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