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N Engl J Med. 2015 Mar 26;372(13):1193-203. doi: 10.1056/NEJMoa1414264. Epub 2015 Feb 18.

Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema.

Collaborators (1046)

Browning D, Antoszyk AN, Price AK, Fredenberg SL, Herby JT, Fleming CJ, McClain AA, Ennis SA, Gallagher KR, Karow AS, Grupp AC, Puskas D, Watson L, Bojaj SJ, Balasubramaniam UM, McClain D, Styles DR, Kuopus JA, Kimrey K, Clark LM, Jackson LA, McOwen MD, Dunlap M, Held SJ, Pieramici DJ, Nasir MA, Castellarin AA, Dhoot D, Fishbein S, Giust J, Wan L, Hanna MS, Rabena MD, Smith J, Bone LJ, Avery K, Giust M, Walker A, Shook AH, Esau S, Ruvalcaba NL, Wells JA, Clark W, Johnson DL, Payne JF, Swinford TR, Taylor MM, Garrison CL, Miller PD, Houlahan AR, O'Neill CA, Floyd A, Parker CC, Sease C, Graham T, Spencer R, Ogbuewu TN, Studebaker A, Huggins T, Spivey R, Jones B, Williams A, Petty R, Poston EL, Ward G, Baker CW, Tilford RH, Caldwell TM, Lambert LF, Palmer MJ, Martin TR, Williams TR, Kettler S, Camp AB, Silva PS, Arrigg PG, Sharuk GS, Shah ST, Sun JK, Westerfeld C, Andreoli CM, Aiello LP, Schlossman D, Murtha T, Kwak H, Flores FM, Stockman ME, Kieser T, Krigman MN, Bestourous L, Weimann ES, Cavallerano JD, Hock KM, Robertson MA, Kirby RK, Papaconstantinou SL, Madigan KM, Cavicchi RW, Palitsch KA, Yilmaz T, Berger BB, Jhaveri CD, Moore T, Manhart GJ, Walsh RA, Gunderson I, Riepen D, Bravenec CA, Reid RM, Ren Y, Ostrander B, Stovall CC, Elman MJ, Liss RA, Leder HA, Starr J, Belz JL, Putzulo CK, Sandler DR, Simmons JL, Singletary PV, Davis A, Simpson PM, Coffey T, Ketner DJ, Cain T, Metzger AM, Sotirakos P, Elman MJ, Liss RA, Leder HA, Starr J, Belz JL, Putzulo CK, Sandler DR, Simmons JL, Singletary PV, Davis A, Simpson PM, Coffey T, Ketner DJ, Cain T, Metzger AM, Sotirakos P, Marcus DM, Singh H, Roberts CN, Floyd GL, Ortiz SO, Mims V, Foster L, Coursey C, Gardner JC, Ivey K, O'Keefe JS, Astruc JA, Schwent BJ, Tabassian AR, Rosen SA, Vaughan DC, Michaels J, Arndt NJ, Maziarz JJ, Friedman SM, Moinfar N, Williamson KA, Fagan DF, Dawson KL, Walters PN, McKinney A, Carlton S, Kwun RC, Knudsen VL, Winward KE, Swartz M, Howard JG, Riley M, Taylor G, Holt M, Winward JG, Walsh A, Taylor T, Walsh D, Hampton G, Brown JS, Seth RK, Sienkiewycz LJ, Appleton DA, Grinnell CJ, Cowley CA, Kwasniewski LM, Manley ML, Robarge NE, DeSantis SR, Hay PB, DeForge TM, Wykoff CC, Wong TP, Chen E, Brown DM, Kim RY, Major JC, Schefler AC, Fish RH, Benz MS, Lipman M, Hutson A, Landaverde N, Chancey AE, Cone C, Royse T, Sneed VA, Almanza BA, Dives B, Richter BA, Kegley EN, Lauer AK, Flaxel CJ, Bailey ST, Schain M, Lundquist AD, Hanel SA, Ira SD, Nolte SK, Steinkamp PN, Ryan DM, Pickell SR, Hui JT, Brix M, Barth J, Howell CS, Fox GM, Cooper BA, Batlle IR, Manning LR, Batlle KA, Wyrick H, Pippin K, Perkins S, Yeager FT, Rush RB, Gardner GR, Rush C, Hawkins JR, Dumas B, Ysasaga B, Shah CP, Morley MG, Wiegand TW, Cleary TS, Topping TM, Colegrove L, Bechtel K, Johnson B, Lebedew L, Lorius N, Chong SG, Stone JL, Jones MC, Donovan D, Malone S, Graham M, Santos A, Bennett SA, Blinder KJ, Smith BT, Nobel GS, Weeks RF, Hoehn EA, Stuart MA, Pepple KE, Boyd LK, Pulliam BG, Schremp SA, Guevara SL, Wehmeier J, Wright TL, Gabel DL, Miller DG, Schartman JP, Singerman LJ, Coney JM, Novak MA, Rao LJ, Rath SC, McNamara E, Stone L, Smith VA, Rykena C, DuBois KA, Ilc MA, Tanner V, Drury K, Nitzsche TM, Greanoff GA, DuBois JC, Burgess SK, Lara TM, Pereda NH, Fernandez CV, Davis D, Quinchia E, Workman K, Nielsen JS, Sohn JH, Alliman KJ, Saggau DD, Parker M, George B, Eastvold CL, Sells K, Woehl TJ, Johnson MA, Keenan H, Coleman JL, Spillman J, Freeman S, Schmidt LS, Boender LM, Partin JL, Bennett BR, Rostvold J, Stone CM, Raymer LR, Menzel AK, Rickman LD, Campbell B, Sherlin LP, Hawkins LH, Buckner ML, Matsipura ON, Price PA, Ghuman A, Raskauskas PA, Sharma AG, Wing G, Walker JP, Knips E, Kiesel C, Peters CY, Ryan C, Greenhoe L, Torres NN, Youngblood RJ, Turnbo D, Leslie AH, Schoeman EC, Kiesel RK, Kingsley RM, Shah VA, Leonard RE, Miller HR, Icks S, Bergman VA, Drummond VK, Ross BL, Ellis RD, Whittington TR, Almeida SR, Butt AM, Burris R, Peters MA, Lee MS, Tlucek PS, Ma C, Hobbs S, Milliron AC, Ho SL, Kopfer M, Logan J, Hoerner C, Khawly JA, Rahman HT, Abdelgani D, Miller PS, Fredrickson D, Pineda E, Lopez D, Lowd DK, Blank C, Martinez LR, Muniz JE, Gottlieb J, Ip MS, Blodi BA, Dietzman KA, Burke KF, Smith CM, Olson SR, Wealti AM, Reed SL, Krolnik DA, Peterson JC, Gonzalez VH, Diaz-Rohena R, Santiago JG, Adyanthaya R, Patel NR, Anaya D, Garcia D, Cruz EE, Alvarez CA, Iracheta R, Rodriguez J, Cantu MR, Flores RR, Jasso H, Rodriguez R, Miranda K, Lozano KR, Garza M, Aguero L, Sandoval AL, Montemayor M, Alonso S, Garza S, DiLoreto DA, Ramchandran RS, Kleinman DM, O'Gara GW, Czubinski AM, MacDowell P, Steinmetz KM, Castillo DA, Yu YF, Tongue SM, Keim MS, Hollar R, Deats BN, Richardson BS, Singer L, Pannell TA, Daniels SA, Ranchod TM, Leong CJ, Touson S, Earl SR, Bartlett MC, Fernando C, Factor D, Garcia J, Nguyen AK, Hom B, Walker C, Marudo GM, Suazo JC, McNeil LM, Hanamoto F, Hughes MD, Ross RD, Sanford SM, Markiewicz NM, Utley TM, Henderson S, Lippincott JH, Streasick P, Glazer LC, Garber FW, Zheutlin JD, Listerman AD, Feehan CE, Cruz HL, Kuitula DE, Rainey OP, Weatherbee S, Googe JM, Shuler R, Anderson NG, Perkins SL, Oliver K, Grindall N, Arnold A, Beerbower J, Hunt C, Schulz KL, Oelrich SM, Whetstone JK, Walsh J, Morris C, Wong RW, Nixon PA, Leon JL, Montesclaros CA, Leung CE, Le P, Harborth CL, Rodriguez MA, Mangham C, Aaberg TM, Westhouse SJ, Vincent HL, Malone R, Karsten KL, Maturi RK, Harless AM, Novak CK, Bleau LA, Steele T, Harris C, Bildner A, Maple A, Stone TW, Isernhagen RD, Kitchens JW, Holcomb DM, Van Arsdall J, Buck M, Slade EA, Chiu MT, Reddy AK, Wyant FW, Montano-Niles MM, Carter LJ, Maerki S, Tartaglia L, Gomez PP, Maestas SA, Shanta C, Jimenez LM, Stoltz RA, Vanderveldt SL, Lampert SI, Marcus LG, Fulbright S, Martin JP, Novack RL, Liao DS, Lo TE, Kurokouchi J, Ngo R, Hoang CV, Sierra J, Zamboni A, Protacio EG, Kessinger J, Garg S, Houghton OM, Ulrich JN, Chavala SH, DuBose EL, Barnhart CJ, Karmalkar M, Jani PD, Goble J, Cantrell D, Esquejo RL, Shah SN, Harmon N, Dhalla MS, del Cid MR, Halperin LS, Brady JA, Hamlin M, Lopez ML, Mariano J, Neale CM, Veksler RR, Mannarelli A, Coffee RE, Carvounis PE, Hemati P, Dorenbach CJ, Joshi AS, Leger A, Barnett DB, Morales JF, Mansour SE, Choyce C, Dirawatun AL, Nagy EA, Kerkstra JC, Fan JT, Suthar MB, Rauser ME, Santiago G, Cerdenio LM, Perez BJ, Halsey KE, Kiernan WH, Knabb J, Catren R, Shami M, Arrington BK, Neuling KS, Meeks A, Garcia NR, Blair K, Rhymes GK, Medrano J, Kim JE, Weinberg DV, Stepien KE, Connor TB, Williams VV, Kaczanowski TL, Packard KL, Flanders J, Barwick V, Winter PA, Beringer JR, Selchert KJ, Lehr JT, Rodriguez-Roman E, Jones T, Haddox ME, Pena M, Hernandez B, Chan CK, Lalezary M, Lin SG, Walther KS, Gonzales T, Myers LE, Huff KM, Chace R, Kallay S, Stevens K, Dolbec N, Baker-Hill R, Surette J, Rose SJ, Connolly BP, Guillet EG, Hall EF, Yagoda MM, Doran MJ, Burgess M, Reynard A, Powers M, Territo J, Mein CE, Chica MA, Lane R, Holy SE, Kirschbaum L, Martinez VD, Baker J, Kincaid CG, Castillo E, Wienecke CS, Schlichting SL, Nakoski B, Diddie KR, Cadwell DM, Van Arsdale L, Boisvert TF, Galonsky J, O'Hayer S, Johnson ML, McCabe FJ, Baker BJ, Defrin MH, Lampson MV, Pratte H, Baron SA, Borelli AS, Davidorf FH, Wells MB, Chang S, Christoforidis JB, Letson AD, Salerno JA, Perry JG, Shelley SE, Fish PJ, Scott MH, Dixon JA, Walsh SR, Ozpirincci PM, Tebon BL, Moyle MJ, Pavlica MR, Matta NS, Brubaker CM, Backer AB, Bhagat N, Fay C, Mikheyeva T, Lazar M, Ellenberger JD, Malpica B, Brucker AJ, Kim BJ, VanderBeek BL, Drossner S, DuPont JC, Salvo R, Engelhard SB, Berger JM, Morales S, Serpentine B, Kaufman PL, McCluskey JD, Wynne KT, Jordan J, Watson B, Wirthlin RS, Guglielmo ES, Dittman EA, Waidelich DC, Garza CJ, Stone AM, Oakes AN, Suner IJ, Hammer ME, Peden MC, Traynom JR, DenBoer R, Vargo H, Ramsey S, Malzahn AK, Jeffres D, Chaudhry NA, Shah SP, Haffner GM, German E, Moreau S, Fox LA, Matteson JM, Pelletier JL, Fontecchio A, Morse E, McNamara G, Laglivia MG, Scherf ML, LaPre A, Cocilo JA, Das A, Friesen L, Franco M, Lucero J, Frazier M, Laviolette R, Mian UK, Riemer RL, Koestenblatt E, Wolf LV, Kim C, Katkovskaya I, Otoo E, Ellerbe KA, Boyd K, Costa C, Edwards PA, Gao H, Hessburg T, Desai U, Murphy J, Monk MK, Hall J, Mazurek M, Ventimiglia KM, Rusinek BA, Stern BA, Brouhard K, Weier KM, Allis M, Shaken J, Massu NM, Troszak TA, Burley D, Bhavsar AR, Emerson GG, Jones JM, Anderson TA, Gilchrist A, Peloquin MD, Gaid G, Vang Y, Ryan S, Vang D, Evans AC, Scherer T, Lazarus HS, Bunch DP, Davis LC, Booth K, Trimble M, Bledsaw MA, Moore J, Rosberger DF, Groeschel S, Madry MA, DiGirolamo N, Pressley D, Santora R, Gomez YM, Olsen KR, Bergren RL, Conrad P, Rath PP, Vyas AP, Liu JC, Merlotti LA, Chamberlin JL, Mechling HM, Kelly ME, Marfisi K, Yeckel KA, Bennett VL, Schultz CM, Rigoni GA, Walter J, Forish MA, Fec A, Foreman CL, Steinberg D, McBroom KD, Chen MC, Levy MH, Torres W, Jelemensky P, Raphael TL, Rich J, Sneath M, Kinyoun JL, Vemulakonda GA, Rath SA, Ernst PK, Pettingill JA, Jones RC, Clifton BC, Leslie JD, Solomon SD, Bressler NM, Levin LK, Donohue D, Frey M, Larez L, Murray K, Denbow RL, Graul J, Emmert D, Herring C, Rhoton N, Belz J, Lyon AT, Mirza RG, Krug AM, Ramirez C, Kaminski L, Castro-Malek AL, Mills AN, Rozenbajgier Z, Skelly ML, Simjanoski E, Degillio AR, Lim JI, Chau FY, Niec M, Johnson T, Ovando Y, Janowicz M, Carroll C, Gross JG, Fishburne BC, Flowers AM, Stroman R, Ochieng C, McDowell AS, Paul AM, Price RL, Drouilhet JH, Lacaden EN, Nobler DJ, Cummings HL, Long DJ, McCord B, Robinson J, Swift J, Maynard JP, Pahk PJ, Palmer-Dwore H, Dave DH, Pacheco M, Galati BA, Simpson E, Barkmeier AJ, Vogen DL, Berg KA, Howard SL, Burrington JM, Morgan JA, Overend JT, Goddard S, Lewison DM, Tesmer JL, Greven CM, Fish J, Everhart C, Clark MD, Miller DT, Hendrick AM, Hubbard GB, Yan J, Cribbs BE, Curtis LT, Brower JL, Dobbs JL, Jordan DJ, Ahmad BU, Huang SS, Sedlacek HM, Hornsby CL, Ferguson LP, Carlton K, Sholtis KA, Allchin P, Clow C, Harrod MA, Pankhurst G, Baum-Rawraway I, Hrvatin SA, Gentile RC, Yang A, Carrasquillo-Boyd W, Masini R, Samy CN, Kraut RJ, Shirley K, Corso L, Ely K, Scala E, Gross S, Alava V, Margalit E, Neely DG, Blaiotta M, Hagensen L, Harris AE, Lennon RL, Cota DR, Wilson L, Wells JA 3rd, Aiello LP, Beck RW, Bressler NM, Bressler SB, Chalam KV, Danis RP, Arnold-Bush BJ, Ferris F, Friedman SM, Glassman AR, Scott MH, Sun JK, Wong RW, Glassman AR, Beck RW, Almukhtar T, Arnold-Bush BJ, Dale BB, Baptista A, Connor C, Conner J, Constantine SR, Dowling K, Dupre SS, Ayala AR, Huggins ML, Inusah S, Johnson PA, Loggins BL, McClellan SL, Melia M, Battle E, Stockdale CR, Stanley D, Jaffe G, Balsley B, Barbas M, Burns R, Busian D, Ebersohl R, Heydary C, McEwan S, Myers J, Robertson A, Shields K, Thompson G, Winter K, Young E, Danis RP, Davis MD, Huang Y, Blodi B, Domalpally A, Reimers J, Vargo P, Wabers H, Myers D, Lawrence D, Allan J, Jampol LM, Bressler NM, Antoszyk A, Baker CW, Sun JK, Wells JA 3rd, Friedman S, Bressler SB, Scott IU, Schron E, Everett DF, Miskala PH, Connett J, Abrams G, Barnbaum DR, Flynn H, Weinstock RS, Wilkinson CP, Wisniewski S, Genuth S, Frank R, Aiello LP, Antoszyk AN, Baker CW, Beck RW, Bressler NM, Bressler SB, Danis RP, Davis MD, Elman MJ, Ferris FL 3rd, Glassman AR, Gross JG, Jaffe GJ, Jampol LM, Maturi RK, Schron E, Sun JK, Wells JA 3rd, Bhavsar A, Brucker AJ, Chalam KV, Everett DF, Fish J, Friedman S, Googe J Jr, Holcomb DM, Lauer A, Marcus DM, McClain A, Perez BJ, Scott IU, Starr J.

Abstract

BACKGROUND:

The relative efficacy and safety of intravitreous aflibercept, bevacizumab, and ranibizumab in the treatment of diabetic macular edema are unknown.

METHODS:

At 89 clinical sites, we randomly assigned 660 adults (mean age, 61±10 years) with diabetic macular edema involving the macular center to receive intravitreous aflibercept at a dose of 2.0 mg (224 participants), bevacizumab at a dose of 1.25 mg (218 participants), or ranibizumab at a dose of 0.3 mg (218 participants). The study drugs were administered as often as every 4 weeks, according to a protocol-specified algorithm. The primary outcome was the mean change in visual acuity at 1 year.

RESULTS:

From baseline to 1 year, the mean visual-acuity letter score (range, 0 to 100, with higher scores indicating better visual acuity; a score of 85 is approximately 20/20) improved by 13.3 with aflibercept, by 9.7 with bevacizumab, and by 11.2 with ranibizumab. Although the improvement was greater with aflibercept than with the other two drugs (P<0.001 for aflibercept vs. bevacizumab and P=0.03 for aflibercept vs. ranibizumab), it was not clinically meaningful, because the difference was driven by the eyes with worse visual acuity at baseline (P<0.001 for interaction). When the initial visual-acuity letter score was 78 to 69 (equivalent to approximately 20/32 to 20/40) (51% of participants), the mean improvement was 8.0 with aflibercept, 7.5 with bevacizumab, and 8.3 with ranibizumab (P>0.50 for each pairwise comparison). When the initial letter score was less than 69 (approximately 20/50 or worse), the mean improvement was 18.9 with aflibercept, 11.8 with bevacizumab, and 14.2 with ranibizumab (P<0.001 for aflibercept vs. bevacizumab, P=0.003 for aflibercept vs. ranibizumab, and P=0.21 for ranibizumab vs. bevacizumab). There were no significant differences among the study groups in the rates of serious adverse events (P=0.40), hospitalization (P=0.51), death (P=0.72), or major cardiovascular events (P=0.56).

CONCLUSIONS:

Intravitreous aflibercept, bevacizumab, or ranibizumab improved vision in eyes with center-involved diabetic macular edema, but the relative effect depended on baseline visual acuity. When the initial visual-acuity loss was mild, there were no apparent differences, on average, among study groups. At worse levels of initial visual acuity, aflibercept was more effective at improving vision. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01627249.).

PMID:
25692915
PMCID:
PMC4422053
DOI:
10.1056/NEJMoa1414264
[Indexed for MEDLINE]
Free PMC Article

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