, Foster M, Brown J, Fowlis R, Radyk M, Frandsen B, Frandsen B, Friedman R, Arroyo L, Gabelman M, Mendez A, Gabriel J, Barrientos I, Gaffney M, Jones J, Garcia B, Zambrano R, Garrioch G, Clement J, Gaudet D, Delisle J, George J, Thomas-Beasley J, George A, Stewart C, Ghafouri M, Delozier A, Gibbs L, Ross MJ, Giles P, Guin M, Giri J, Medenilla E, Glass H, Tiernan P, Gleason G, Miao M, Goldhaber S, Morrison R, Gonzalez E, Vazquez M, Gordon J, Mahan B, Graham B, Loomis E, Gray J, Weir T, Green CP, Turner S, Greer G, Phillips B, Grover N, Ta L, Gunapooti M, Snodgrass B, Christie F, Gupta S, Parrish M, Gurbel P, Barbour C, Gutierrez E, Aveloo RM, Hage F, Valaiyapathi B, Hage-Korban E, Childs A, Hakim J, Shannon C, Hamroff G, Pankovic C, Harrison A, Harrison K, Hartleib M, Otis R, Headley D, Spencer D, Henry R, Diaz E, Herman L, Nealy C, Hermany P, Meissner-Dengler S, Hess A, Mcpherson C, Hinchman D, Luck K, Horton E, Hsue P, Li D, Humiston D, Rodriguez S, Huth M, Eisenhaure JA, Ijem J, Smith E, Isajiw G, Grande S, Izuora K, Patel A, Jagan N, Jagan L, Jagota A, Jaluria N, Reigle H, Jarzabkowski D, Schwartzkopf P, Johary A, Wells C, Johnston J, Hickey L, Johnstone M, Michaelian M, Jones A, Bartholomaus L, Jutzy K, Baig H, Kapoor N, Kapoor N, Kayembe T, Kayembe K, Keogh M, Hernandez M, Khan W, Rizvi M, Kiesz R, Gora B, Kim N, Fortanely B, Kivitz A, Morrison P, Kopfler W, Shelton C, Koser A, Cook D, Koshal V, Petrik L, Kostis W, Hughes A, Kottam A, Basic-Panic B, Krishna A, Kerr B, Krishnan M, Choate N, Kumar A, Suri A, Kumar V, Hartmiller J, Kwan T, Tsang J, Labonte R, Burke M, Labroo A, Lopez C, Landau C, Cullen T, Landzberg J, Reyes R, Langevin E, Faucett S, Lau J, Johnson S, Le May M, Abarbanel T, Ledger G, Holmes Z, Ledo-Sanchez G, Ruiz A, Lee E, Smothers H, Liang W, Grundy J, Liberman J, Lessila C, Lupovitch S, Bellini S, Madoff L, Jimenez M, Malik S, Erande A, Mamdani S, Felix L, Manning H, Sukhu S, Mansour S, Vallieres C, Marin V, Woods R, Martin L, Marshall L, Martin M, Gunter T, Mastouri R, Hannemann E, Mathieu G, Mavromatis K, Patel R, McClure J, Ferguson R, McCormick B, Kiser J, McGough M, McGrew F, Briscoe K, McNeil D, Schulze J, Mediratta S, DuPont A, Mego C, Rivas C, Meholick A, Black L, Melton J, Hightower B, Mendelson R, Ullah T, Messerli A, Hull A, Mian N, Griffiths K, Miccio A, Domingo M, Miller D, Brounce G, Miller W, Tessmar C, Miller S, Gleaton K, Mishra U, Felpel S, Mody F, Strugatsky S, Montero M, Ipock R, Morris M, Knight R, Morytko J, Shatsky K, Moustafa M, DiRenzo S, Muhammad M, Khuwaja A, Mukherjee A, Bozek B, Mulkay A, Saha B, Mumtaz S, Chaudhay K, Murray J, Baker S, Murrow J, Smith A, Murthy VS, Miller M, Nappi A, Stewart W, Nicholas M, Kulam P, Nixon W, Abath C, Nwadiaro N, Laporte T, Ofori C, Kilner P, Oh C, Nielson T, O'Rourke D, Beaudry S, Ou J, White M, Owen S, Andry A, Pacifico L, McDonald A, Padron F, Duconger N, Papasifakis E, Showole O, Parker J, Hsu E, Pena J, Peniston J, Fudala A, Peterson S, VanSickle L, Peterson N, Allen A, Pettis K, Jamison S, Phaneuf DC, Drouin K, Piacentine S, Pritchard L, Pianko L, Borges P, Pish R, Clark R, Polasek P, Schlapbach D, Polonsky T, Hart T, Pulsipher D, Leonard K, Puppala J, McGettes M, Quintana O, O'Brien C, Raddatz D, Gilmore C, Raimondo E, Swatton M, Ramanathan K, Johnson L, Ramappa P, Covert K, Ramirez S, Ciffone N, Ramnauth S, Ingenito S, Ramos S, Aparicio J, Rao S, Saylor R, Rao V, Alford S, Rave M, Stark K, Reddy R, Bentley M, Reddy M, Conner C, Reinhardt S, Bongarzone M, Reza S, Reed C, Riaz K, Weller C, Rice L, Turner J, Richwine R, Pazier P, Rider J, Marach W, Roberts J, Meyer L, Rohr K, Crowley S, Roongsritong C, Neumann B, Rosenbloom A, Snape S, Rosenson R, Chen Q, Roth S, Rao P, Rough R, French D, Rowe S, Atkinson U, Sacco J, Rawlins M, Safi A, Green C, Saini S, Bullock B, Saklayen M, Miller C, Salacata A, McQuarrie M, Santora L, de la Mora K, Sardar Z, Anwar M, Sarembock I, DeFosse C, Sartori M, Cantu A, Saxena S, Beaman R, Schmedtje J, Furry C, Schmidt J, Propst J, Schneider L, Askew T, Schnitzler R, Kirschbaum L, Schwartz S, Grabeau R, Schwartz D, Flanagan J, Schweikert R, Frederick T, Seagle R, Seagle T, Seidman B, Muller I, Selagamsetty M, Selagamsetty S, Severino-Pacheco N, Figueroa M, Shah A, Dhawan M, Shah M, Harris M, Shapero P, Storm D, Shavelle D, Caro J, Shayani S, Hodnett P, Shin V, Kells T, Sierra Quinones Y, Ramos G, Silverberg J, Stone F, Simmons D, Dorsch J, Simon W, Grimes K, Singal SR, Sidhu A, Singal D, Dalcomine C, Singh N, Mall C, Codogan S, Singh D, Newman B, Sinnaeve L, Jarecshi J, Siva C, Duffy M, Slim HB, Dow V, Sorof S, Fuentes S, Sosa-Padilla M, Ayala M, Sotolongo R, Skiles B, Spadafora P, Illsley E, Srivastava S, Brazee L, St Maurice F, Staab P, Phillips W, Stahl L, Fulks E, Stimac J, Gowing C, Stoddard M, Longaker R, Stoll D, Ward K, Strain J, Kunz C, Swarup A, Salama S, Syan G, Bobbie C, Szatkowski A, Barker D, Talano J, Halbert M, Tallet J, Ferrin S, Tan J, Magro S, Tandon N, Johnson K, Tang S, Hartman J, Tannenbaum A, Mcgarr K, Tariq M, Gassier B, Tawakol A, Tung B, Taylor J, Kolibas J, Thadani U, Alexander D, Thakkar M, Tucker A, Thakore A, Noonan N, Tirmizi O, Chand D, Toledano A, Mehta N, Treasure C, Treasure L, Truong H, Velasquez S, Tucker S, Lewis D, Unrein C, Waller J, van Fossen D, Durant M, Vazquez-Tanus J, Cruz J, Velji A, Velji A, Elituv R, Verma R, White D, Vijay N, Washam M, Vijayasekaran S, Franklin A, Vizel S, Fox B, Vogel C, Johnson M, Vora K, Carmon S, Vyselaar J, Chauhan K, Waggoner D, Kelley E, Wali A, Schade D, Walia J, Sheena H, Walia D, Long L, Ward S, Grassi-Friedman T, Watson R, Troy R, Weiss S, Lenoir AM, Wessel T, Boyette A, Westcott R, Burroughs K, White L, Payne B, Wilkett D, Sweet S, Wilson V, Purcell T, Wilson S, Bergeron P, Zarich S, Assalone V, Zidel B, Singh V.

Abstract

BACKGROUND:

Inflammation is causally related to atherothrombosis. Treatment with canakinumab, a monoclonal antibody that inhibits inflammation by neutralizing interleukin-1β, resulted in a lower rate of cardiovascular events than placebo in a previous randomized trial. We sought to determine whether an alternative approach to inflammation inhibition with low-dose methotrexate might provide similar benefit.

METHODS:

We conducted a randomized, double-blind trial of low-dose methotrexate (at a target dose of 15 to 20 mg weekly) or matching placebo in 4786 patients with previous myocardial infarction or multivessel coronary disease who additionally had either type 2 diabetes or the metabolic syndrome. All participants received 1 mg of folate daily. The primary end point at the onset of the trial was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Near the conclusion of the trial, but before unblinding, hospitalization for unstable angina that led to urgent revascularization was added to the primary end point.

RESULTS:

The trial was stopped after a median follow-up of 2.3 years. Methotrexate did not result in lower interleukin-1β, interleukin-6, or C-reactive protein levels than placebo. The final primary end point occurred in 201 patients in the methotrexate group and in 207 in the placebo group (incidence rate, 4.13 vs. 4.31 per 100 person-years; hazard ratio, 0.96; 95% confidence interval [CI], 0.79 to 1.16). The original primary end point occurred in 170 patients in the methotrexate group and in 167 in the placebo group (incidence rate, 3.46 vs. 3.43 per 100 person-years; hazard ratio, 1.01; 95% CI, 0.82 to 1.25). Methotrexate was associated with elevations in liver-enzyme levels, reductions in leukocyte counts and hematocrit levels, and a higher incidence of non-basal-cell skin cancers than placebo.

CONCLUSIONS:

Among patients with stable atherosclerosis, low-dose methotrexate did not reduce levels of interleukin-1β, interleukin-6, or C-reactive protein and did not result in fewer cardiovascular events than placebo. (Funded by the National Heart, Lung, and Blood Institute; CIRT ClinicalTrials.gov number, NCT01594333.).

PMID:
30415610
DOI:
10.1056/NEJMoa1809798
[Indexed for MEDLINE]

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