Four-Year Visual Outcomes in the Protocol W Randomized Trial of Intravitreous Aflibercept for Prevention of Vision-Threatening Complications of Diabetic Retinopathy
Authors: Maturi Raj K. , Glassman Adam R. , Josic Kristin , Baker Carl W. , Gerstenblith Adam T. , Jampol Lee M. , Meleth Annal , Martin Daniel F. , Melia Michele , Punjabi Omar S. , Rofagha Soraya , Salehi-Had Hani , Stockdale Cynthia R. , Sun Jennifer K. ,   DRCR Retina Network, Browning David , Allen John Bradley , Antoszyk Andrew N. , Wilson Amanda H. , Murphy Brittany A , Fleming Christina J. , Mahr Courtney , Price Angela K. , Clark Justin , Ennis Sarah A. , Fredenberg Sherry L. , Jones Taylor S. , Nayar Monica D. , Bratcher Kayla A , McShea Kaitlin T. , Breglio Erica , Mutch Christina , Gentile Angella K. , Shore Carol A , McClain Donna , Clark Loraine M. , Jackson Lisa A. , Watson Lynn , McOwen Michael D. , Ross Tracy A. , Balasubramaniam Uma M. , Stobbe Shannon , Ramirez Yvonne , Ahmed Sara , Ramirez Stephanie , Boldbaatar Undariya , Quintero Valeria , Ceja Evelyn , Lee Scott F. , Cortes Jesus , Tran Katie , Ma Mary , Tran Mailan , Nguyen Nikki , Castillo Lily , Reyes Janet , Gasperian Karen , Parnes Robert E. , Stockman April L. , Shirey Jennifer , Stambaugh Kylie , Glaspell Lora , Toomey Leslie , Goldizen Angie , Wykoff Charles C. , Brown David M. , Schefler Amy C. , Shah Ankoor R. , Chen Eric , Major James C. , Benz Matthew S. , Fish Richard H. , Kim Rosa Y. , Wong Tien P. , Munoz Jose , Estes Maura A , Ortega Ilsa , Rodriguez Diana , Park Daniel , Hutson Amy , Twining Garret L , Serpas Mireya , Karani Sadia Y , Supapo Stacy M. , McCoy Tyneisha , Foerster Danee , Smith Calley N. , Almanza Belinda A. , Oviedo Miguel , Vela Melina , Webb Nina A. , Yee Rebecca , Sneed Veronica A. , Koger-Grifaldo Heather , Quellar Elizabeth , Wolff Lisa M , Burt Lindsay , Salinas Luis R. , James Miranda F , Sharma Devendra , Kegley Eric N. , Richter Beau A , Stoever Cary A. , Garcia David , Pieramici Dante J. , Castellarin Alessandro A. , Dhoot Dilsher , Learned Daniel L. , Steinle Nathan , Carbajal Carmen , Hong Gina , Giust Jack , McDermott John , Ray Jamison C , Card Kevin , McKee Kate M , Dahlberg Libby , Munoz Marco A , Castillo Nancy , Budvytyte Laura , Smith Jerry , Avery Kelly , Aromin Krisianne , Shook Aimee H. , Council Olivia S. , Spaeth Susan , Marcus Dennis M. , Singh Harinderjit , McCarty Daisy J , Simons Elizabeth W , Whitaker Geri K , Farooq Amina , Ortiz Siobhan O. , Bailey Thomas , Foster Lindsay Allison , Woodward Michele , Ivey Ken , Jung Jesse J. , Lit Eugene Stephen , Winje Heidi A. , Zamora Maria , Balakrishnan Renjini , Kim Jihyun , Machacon Joshua R , Kwan Mae , Ricks Helen , Frambach Caroline , Bustamante Denise Joy , Dizon Anne Grace , Jamali Afsoon , Miranda Maria , Lightman David A. , Saxe Stephen J , White Lorraine , Harless Ashley M. , Retrum Myra K , Brown Erin , Novak Carolee K. , Fiscus Holly , Morrow Stephanie J. , Harris Charlotte , Steele Thomas , Sarmiento Yesenia , Tilford Ron H. , Baker Jil D , Caldwell Tracey M. , Orr Margaret J. , Sharp Mary J. , Sedberry Kylie S. , Alcaraz Sonya L , Kettler Samantha , Camp Alecia B. , Berger Brian B. , Jhaveri Chirag D. , Chexal Saradha , Jonna Gowtham , Wilson Daniela Mariel , Vega Pereira Daniela , Seidu Tina A , Gunderson Ivana , Reid Ryan M. , Harara Abla M , Gatavaski Valerie , Ren Yong , Stovall Christopher C. , Corak Boris , Wong Robert W. , Nixon Peter A. , Martinez Jose A. , Le Phillip V. , Rodriguez Margaret A. , Montesclaros Chris A. , Vargas Corinne C , Karsaliya Gopal , Mangham Cory , Aiello Lloyd Paul , Sharuk George S. , Roh Miin Irene , Arrigg Paul G. , Silva Paolo S. , Shah Sabera T. , Stockman Margaret E. , Olesker Tanya , Rhee Jae W , Cavallerano Jerry D. , Bestourous Leila , Krigman Michael N. , Sehizadeh Mina , Glynn Shireen , Papaconstantinou Steve L. , Cavicchi Robert W. , Carli William , Sampani Konstantina , Weimann Elizabeth S. , Googe Joseph M. , Anderson Nicholas G. , Shuler R. Keith , Oliver Kristina , Morris Steve , Asher Julie , Walsh Justin , Seitz Vicky L. , Wheeler Jeff , McCoy Summer , Milstead Katie , Lince Raul E. , Oelrich Sarah M. , Gilbreath Caitlin , Griffone Hodge A. , Kooragayala Lakshmana Murthy , White-Walker Meuzette , Jackson Minuette S , Sewell Shakirah J , Lewis Chenavia , Nkemka Chigozie , Sircar Samantha , Thompson Kenneth , Goff Adam , Sierpina David Isaiah , Chalam Kakarla V. , Rauser Michael E. , Kim Samuel C. , Ramirez Tina L , Garcia Vivian L , Hernandez Raquel , Pereyra Rebecca K , Easterly Marcia , Midgett Jacqueline V , Paw Jayson S , Tampubolon Anthoni , Thomas Nadiya , Obispo Rene G. , Alset Adel E , Tellez Moises , Koushan Keyvan , Jeyabalachandran Myuri , Fung Pauline , Amiri Arman , Hegarty Stephanie , Navanathan Paviya , Thakker Parita , Dutta Devjani , Leung Gloria , Wong Jennifer , Brent Michael Henry , Mandelcorn Efrem D. , Murari Swetha , Moon Michelle , Sutakovic Olivera , Chen Lina , Hampton-Hampejskova Lindsay , Turhal Bilgin , Mowatt Claire , Brown Ian , Kotei Isaac A , Bolychuk Susan , Velez Gisela , Coleman Javon N , Leon Madeline , Parry Maa Ahema , Mykhaylyk Oksana , Sweeney Travis , Johnson Elizabeth I. , Chang Nicholas , Mastrodomenico Nicholas R , Ortega Michael D. , Taylor Thomas , Calixto Shayina M , Larkin Jean , Myers Joseph A. , Caro Jhan Carlos , Aho Amanda , Saez Armando , LaFountain Beatriz , Girard Crystal , Manuel Christine , Pallipeedikayil Chandapilla C. , Weng Christina Y. , Scholle Tahira , Rico Peter , Baker Laura A , Chatham Becky R. , Blacutt Wendy , Romany Gihan , Cai Jiping , Joshi Annika S. , Leger April , Nguyen Jessica , Morales Joseph F. , Barnett Dana B. , Cunningham Matthew A. , Mavrofrides Elias C. , Houston Samuel K. S. , Kumar Jaya B. , Haddox Martha , Gomez Ramona , Rodriguez-Roman Elaine , Pineda Francisco , Rodriguez Alma , Thomas Chanell , Figueroa Dianelis , Holle Timothy S , Elman Michael J. , Leder Henry A. , Starr JoAnn , Kreis Kate N , Belz Jennifer L. , Robinson Twyla J , Smalls Travis J. , Coffey Teresa , McCalla Alesia K , Thompson Amy , Ringrose Christine , Sandler Dallas R. , Wentz Katherine L , Vierheller Joshua , Singletary Pamela V. , Simpson Perel M. , Cain Terri , Sotirakos Peter , Metzger Ashley M. , Edwards Albert O. , Hunter Allan A. , Carroll Lillian A , Gregorich Nicole M , Kogutkiewicz Natalie W , Wallace Jonathan , Zuniga Jessica , Lebien Ryan G. , Muhlnickel Nicole , Everett Andrew G. , Rosberger Daniel F. , Brooks Nneka O. , Wangmo Phuntsho , Acevedo Sandra , Bendarkawi Sarah , Gyaltshen Sonam , Pickell Joshua A , Yaseen Mohammed , Gomez Yenelda M. , Brucker Alexander J. , Bhutani Devica L , DuPont Joan C. , Drossner Sheri , Johnson Kennedy N , Chen Judy , Berger Jim M. , Devine Cheryl , Freeman Sara , Seetharam Shabari S. , Schadlu Ramin , Prasad Anita , Smith Brigid , Butler Lindsey , Zaborowski Annemarie , Hylands Jacob Michael , Tonche Juan , Breazeale Richard I. , DeCroos Francis C. , Shah Rohan J. , Ghodasra Devon , McBee Steve W. , Clements Jacob , Menefee Kate , Lewis Brianna J , Duncan Courtney , Woods David , McDonald Elizabeth Lisa , Melendrez Roger P. , Moshiri Ala , Yiu Glenn C. , Wallace Cynthia , Macias Denise C , Beliveau Angela M. , Arnold Marisa E. , Garcia Susan , Deo Sashi , Slabosnitskiy Igor , Peterson John , Chandra Karishma , Kaufman Paul L. , McCluskey Jessica D. , Wynne Kathy T. , Weaver Cynthia , Watson Brandun , Cook Carlos R. , Romero Rosario , Matloff Sarah , Tanner Scott , Gilbert Kristin , Ulrich Jan Niklas , Garg Seema , DuBose Elizabeth L. , Bhansali Kanika A , Barnhart Cassandra J. , Dahringer Jesse C. , Esquejo Rona Lyn , Sharpe Houston P , Cantrell Debra , Grout Sean , Jones Veronica , Gross Jeffrey G. , Neamtu Victor A. , Gross Joel , Klapper Vincent , Flowers Amy M. , McDowell Angelique SA , Price Randall L. , Ghuman A. Thomas , Sharma Ashish G. , Raskauskas Paul A. , Walker Joseph P. , Maro Kristi , Toleman Lee T , Kiesel Cheryl , Peters Crystal Y. , Ryan Cheryl , Knips Eileen , Leslie Anita H. , Arevalo Alice , Kiesel Raymond K. , Moinfar Nader , Friedman Scott M. , Rehling Shannon M , Wendel Ceara L , Fagan Damanda F. , Williamson Kimberly A. , Andrews Jacqueline , Seyez Karen L , Williams Shana E , McKinney Allen , Bobbitt Brenda J. , Gonzalez Victor Hugo , Patel Nehal R. , Adyanthaya Rohit , Salinas Yesenia , Salinas Nancy L , Reyes David A. , Navarro Elyssa , Garza Angelina , Ibarra Amber B , Pina Ana L , Velasquez Brenda , Cabrera Isaac , Arredondo Janette , Cantu Monica R. , Chavez Enrique , Flores Rebecca R. , Diaz Yvonne , Alonso Samuel , Garza Santos , Tamez Stephanie , Montemayor Monique , Townsend Justin H. , Taha Jessica , Rodriguez Belen , Gutierrez Ailen E , Rodriguez Alexey Gomez , Mendoza Enelda Idalia , Perez Liliana P. , Mawdesley Megan , Asklar Shannon B , Rego Tanya Nicole , Sparling Brandon Michael , Fernandez Ailen Graces , Campbell J. Peter , Bailey Steven T. , Flaxel Christina J , Lauer Andreas K. , Hwang Thomas S. , Schain Mitchell , Lundquist Ann D. , Ira Shirley D. , Maykoski Jennifer K , Pickell Scott R. , Howell Chris S , Ukachukwu Chiedozie , Ryan Dawn M. , Barth Jordan , Hui Jocelyn T. , Brown Jamin S. , Hampton G. Robert , Sienkiewycz Laurie J. , Dorr Christine M. , Spuches Lisa , Manley Michelle L. , Kwasniewski Lynn M. , Robarge Nicole E. , DeSantis Stefanie R. , DeForge Teresa M. , Barker Jeffrey P , Miller Abigail , Grigorian Ruben A. , Jois Latha M , Webb Rebecca , Morris Rebecca , David Sharoon , Douglas Dusti D , Pena Faith , Stone Cameron McLure , Hall McCayla Elise , Menzel Andrea K. , Hamrick Monica , Raymer Lea R. , Rickman Leslie D. , Machen Donna , Overbey Julia Crokett , Hawkins Lisa H. , Smith Melissa , Price Paula A. , Cruess Alan F. , Dickinson John D. , Gupta R. Rishi , Cranston Alec M , Caldwell Meggie D , Durling Stacey , MacDonnell Trina , Hynes Mitzi , Fox Gregory M. , Cooper Blake A. , Dyer David S. , Batlle Ivan R. , Christensen Ryan D. , Singh Ravi S. J. , Ainley Lexie R. , Batlle Karla A. , Hinkel Holly A , Wyrick Holly , VandeVelde Amber R , Yeager Frank T. , Pippin Katherine , Shami Michel , Saldivar Yolanda , Meeks Ashaki , Gardner Glenn R , Olsen Karl R. , Knickelbein Jared E. , Bergren Robert L. , Doft Bernard H. , Merlotti Lori A. , Stepansky Lois , Walter Julie , Ostroska Phyllis P , Diperna Dawn , Chan Clement K. , Lalezary Maziar , Gonzales Tiana , Gieser Tonya M , Walther Kimberly S. , Aldana Isela , Myers Lenise E. , Pettit Kristina , Huff Kenneth M. , Handza Jason M. , Oudshoff Bronson , Glover Christina , McGahee Corey T. , Carey Annette M. , Lara Tirso M. , Burgess Stuart K. , Pereda Noel H. , Villa Adriana , Davis Deborah , Workman Karen , Oberlander Mark , Patel Apurva K. , Ma Colin , Peters Mark A. , Tlucek Paul S. , Puckett Brian S , Smith Pualani , Ho Stephanie L. , Charpentier Margaret E , Kopfer Marcia , Hoerner Christine , Chen Melvin , Jelemensky Peggy A. , Basham Samantha R. , Raphael Tara L. , Miller Rosa , Sneath Mark , Qureshi Jawad A. , Warminski Johnathan D. , Dajee Kruti P. , Dunn Gregory A , Cowart Victoria E. , Watkins Andre , Murillo Diana , Ortiz Denise , Navajas Eduardo Vitor , Cao Sijia , Jovanovic Mira , Wiens Theresa , Han Sherry , Grant Kelly , Godfrey Anne-Marie , Harrison Bryan , Solomon Sharon D. , Bressler Susan , Frey Mary , Donohue Deborah , Levin Lisa K. , Cain Dennis , Distle Russ , Lyon Alice T. , Gill Manjot K. , Seddon Nicole M , Thakkar Priya M , Mwale Chisomo , Ramirez Carmen , Santillanes Crystal , Davies Evan C , Pecht Julie , Moore Anson , Moore Cason , Veto Kaitlyn , Barragan Maritza , Simjanoski Evica , Lim Jennifer I. , Chau Felix Y. , Sun Jie , Stankovic Natasa , Johnson Tametha , Martinez Ben , Degillio Andrea , Janowicz Mark , Grover Sandeep , Hamdani Ghulam Shabbir , Smith Jazzmin N , Babaria Romesh , Mynampati A Bharani Krishna , Gottlieb Justin , Blodi Barbara A. , Dietzman Kristine A. , Smith Christopher M. , Adler Angela M. , Krolnik Denise A. , Reed Sandie L. , Gentile Ronald C , Choi John Bo Soo , Rivas Melissa , Masini Robert , Carrasquillo-Boyd Wanda , Lehr John T. , Pendarvis Brittany M. , Delgado Mari , Haddox Martha Eileen , Lynch Patricia , Atnip Robert , Bramble Atira , Willer Ashley E , Hutchings Chase , Rodriguez Julian , Dreessen Kyle , Pena Mark , Rosenthal William N. , Heim Elizabeth N. , Lamaster Sarah N. , Stewart Mary C , Varner R. Scott , Dunn Courtney J , Chica Moises A. , Mein Calvin E. , Adams Lydia , Kirschbaum Lita , Bermea Jenny M , Cloudt Sara L , Lopez Victoria , San Roman Jonathan , Bankston Samantha , Wienecke Christopher Sean , Nakoski Brenda , Bhandari Ramanath , Shaw Jennifer , Evans Bradley C. , Moushon Gaylan W , Fox Amanda , Anderson Braden , Wessel Caitlyn , Frye Dennis , Karrick Kris , Bhavsar Abdhish R. , Gilchrist Andrea , Moreno Celeste , Sweet Jason R , Peloquin Matt D. , Vang Denise , Kinney Erin C. , Evans Alanna C. , Haffner Gregory M. , DeClement Andrea L. , Hurst Leslie D , Anderson Patricia L , Esteves Stephanie , Enxuto Adriana N , Morse Emily , Christoforidis John B. , Brickman-Kelleher Jill , Bulau Sue A. , Fryer Patricia H , Haymore Dennis , Wells John A. , Swinford Tiffany R. , Ogbuewu Tiffany N. , Spivey Robbin , Studebaker Ashley , Nielsen Jared S. , Alliman Kyle J. , Woehl Tami Jo , Parker Marianne , Riley Erin L , Bowers Jack , Bix Paula L , Spillman Jamie , Ridgway Spencer D , Boender Lisa M. , Beck Roy W. , Baptista Alyssa , Beaulieu Wesley T. , Calhoun Claire T. , Constantine Sharon R. , Correia Isabella , Dale Brian B. , Dupre Simone S. , Franklin Crystal A. , Galusic Sandra , Huggins Meagan , Hunter Brenda L. , Johnson Paula A. , Kelly Brittany , Maguire Maureen G. , Meadows Britney , Zokruah Alice , Liu Danni , Preston Carin M. , Bhargava Sangeeta , Barkmeier Andrew J. , Baskin Darrell , Blodi Barbra , Chew Emily , Ferris Frederick L. , Jaffe Glenn J. , Bressler Neil M. , Lujan Brandon , Kim Judy E. , MacCumber Mathew W. , Abrams Gary , Barnbaum Deborah , Flynn Harry , Rudser Kyle , Sternberg Paul , Weinstock Ruth , Wisniewski Stephen 
Published: February 2023

ImportanceAnti–vascular endothelial growth factor (VEGF) injections in eyes with nonproliferative diabetic retinopathy (NPDR) without center-involved diabetic macular edema (CI-DME) reduce development of vision-threatening complications from diabetes over at least 2 years, but whether this treatment has a longer-term benefit on visual acuity is unknown.ObjectiveTo compare the primary 4-year outcomes of visual acuity and rates of vision-threatening complications in eyes with moderate to severe NPDR treated with intravitreal aflibercept compared with sham. The primary 2-year analysis of this study has been reported.Design, Setting, and ParticipantsRandomized clinical trial conducted at 64 clinical sites in the US and Canada from January 2016 to March 2018, enrolling 328 adults (399 eyes) with moderate to severe NPDR (Early Treatment Diabetic Retinopathy Study [ETDRS] severity level 43-53) without CI-DME.InterventionsEyes were randomly assigned to 2.0 mg aflibercept (n = 200) or sham (n = 199). Eight injections were administered at defined intervals through 2 years, continuing quarterly through 4 years unless the eye improved to mild NPDR or better. Aflibercept was given in both groups to treat development of high-risk proliferative diabetic retinopathy (PDR) or CI-DME with vision loss.Main Outcomes and MeasuresDevelopment of PDR or CI-DME with vision loss (≥10 letters at 1 visit or ≥5 letters at 2 consecutive visits) and change in visual acuity (best corrected ETDRS letter score) from baseline to 4 years.ResultsAmong participants (mean age 56 years; 42.4% female; 5% Asian, 15% Black, 32% Hispanic, 45% White), the 4-year cumulative probability of developing PDR or CI-DME with vision loss was 33.9% with aflibercept vs 56.9% with sham (adjusted hazard ratio, 0.40 [97.5% CI, 0.28 to 0.57]; P &amp;lt; .001). The mean (SD) change in visual acuity from baseline to 4 years was −2.7 (6.5) letters with aflibercept and −2.4 (5.8) letters with sham (adjusted mean difference, −0.5 letters [97.5% CI, −2.3 to 1.3]; P = .52). Antiplatelet Trialists’ Collaboration cardiovascular/cerebrovascular event rates were 9.9% (7 of 71) in bilateral participants, 10.9% (14 of 129) in unilateral aflibercept participants, and 7.8% (10 of 128) in unilateral sham participants.Conclusions and RelevanceAmong patients with NPDR but without CI-DME, at 4 years treatment with aflibercept vs sham, initiating aflibercept treatment only if vision-threatening complications developed, resulted in statistically significant anatomic improvement but no improvement in visual acuity. Aflibercept as a preventive strategy, as used in this trial, may not be generally warranted for patients with NPDR without CI-DME.Trial RegistrationClinicalTrials.gov Identifier: NCT02634333