Mediation of Age and Thrombectomy Outcome by Neuroimaging Markers of Frailty in Patients With Stroke
Authors: Benali Faysal , Singh Nishita , Fladt Joachim , Jaroenngarmsamer Tanaporn , Bala Fouzi , Ospel Johanna M. , Buck Brian H. , Dowlatshahi Dar , Field Thalia S. , Hanel Ricardo A. , Peeling Lissa , Tymianski Michael , Hill Michael D. , Goyal Mayank , Ganesh Aravind ,   ESCAPE-NA1 Investigators, Barber Philip A. , Smith Eric E. , Bal Simerpreet , Subramanian Suresh , Peters Steven , Couillard Philippe , Klein Gary , Stys Peter , Coutts Shelagh B. , Wong John , Mitha Alim , Eesa Muneer , Morrish William , Alqatani Saad , Kashani Nima , Venkatesan Prasanna , Teleg Ericka , Sitaram Amith , Graham Brett , Gaal Stephen van , Moussaddy Aimen , Chakraborty Debabrata , Maraj Nicholar , Lockey Andrew , Chen Shuo , Singh Ravinder , Alsultan Abdulaziz Sulaiman , Asunsian Ria , Tse Dominic , Doshi Darshan , Volny Ondrej , Ojha Piyush , Wadhwa Ankur , Marko Martha , Singh Nishita , Wasyliw Sanchea , Ryckborst Karla J. , Kenney Carol , Save Supriya , Jambula Anitha , Newcommon Nancy , Hull Gavin , Blackstock Darcy , Kiszczak Sharon , Zimmel Leslie , Wright Michelle , Jahraus Cari , Andersen Linda , Bohn Shelly , Paul Joseph , Buck Brian H. , Butcher Kenneth S. , Shuaib Ashfaq , Jeerakathil Tom , Jickling Glen , Emery Derek J. , Rempel Jeremy , Ower Richard J. , Ashforth Robert , Yeo Tom , Kotylak Trevor B. , O;Kelly Cian , Chow Michael , Siddiqui Mizaffar , Saqqur Maher , D'Souza Atlantic , Lloret Mar , Butt Asif , Nomani Ali , Kalashyan Hayrapet , Thirunavukkarasu Sibi , Jabs Juline , Fairall Paige , Piquette Lori , Phillips Stephen J. , Green A. Laine , Gubitz Gordon J. , Heidenreich Jens O. , Huynh Thien , Shankar Jai J. S. , Maloney William J. , Vandorpe Robert , Schmidt Matthias H. , Pickett Gwynedd E. , Weeks Adrienne , Jarrett Juditch , MacDonald Debbie , Arsenault Joanna , Kinnear Ruth , Mandzia Jennifer L. , Mayich Michael , Boulton Melfort , Bullrich Maria Bres , Fridman Sebastian , Kiwan Ruba , Lee Donald , Lownie Stephen , Khaw Alexander V. , Pandey Sachin K. , Sharma Manas , Sposato Luciano A. , Wade Kevin , Beauchamp Beth , Lambourn Lindsay , Amato-Marziali Belinda , Roy Daniel , Deneault Nicole , Deschaintre Yan , Gioia Laura C. , Jacquin Grégory , Odier Céline , Stapf Christian , Iancu Daniela , Raymond Jean , Weill Alain , Lapierre Marlène , Jadil Nadia , Jolteus Judlène , Teitelbaum Jeanne , Angle Mark , Hannouche Mathew , Badawy Mohamed , Letourneau Justin , Cortes Maria , Linnell Grant , Tampieri Donatella , Vieira Lucy , Legault Catherine , Durcan Liam , Moore Angela , Cole Erin , Magnussen Claire , Salmon Kristiana , Khalil Salma , Desloges Isabelle , Waxman Lindsay , Abdon Wynne , Lai Sonia , Dowlatshahi Dar , Shamy Michel , Stotts Grant , Blacquiere Dylan , Lesiuk Howard , Quateen Aiman , Drake Brian , Dewar Brian , Daham Zeinab , Kelly Michael E. , Hunter Gary , Peeling Lissa M. , Graham Brett R. , Whelan Ruth , Garner Aaron J. , Urroz Lilian , Maley Sharleen , Silver Frank L. , Casaubon Leanne , Pikula Aleksanda , Campo Martin del , Schaafsma Joanna , Jaigobin Cheryl , Krings Timo , Pereira Vitor , Agid Ronit , Farb Richard , Kalman Libby , Cayley Anne , Williams Janice , Stewart Tim , Misquitta Karen , Bharatha Aditya , Selchen Daniel H. , Marotta Thomas R. , Sarma Dipanka , Montanera Walter J. , Spears Julian , Saposnik Gustavo , Kostyrko Pawel , Li Yangmei , Parra-Farinas Carmen , Diestro Jose Danilo Bengzon , Camden Marie-Christine , Verreault Steve , Mackey Ariane , Audet Marie-Eve , Milot Geneviève , Lavoie Pascale , Gariépy Jean-Luc , Collard Karine , Haché Annette , Sahlas Demetrios J. , Alshanbari Ahmed M. , Baldwin Josephine , Catanese Luciana , Chen Bing Y. , Sa Boasquevisque Danielle de , Deshmukh Aviraj S. , Knapman Josrdan M. , Lamers Shana , Larrazabal Ramiro A. , MacMillan Susan V. , Mai Lauren M. , Mattai Alicia M. , Nayar Sumiti , Ng Kuan H. , Oczkowski Wieslaw J. , Perera Kanjana S. , Shawawrah Mays A. K. , Shoamanesh Ashkan , Sobhi Gita , Syed Nabeel M. , Yaher Noran Y. , Vandervelde Cheyanne , Wang Di , Field Thalia S. , Van Gaal Stephen C. , Teal Philip A. , Benavente Oscar R. , Wilson Laura K. , Mann Sharanpal K. , Yip Samuel , Murphy Colleen B. , Heran Manraj K.S. , Rohr Axel , Settecase Fabio , Redekop Gary J. , Haw Charles S. , Maclean Genoveva , Murray Karina , Chiu Rosalin , Flexman Alana M. , Strecha Eilidh , Gayton Yolanda , Yip Judy , Swartz Richard H. , Boulos Mark I. , Gladstone David J. , Yu Amy Y. , Hopyan Julia J. , Khosravani Houman , Manosalva Alzate Herbert A. , Southwell Alisia , Kamra Maneesha , Lopes Kaitlyn N. , Kapoor Arunima , da Costa Leodante , Yang Victor X. D. , Dyer Erin E. , Shah Ruchir A. , Knowles Brenda M. , Nichols Jennifer , Patterson Jennifer L. , Cope Krista A. , Dickerson Lee , Barton Katrina K. , Gray Kimberly D. , Massengale Ticey N. , Miller Melanie G. , Simpson Cindy , Walker Sabrina , Tennyson-Yemm Chlin R. , Frei Donald F. , Bellon Richard J, , Atchie Benjamin N. , Kaminsky Ian A. , Wilson Duandelyn C. , Schraeder Nicolle L. , Arias Eric J. , Kodis Lisa M. , Talley Mark E. , Edinger Alex A. , Talley Tiffany C. , Dempsey Ita P. , Williams Laurie A. , Williams Scott A. , Kupniewski Sonny , Fasbinder Brad K. , Snead Joanna M. , Choe Hana , Mackenzie Larami , Weisman David C. , Kozak Osman S. , Shah Qaisar A. , Gzesh Dan , Kulandaivel Kandan , Khoury John S. , Klein Brad , Bussinger Patricia A. , Griffin Lisa R. , DePalmo Ashley L. , Oliva Cynthia , Jadhav Ashutosh , Jovin Tudor , Kenmuir Cynthia , Jankowitz Brian , Gross Bradley , Rocha Marcelo , Starr Matthew , Brown Merritt , Hawkes Chrstine , Shah Kavit , Tememe Danoushka , Walker Gregory , Patel Pratit , Klein Bradley , Ziayee Habibullah , Limaye Kaustubh , Baxendell Lisa , Glichrist Vicki , Feineigle Patricia , Toseki Haibach Kelsea , Van Every Cathy , Desai Shasvat , Zulfiqar Maryam , Gibson Linda , Barrett Sean , Turkel-Parrella David , Arcot Karthikeyan , DiCrescento Steven , Farkas Jeffrey , Filipowski Gregory , Frontera Jennifer , Joset Danielle , Liff Jeremy , Scher Erica , McDougall Cameron G. , Kelly Cheryl E. , Patel Akshal S. , Monteith Stephen J. , Starkman Sidney , Atchaneeyasakul Kunakorn C. , Burgos Adrian M. , Anne Y. Chua Janice , Gaines Nathan D. , Grunberg Ileana D. , Guzy Judy , Liu Zuolu , Maluste Neil D. , Ramirez Lucas , Sharma Latisha K. , Heck Donald , Brown Morry , McDonald Colin , Calderon Mateo , Hargis Mitch , Roels Christina , Emmady Prabhu , Alvi Talat , Jayaraman Mahesh V. , Cutting Shawna M. , Smith Wendy J. , Foley Susan M. , Paolucci Gino A. , Haas Richard A. , Quinn Katie A. , Fuller Lindsey R. , Brierley Rebecca E. , Watkins Christina C. , Demir Nicole C. , Lopez George A. , Vargas Alejandro , Osteraas Nicholas , Holtz Becky , Sauvageau Eric , Aghaebrahim Amin , Chmayssani Mohamad , Naval Neeraj S. , Day Jason S. , Dellorso Scott M. , Ludwig Benjamin J. , Schemmel Derek J. , Ebreo Nancy , Bell Karen , Lewis Lanai , Delucia Marjorie , Haussen Diogo , Frankel Michael , Bhatt Nirav , Bianchi Nicolas , Anderson Aaron , Belagaje Samir , Liberato Bernardo , Rangaraju Srikant , Al-Bayati Alhamza R. , Grossber Jonathan , Craft Leah P. , Schindler Kiva , Schaad Erin , Schultz Meagan , Sutherly Lorretta J. , Doppelheuer Shannon , Charlton Jacquelyn , Faggard Jason , Barbret Zuzana , DukSoo Han Ethan , Walters Robin , Dolia Jaydevsinh , El-Jamal Sleiman , Eby Brendan , Saleem Yasir , Pearl Harrison , Patel Kishan , Rahman Haseeb , Butt Reema , English Stephen , Puri Ajit S. , Howk Mary , Singh Jasmeet , Massari Francesco , DeMacedo Rodrigues Katyucia , Kuhn Anna L. , English Joey D. , Barazangi Nobl , Telischak Nick , Kim Warren , Ross Josh , DeVole Nata , Redford Jessica , Ferreira Melina , Ponting Katie , Shen Helen , Bedenk Ann , Patel Susila , Fernandess Julia , Ke Michael , Spokoyny Illanit , Gao Billy , Tong David , Chen Charlene , Wong Christine , Choe Jessica , Martin Coleman O , Summers Debbie V. , Boutwell Christine M. , Olds Karin E. , Crandall Suzanne C. , Eatman John D. , Akhtar Naveed , Holloway William , Halpin Jared S. , Donegan Brett , Schindler Joseph L. , Hwang Daiv Y. , Gilmore Emily J. , Petersen Nils , Sheth Kevin N. , Brown Stacy Y. , Beekman Rachel B. , George Benjamin P. , Kaddouh Firas , Falcone Guido J. , Wira Charles R. , Matouk Charles C. , Loomis Caitlin , Amin Hardik , Stretz Hans Christoph , Narula Reshma , Jasne Adam S. , Sansing Lauren H. , Agarwal Tijil , Jasak Sara D. , Fontaine Briana D. , King Zachary , Kouhn Lindsey R. , Orgass Hailey , Leary Megan A. , Nye Joan L. , Halbert Kelsey , Nystrom Karin V. , Neuschatz Kaile B. , Petrucci Dawn M. , Coppola Anna M. , Joyce Treasure A. , Hou Sam Y. , Umekubo Mark S. , Nakamura Catrice M. , Ovando Renee M. , Zuniga Diana , Nien Yih Lin , Basto Fernando Mayor , Arch Allison E. , Jong Laura T. , Conrad William A. , Abbott Tara C. , Yao Jay Z. , Caganap Scott D. , Jordan John E. , Teitelbaum George P. , Darflinger Robert J. , Kelly Daniel F. , Gupta Rishi , Budzik Ronald F. , Czerniak Jennifer H. , Groezinger Katherine M. , Hicks William J. , Kaskar Omran B. , Katz Brian S. , Loochtan Aaron I. , Pema Peter J. , Rai Vivek , Vora Nirav A. , Brown Amanda , Goodman Diane , Danenbergs Barb , Gossett Monica , Bang Oh Young , Chung Jong-Won , Jeon Pyoung , Kim Keon Ha , Lim Yun Jeong , Hoe Heo Ji , Nam Hyo Suk , Kim Young Dae , Park HyungJong , Hwang In Gun , Ha Wooseok , Choi Jin Kyo , Jeong Kyungsun , Rha Joung-Ho , Park Hee-Kwon , Yoon Cindy W. , Kim Bo-Kyung , Sohn Sung-Il , Kim Chang-Hyun , Yoo Joonsang , Hong Jeong-Ho , Park Hyungjong , Kim Sohyeon , Choi Moonkyung , Bae Hyoeun , Lee Jun Seok , Lee Jae-Joon , Jun Go-Eun , Jeon Sujeong , Campbell Bruce C. V. , Mitchell Peter J. , Yassi Nawaf , Davis Stephen M. , Donnan Geoffrey A. , Parsons Mark W. , Yan Bernard , Dowling Richard J. , Bush Steven J. , Wu Teddy Y. , Shan Darshan G. , Zhao Henry , Salvaris Patrick , Alemseged Fana , Ng Felix C. , Williams Cameron , Balabanski Anna , dos Santos Angela , Ng Jo-Lyn , McDonald Amy , Jackson David , Tsoleridis Jessica , Pesavento Lauren , Kleinig Timothy John , Drew Roy , Cranefield Jennifer , Scroop Rebecca , Cagi Lavenia , Harvey Jackson , Waters Michael J. , Thornton John , Brennan Robert P. , O'Hare Alan , Power Sarah , Williams David JP , Boyle Karl , Moynihan Barry J. , Liddy Ann-Marie , Large Margaret , Cullen Ailbhe , Walsh Roisin , Martin Emma , Lynch Julie , McElroy Sinéad , Murphy Seán , Coveney Sarah A. , Deegan Caroline , Horgan Gillian , Kelly Peter , Laffan Aoife , Llamas-Osorio Yudy , Lynch Catherine T. , Mac Mahon Peter J. , Marnane Michael , McCabe John J. , Burns Paul A. , Tauro Suzanne , Cuddy Sarah , Rennie Ian , Smyth Graham , Flynn Peter , Wiggam Ivan , Kerr Enda , Gordon Patricia , Fearon Patricia , Roberts Geralt , Patterson Cathy , Adams Karen , Wells Brian , McFarland Margaret , Moreira Tiago , Sjöstrand Christina , Mazya Michael , Almqvist Håkan , Wahlgren Nils , Steinberg Anna , Cooray Charith , Eriksson Einar , Thorén Magnus , Keselman Boris , Ahmed Niaz , Holmberg Åke , Axelsson Maria C. , Berglund Annika , Golsari Amir , Hoppe Julia , Deb-Chatterji Milani , Cheng Bastian , Barow Ewgenia , Schlemm Eckhard , Lettow Iris , Jensen Märit , Otto Dagmar , Jaramillo Kirsten , Appelbohm Hannes , Fiehler Jens , Bester Maxim , Schönfeld Michael , Brekenfeld Caspar , Holst Brigette , Wortmann Ginette , Koch Friederike , Gerber Johannes C. , Abramyuk Andrij , Kaiser Daniel , Winzer Simon , Prakapenia Alexandra , Pallesen Lars-Peder , Siepmann Timo , Barlinn Kristian , Haase Kathrin , Sauer Angela , Psychogios Marios-Nikos , Liman Jan , Brehm Alex , Maus Volker , Hollstein Nicole , Reinke Annika , Neitz Gustav , Schnieder Marlena , Schwarz Margret , Ibrahim Allam , Müller Julia , Meister Stefanie , Bäumle Berit , Chapot René , Pilgram-Pastor Sara , Wallocha Marta , Stauder Michael , Celik Ekin , Stracke Paul , Müller Nicole , Weber Ralph , Veltkamp R. , Nagel Simon , Ringleb Peter Arthur , Heyse Miriam , Amiri Hemasse , Mundiyanapurath Sibu , Chen Min , Beyrle Elisabeth , Beck Perdita , Möhlenbruch Markus Alfred 
Published: January 2024

Importance

Age is a leading predictor of poor outcomes after brain injuries like stroke. The extent to which age is associated with preexisting burdens of brain changes, visible on neuroimaging but rarely considered in acute decision-making or trials, is unknown.

Objectives

To explore the mediation of age on functional outcome by neuroimaging markers of frailty (hereinafter neuroimaging frailty) in patients with acute ischemic stroke receiving endovascular thrombectomy (EVT).

Design, Setting, and Participants

This cohort study was a post hoc analysis of the Safety and Efficacy of Nerinetide (NA-1) in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1) randomized clinical trial, which investigated intravenous (IV) nerinetide in patients who underwent EVT within a 12-hour treatment window. Patients from 48 acute care hospitals in 8 countries (Canada, US, Germany, Korea, Australia, Ireland, UK, and Sweden) were enrolled between March 1, 2017, and August 12, 2019. Markers of brain frailty (brain atrophy [subcortical or cortical], white matter disease [periventricular or deep], and the number of lacunes and chronic infarctions) were retrospectively assessed while reviewers were blinded to other imaging (eg, computed tomography angiography, computed tomography perfusion) or outcome variables. All analyses were done between December 1, 2022, and January 31, 2023.

Exposures

All patients received EVT and were randomized to IV nerinetide (2.6 mg/kg of body weight) and alteplase (if indicated) treatment vs best medical management.

Main Outcome and Measures

The primary outcome was the proportion of the total effect of age on 90-day outcome, mediated by neuroimaging frailty. A combined mediation was also examined by clinical features associated with frailty and neuroimaging markers (total frailty). Structural equation modeling was used to create latent variables as potential mediators, adjusting for baseline, early ischemic changes; stroke severity; onset-to-puncture time; nerinetide treatment; and alteplase treatment.

Results

Among a total of 1105 patients enrolled in the study, 1102 (median age, 71 years [IQR, 61-80 years]; 554 [50.3%] male) had interpretable imaging at baseline. Of these participants, 549 (49.8%) were treated with IV nerinetide. The indirect effect of age on 90-day outcome, mediated by neuroimaging frailty, was associated with 85.1% of the total effect (β coefficient, 0.04 per year [95% CI, 0.02-0.06 per year]; P &amp;lt; .001). When including both frailty constructs, the indirect pathway was associated with essentially 100% of the total effect (β coefficient, 0.07 per year [95% CI, 0.03-0.10 per year]; P = .001).

Conclusions and Relevance

In this cohort study, a secondary analysis of the ESCAPE-NA1 trial, most of the association between age and 90-day outcome was mediated by neuroimaging frailty, underscoring the importance of features like brain atrophy and small vessel disease, as opposed to chronological age alone, in predicting poststroke outcomes. Future trials could include such frailty features to stratify randomization or improve adjustment in outcome analyses.