Interleukin 6 and Cardiovascular Outcomes in Patients With Chronic Kidney Disease and Chronic Coronary Syndrome
Authors: Gorav Batra, Tatevik Ghukasyan Lakic, Johan Lindbäck, Claes Held, Harvey D. White, Ralph A. H. Stewart, Wolfgang Koenig, Christopher P. Cannon, Andrzej Budaj, Emil Hagström, Agneta Siegbahn, Lars Wallentin, Miguel Bustamante Labarta, Luis R Cartasegna, Sergio Chekherdemian, Jose L Cuello, Pedro Elías, Jorge Giordano, Alfredo Hirschson, Miguel Angel Hominal, Julio O Ibañez, Horacio O Jure, Marcos Litvak, Stella M Macin, Ignacio Jorge MacKinnon, Laura Elena Maffei, Oscar R Montaña, Aldo D Prado, Jorgelina M Sala, Vanina (FPI) Gorosito, Ramiro A Sanchez, David Brieger, Derek Chew, David Cross, Ferdinandus J De Looze, Ahmad Farshid, Stephen Hall, Henry Krum, Geoff K Lane, Ernesto Oqueli Flores, John (FPI) Stickland, Peter W Purnell, Gregory YF Szto, Peter L Thompson, Jonathan Waites, Maged William, Christophe Beauloye, Jean Boland, Filip Charlier, Herbert JLP De Raedt, Joseph AY Dens, Karl Dujardin, Alain Friart, André Scheen, Erwin Schröder, Peter R Sinnaeve, Stefan LRA Verheye, Pascal Vranckx, José A M Abrantes, Denilson Campos De Albuquerque, Wilma Roberta Ardito, Luciano M Baracioli, Marcelo C Bertolami, Luiz C Bodanese, Raul D Dos Santos Filho, Lilia N Maia, Euler RF Manenti, Roberto L Marino, Clarisse K Ogawa Indio do Brasil, Maria Sanali de Oliveira Paiva, Álvaro Rabelo Alves Junior, Salvador Rassi, Gilmar Reis, Paulo R F Rossi, José Francisco K Saraiva, Haralambi Benov, Boryana Chompalova, Stefan Denchev, Assen Goudev, Valentina Grigorova, Atanas Mihov, Valentina Mincheva, Sylvia Petrova, Angelina Staneva, Dimitar (FPI) Raev, Snezhanka Tisheva, Ronnie Aronson, Jacques Bedard, Rakesh K Bhargava, David Borts, Christian Constance, Jean Cusson, Richard F Davies, John Ducas, Murdo ER Ferguson, Ronald M Goldenberg, Francois Grondin, Gabor Gyenes, Frank Halperin, Jan Kornder, Simon Kouz, Andre Y Lainesse, Rolland Leader, Lawrence A Leiter, Eva M Lonn, Alain Milot, Murray E Pearce, Lew Pliamm, Calvin N Powell, Barry F Rose, Dennis W Rupka, Anthony JD Siega, Peter W (FPI) Klinke, Eric St-Amour, Paul Talbot, Jean-Claude Tardif, Steven J Tishler, Lawrence Title, Graham C Wong, Christopher E (FPI) Buller, Monica Andrea Acevedo Blanco, Francisco Javier Albornoz Alarcon, Edgardo Escobar, Fernando Florenzano Urzua, Oneglio Antonio Pedemonte Villablanca, Juan Carlos Prieto Dominguez, Patricio Sanhueza Cardemil, Paola Elena Varleta Olivares, Hong Chen, Jiyan Chen, Yugang Dong, Junbo Ge, Ben He, Yong Huo, Weimin Li, Xin-li Li, Yuhua Liao, Meng Wei, Xiaowei Yan, Ping Ye, Zuyi Yuan, Yun Zhang, Jianhua Zhu, Ondrej Cermak, Vratislav Dedek, Lumir Francek, Hana Grunfeldova, Jan Hubac, Pavel  (FPI) Franc, Ivana Kellnerova, Zdenek Klimsa, Josef Kroupa, Ladislav Kuchar, Ales Linhart, Jan Malecha, Jiri Povolny, Tomas Velimsky, Roman Volf, Vladimir  (FPI) Jirka, Lia Bang, Peer (FPI) Grande, Lars Frost, Steen E Husted, Rikke V Laursen, Tonny  (FPI) Nielsen, Anu Hedman, Piibe Muda, Ulle Planken, Claude Barnay, Christophe Bauters, Gilles Bayet, Jacques Bonnet, Eric Bruckert, Yves Cottin, Jean-Pierre Courreges, Nicolas Danchin, Eric Decoulx, Jean-Michel Demarcq, Jean-Luc Dubois-Rande, Meyer Elbaz, Khalifé Khalife, Michel Krempf, Eric Maupas, Michel Ovize, José Gérald Roul, François Schiele, Jean-Pierre (FPI) Bassand, Gabriel Steg, Bernard Vaisse, Ulrich Michael Aigner, Udo Bavendiek, Dieter (FPI) Fischer, Gisela Benedix, Hilmar Boeneke, Jochen Bott, Bernadett Brado, Marianne Buhr, Christian Butter, Steffen Fischer, Andreas Foerster, Marc Oliver Grad, Josef Grosskopf, Markolf Hanefeld, Susanne Hoeltz, Horst-Michael (FPI) Frick, Gabriele Illies, Thomas WGE Jung, Barbara Kademann, Gert Kahrmann, Alexandra (FPI) Bourrat, Thomas (FPI) Horacek, Regina (FPI) Reusch, Gerhard Klausmann, Christiane Klein, Karl Heinz Krause, Detlev Kuesters, Klaus-Peter Mellwig, Thomas Menke, Steve Mueller, Gerhard Neumann, Ruth Nischik, Andreas Preusche, Martin Prohaska, Stefan Franz Regner, Wilfried Rein, Reinhard Rummel, Holger Samer, Thomas Schaefer, Isabelle Schenkenberger, Ekkehard Schmidt, Norbert Schoen, Andreas Schreckenberg, Uwe Schulze, Joachim (FPI) Wunderlich, Hae-Young Sohn, Volker  (FPI) Klauss, Nicole Toursarkissian, Jan-Gerrit Voigt, Dirk Weber, Bernhard R Dr.med Winkelmann, Dirk Zuechner, Dimitrios Alexopoulos, Maria Anastasiou-Nana, Dimitrios (FPI) Kremastinos, Moses Elisaf, Parashos Geleris, Ioannis Kallikazaros, Athanasios Kranidis, Athanasios Manolis, Ioannis Mantas, Christoforos Olympios, Dimitrios Tziakas, Vassilis Voudris, Yat Yin Homer Lam, Wai Kwok Gabriel (FPI) Yip, Chung Wah David Siu, Béla Benczúr, Andrea Hornyik, Zoltán László, András Papp, Anikó Papp, Zsolt Plés, Annamária (FPI) Piros, Imre Szakál, Tibor Túri, Mátyás (FPI) Sereg, András Vértes, Sunitha Abraham, Darshan N Banker, Prakash Chandwani, Rajeev Gupta, Jagdish Hiremath, Santhosh Jayadev, Stigimon Joseph, Jaideep (FPI) Menon, C Keshavamurth, Arun (FPI) Srinivas, Keyur Parikh, Ramesh B Pothineni, Shireesh P Sathe, Jitendra P Sawhney, Sumeet Sethi, Praveen Kumar (FPI) Chandra, Sudhir Varma, Diego Ardissino, Marco Bobbio, Angelo S Bongo, Francesco Cipollone, Andrea (FPI) Mezzetti, Furio Colivicchi, Massimo (FPI) Santini, Giovanni Esposito, Massimo (FPI) Chiariello, Mario Marzilli, Piera Merlini, Luciano Moretti, Zoran Olivari, Giampiero Patrizi, Marco Valgimigli, Hiroshi Amemiya, Kenji Ando, Masashi (FPI) Iwabuchi, Masahiro Endo, Hirotaka (FPI) Nagashima, Ryosuke Kametani, Akihiro Koike, Takehiko Kuramochi, Yuichiro Nakamura, Koji Oku, Masaaki Okutsu, Atsushi Sueyoshi, Wataru Takahashi, Yasuyuki (FPI) Sasaki, Jun Tanabe, Hideki Tanaka, Katsuro (FPI) Kashima, Yutaka Tanaka, Satoshi (FPI) Takeshita, Junichi Teranishi, Tetsuo (FPI) Betsuyaku, Takashi Yamamoto, Seiji Yamazaki, Shoji Yano, Kazuro Yoshida, Jei-Keon Chae, Shung-Chull Chae, Myeong-Chan Cho, Dong-Hoon Choi, Dong-Ju Choi, Taek-Jong Hong, Hui-Kyung Jeon, MyungHo Jeong, Hyo-Soo Kim, Hyun-Joong Kim, Kyu-Hyung (FPI) Ryu, Woo-Shik Kim, Kwon-Sam (FPI) Kim, Sang-Hoon Lee, Do-Sun Lim, Seong-Wook Park, Ki-Bae Seung, Jose-Luis Cervantes-Escárcega, Ismael Hernández-Santamaría, Carlos Jerjes Sánchez-Díaz, Marittza-Arasely Uribe-Rios, Ricardo (FPI) Alvarado-Ruiz, Robbert J De Winter, René Dijkgraaf, Rutger M.G Jansen, Nicole M.J Knufman, Joost (FPI) Frederiks, Adrianus F.M Kuijper, Johannes C Post, Herman R (FPI) Michels, Hendrik W.O Roeters van Lennep, AnHo (FPI) Liem, Pieter C Smits, Hendrik P Swart, Adrianus J Van Boven, Marc ERM Van Daele, Coenraad Van der Zwaan, Clemens Von Birgelen, Iris C.D Westendorp, Laura Davidson, Gerard P Devlin, John M Elliott, Andrew W Hamer, Nigel A Harrison, Richard J (FPI) Rankin, Hamish H Hart, Matthew J Hills, Timothy J O'Meeghan, Douglas S Scott, Jonathan G Tisch, Michael JA Williams, Victor HT (FPI) Chen, Christ Berge, Helge Istad, Terje R Pedersen, Per Anton Sirnes, Bashir Hanif, Riaz Ishaq, Azhar Mahmood Kayani, Muhammad Bilal Ahsan Qureshi, Saulat Siddique, Zia Yaqub, Rafael Doig, Frank (FPI) Britto, Pedro Yanac, Manuel (FPI) Horna, José (FPI) Valdivia, Mario Cesar Zubiate, Nelson S Abelardo, Maria Teresa B Abola, John C Añonuevo, Alberto A Atilano, Federick C Cheng, Emma Y Gaspar-Trinidad, Jorge A Sison, Dennis Jose V Sulit, Rody G Sy, Norbert Lingling Uy, Arkadiusz Chmielinski, Aleksandra Czepiel, Ewa M Guzniczak, Tomasz (FPI) Siminiak, Grzegorz Kania, Krzysztof Kincel, Jerzy Kopaczewski, Jacek Kubica, Roman Lysek, Pawel Miekus, Adam Mlodziankowski, Piotr Napora, Fryderyk Prochaczek, Teresa Ruscika, Janusz Tarchalski, Wieslawa Tracz, Bozena Wrzosek, Gheorghe V Basarab, Imre Benedek, Mircea Cinteza, Madalina I Cristea, Doina R Dimulescu, Daniela Dragusin, Iulia Gabor, Carmen D Ginghina, Cezar E Macarie, Crina Sinescu, Gabriel Tatu-Chitoiu, Dragos Vinereanu, Natalya A Andryushina, Svetlana R (FPI) Baum, Mikhail V Arkhipov, Olga L Barbarash, Svetlana Boldueva, Mikhail V Boyarkin, Arkady P Demko, Marina S Freydlin, Sergei P Golitsyn, Ivan Gordeev, Nikolay Gratsiansky, Yuri A Karpov, Zhanna Kobalava, Vladimir Konstantinov, Andrey D Kuimov, Valery V Kukharchuk, Alexey Panov, Mikhail Y Ruda, Sergey A Sayganov, Vladimir Simanenkov, Olga G Smolenskaya, Larisa P Tsyba, Alexander Y Vishnevsky, Polina K Yakhontova, Sergey S Yakushin, Dmitry A Zateyshchikov, Ludovit Gaspar, Marian Hranai, Martin Kokles, Daniel Pella, Aysha Badat, Karen (FPI) Sliwa-Hahnle, Suzanne Blignaut, Lesley Burgess, Anthony Dalby, Saleem Y Dawood, Thomas Gray, Adrian R Horak, Thomas Mabin, Pravin. Manga, Rajendran. MBChB Moodley, Maria M Pretorius, Frans S (FPI) Hough, Andre Roodt, Jan Saaiman, Hendrik D Theron, Rodrigo Alonso Karlezi, Pedro. (FPI) Mata López, Pedro Aranda Granados, José Ramón Berrazueta Fernández, Daniel Carnevali Ruiz, Almudena Castro Conde, José Mª Cruz Fernández, Eduardo De Teresa Galván, Luis De Teresa Parreño, Isabel Díaz Buschmann, José Ramón Domínguez Escribano, Juan Garcia Puig, Blas Gil Extremera, Jorge Gómez Cerezo, Carlos Miguel Macaya, José Mª Mostaza Prieto, Roberto Muñoz Aguilera, Carlos Pérez Muñoz, Ramón Querejeta Iraola, José Antonio Romero Hinojosa, Luis Miguel Ruilope Urioste, José Sabán Ruiz, Javier Sobrino Martínez, Enma Concepción Suárez Suárez, Iñigo (FPI) Lozano Martínez-Luengas, Faris Al-Khalili, Stellan Bandh, Marie Bennermo, Mikael Dellborg, Johan Herlitz, Per (FPI) Johanson, Lars Hjelmaeus, Karl Landergren, Carina Linderfalk, Carl-Johan Lindholm, Krister Lindmark, Thomas Mooe, Jan Nilsson, Peter Wodlin, Yi-Lwun Ho, Charles Hou, Chien-Hsun Hsia, Shing-Jong Lin, Liang-Miin Tsai, Kuo-Yang Wang, Chunhakasem Chotinaiwattarakul, Srun Kuanprasert, Nakarin Sansanayudh, Piyamitr Sritara, Taworn Suithichaiyakul, Svitlana Andriyevska, Andriy Y Basylevych, Vitaliy I Denesiuk, Lyudmyla G Kononenko, Oleksii M Korzh, Volodymyr M Kovalenko, Igor G Kraiz, Viktoriia Y Lishnevska, Mykhaylo I Lutay, Oleksandr M Parkhomenko, Leonid V Rudenko, Zinaida Y Telyatnikova, Vira Y Tseluyko, Mykola T Vatutin, Vadym A Vizir, Ameet Bakhai, Harbal S Bijral, Edmund (FPI) Stewart, Henry Dargie, Marion G (FPI) Barlow, David P Dutka, Iain N Findlay, Michael Fisher, Diana A Gorog, Adam M Jacques, Ian (FPI) Beeton, Brian Logie, John R Pepper, Marcus D (FPI) Flather, Ian F Purcell, William Scullion, James F (FPI) Thompson, Roxy Senior, David A Simpson, Simon DR Thackray, Mohammed F (FPI) Alamgir, John PH Wilding, Yuk-ki Wong, Abdel M Ahmed, Mark C Antonishen, Keith Atassi, Jose Azocar, Eric M Ball, Christie M Ballantyne, Harold E Bays, Jill E Beavins, Sabrina A Benjamin, Mark R Benson, Peter B Berger, Jeremy W (FPI) Buckley, William R Betz, Robert WW Biederman, Edward W Bisher III, Vera A Bittner, Cristian F Breton, Salvatore Buttaci, Mahesh (FPI) Changlani, John B (FPI) Patterson, Leroy J Byrd, Donald B Canaday, William R Cashion, Harish Chandna, Anna R Chang, John Chin, Harry P Claybrook, Frederick A (FPI) Martin, Kenneth R Cohen, David R Colan, Gregg O Coodley, Marshall A Corson, Robert H (FPI) Knopp, Pathmaja (FPI) Paramsothy, Richard A Cottiero, Paresh Dandona, Michael H Davidson, Kent T (FPI) Kamaradt, Ashwini K Davuluri, Vikas S Desai, Glen D (FPI) Garson, Cara East, Ramin Ebrahimi, Howard S Ellison, Bernard R Erickson, Valerian L Fernandes, Angel R Flores, Steven D Folkerth, Robert E Foster, Raul E Gaona, Timothy J Gardner, William H George, Carl J JR Gessler, Santosh K Gill, Alan S Go, Anne C Goldberg, Marc E Goldschmidt, Timothy A Gorman, Donald F (FPI) Brautigam, John R Guyton, Thomas Haffey, Sheldon D Henry, Paul R Hermany, John A Hoekstra, Michael Hudson, Bruce J Iteld, David B Jack, Frank P Johnson, Bill C Joswig, Amy J Kaissar, Adam D Karns, Robert M (FPI) Karns, Steven R Kaster, Boris Kerzner, Mohammed S Khan, Ismail S (FPI) Ahmed, Joshua Kieval, Edward Kim, Leslie J Klaff, Eric J Klein, Michael J Koren, Edward J Kosinski, Razmig Krumian, Edward B (FPI) Portnoy, Jeffrey T Kuvin, Michael M Langer, Dustin P Letts, Robert S Lipetz, William J Long, Ignatius (FPI) Thomas, Maria Lopes-Virella, Barry C Lubin, Richard A Martin, Bassem Masri, George Matthews, John C (FPI) Corbelli, Kevin McCullum, Alan W Meholick, Jerry R Mitchell, Fariba Modares, Emile Mohler, Charle N Morcos, David K Murdock, Puneet Narayan, Mandeep S Oberoi, Thomas O'Connor, Robert J (FPI) Schnecker, Philip J O'Donnell, Stephen T Ong, Pirouz Parang, John A Pasquini, Rajesh J Patel, Raghotham Patlola, William Penny, Carl J Pepine, Charles H Pierce, Evan A (FPI) Stein, Larry R Popeil, Stephen E Pratt, Robert W Price, Marina Raikhel, Ram C Ravi, Donald (FPI) Cho, James M Rhyne, Mary K Richards, Ernesto Rivera, Jennifer G Robinson, Eli M Roth, Carl J Rubenstein, Jaime D Sandoval, Renee A Sangrigoli, Erichn L Schramm, Arthur Schwartzbard, Gregory T Serfer, Dhiren H Shah, Marc S Shalek, Jeffrey G Shanes, Marigene S Sharma, Elizabeth M (FPI) Bretton, Zafar Sheikh, Neal L Sklaver, Maria Del Pilar Solano, Ronald B (FPI) Goldberg, Nalin K Srivastava, Cezar S Staniloae, Jonathan S Staub, Michael E Stillabower, Damodhar P Suresh, Ireneusz Szulawski, Paul Thompson, Donna M (FPI) Polk, Jodi L Tinkel, Utpal H (FPI) Pandya, Phillip T Toth, Mourhaf Traboulssi, Edward R Tuohy IV, Kari T Uusinarkaus, Nampalli K Vijay, Stephen Voyce, William Wainwright, Holly (FPI) RHancock, James S Walder, Tracy Yu-Ping Wang, Stanley P Watkins, Robert J Weiss, Edwin J Whitney, William J Wickemeyer, John G Willis, Dennis F Wilson, Cyril (FPI) Abrams, Alan Wiseman, Eric Wolfson, David Wright, Edward T Zawada, Suneet (FPI) Verma
Journal: JAMA Cardiology (2021)

<h3>Importance</h3> Inflammation promotes cardiovascular disease and anti-inflammatory treatment reduces cardiovascular events in patients with chronic coronary syndrome. Chronic kidney disease (CKD) is a risk factor for cardiovascular disease. It is unclear how inflammation mediated by interleukin 6 (IL-6) in patients with CKD is linked to cardiovascular disease. <h3>Objective</h3> To investigate associations between IL-6 and cardiovascular outcomes in patients with chronic coronary syndrome in association with kidney function. <h3>Design, Setting, and Participants</h3> This multicenter cohort study included patients enrolled at 663 centers in 39 countries with chronic coronary syndrome who were included in the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) trial. Patients were enrolled between December 2008 and April 2010 and were followed up for a median length of 3.7 years. Analysis in this substudy began September 2020. <h3>Exposures</h3> Exposures were IL-6 and creatinine estimated glomerular filtration rates (eGFR), which were collected at baseline. Associations between continuous and categorical levels (&lt;2.0 ng/L vs ≥2.0 ng/L) of IL-6 and cardiovascular outcomes were tested in association with eGFR cutoffs (normal eGFR level [≥90 mL/min/1.73 m<sup>2</sup>], mildly decreased eGFR level [60-90 mL/min/1.73 m<sup>2</sup>], and moderately to severely decreased eGFR level [&lt;60 mL/min/1.73 m<sup>2</sup>]). <h3>Main Outcomes and Measures</h3> Main outcome was major adverse cardiovascular events (MACE), a composite of cardiovascular death, myocardial infarction, and stroke. <h3>Results</h3> This substudy of the STABILITY trial included 14 611 patients with available IL-6 levels at baseline. The median (interquartile range) age was 65 (59-71) years, and 2700 (18.5%) were female. During follow-up, MACE occurred in 1459 individuals (10.0%). Higher levels of IL-6 were in continuous models independently associated with risk of MACE (<i>P</i> &lt; .001) in all CKD strata. Using predefined strata, elevated IL-6 level (≥2.0 vs &lt;2.0 ng/L) was associated with increased risk of MACE at normal kidney function (2.9% vs 1.9% events/y [hazard ratio, 1.35; 95% CI, 1.02-1.78]), mild CKD (3.3% vs 1.9% [hazard ratio, 1.57; 95% CI, 1.35-1.83]), and moderate to severe CKD (5.0% vs 2.9% [hazard ratio, 1.60; 95% CI, 1.28-1.99]). <h3>Conclusions and Relevance</h3> In patients with chronic coronary syndrome, elevated levels of IL-6 were associated with risk of MACE in all CKD strata. Thus, IL-6 and CKD stage may help when identifying patients with chronic coronary syndrome for anti-inflammatory treatment.