Cause of Death and Predictors of All‐Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation: Data From ROCKET AF

Author:

Pokorney Sean D.1,Piccini Jonathan P.1,Stevens Susanna R.1,Patel Manesh R.1,Pieper Karen S.1,Halperin Jonathan L.2,Breithardt Günter3,Singer Daniel E.4,Hankey Graeme J.5,Hacke Werner6,Becker Richard C.1,Berkowitz Scott D.7,Nessel Christopher C.8,Mahaffey Kenneth W.9,Fox Keith A. A.10,Califf Robert M.11,Anderson J.,Bedwell N.,Bilsker M.,Bruce G.,Agah R.,DeSantis M.,Eisenberg S.,Flores A.,Herzog W.,Klein S.,Snyder H.,Krueger S.,Almaguer E.,Lavie E.,Lee C.,Mallis G.,Modi M.,Woodworth G.,Niazi I.,Peart B.,Sundaram S.,Snoddy B.,Sotolongo R.,Moloney J.,Vijayaraghavan K.,Whittier F.,Yellen L.,Banerjee S.,Lustgarten D.,Suresh D.,Gelernt M.,Levinson L.,Ghanekar R.,Kneller G.,Hall C.,Fadl Y.,Pirwitz M.,French W.,Mayer N.,Pugeda J.,Steel K.,Mody F.,Malik A.,Chandna H.,Go A.,Emlein G.,Bowden W.,Moscoso R.,Hodson R.,Berk M.,Pan D.,Pappas J.,Orchard R.,Lynchard G.,Vijay N.,Khan W.,El Khadra M,Antonishen M.,Cucher F.,Staab M.,Zebrack J.,Borromeo S,Heilman J.,Chaturvedi S.,Makam S.,Turk S.,Hyers T.,Williams G.,Labroo A.,Gill S.,Myears D.,Weinstein J.,Shanes J.,Chandrashekhar Y.,Shah S.,Reiter W.,Logemann T.,Almquist A.,Bhagwat R.,Tak T.,Shen‐Ling J.,Patel P.,Artis A.,Arouni A.,Lauer M.,Kinney K.,Elsen J.,Roan P.,Villafria R.,Sumpter M.,Ip J.,Welka S.,Schifferdecker B.,Sandoval R.,Speirs S.,Jones A.,Haldis T.,Kazmierski J.,Sutherland J.,Dietrich D.,Telfer E.,Berry J.,McElveen A.,Russell J.,Sackett M.,Antonios N.,Smith D.,Vora K.,Kirby A.,Lui H.,Mego D.,Ziada K.,Navas J.,Taussig A.,Koren M.,Vogel C.,Saba F.,Parrott C.,Schneider R.,Shirwany A.,Rubin M.,Treasure C,Bertolet B.,Chang M.,Langberg J.,Becker R.,Cohen Y.,McGrew F.,White J.,Arzola F.,Zelenka J.,Tannenbaum A.,Fernandes V.,Jamnadas P.,Agamasu J.,Collins B.,Jauch W.,Sasseen B.,Hotchkiss D.,Abadier R.,Osunkoya A.,Schlau A.,Chappel C.,Foster M.,Braun E.,Mostel E.,Capo J.,Ashchi M.,Howard V.,Albirini A.,Burger A.,Rolston D.,Staniloae C.,Bacon J.,Wiseman A.,McGarvey J,Sonel A.,Hamroff G.,Chang D.,Daboul N.,Broderick G.,Meholick A.,Corbelli J.,Silverman R.,Raffetto J.,Fishberg R.,Georgeson S.,Held J.,Seidner M.,Saint‐Jacques H.,Heitner J.,Kutalek S.,Friedlander I.,Hutchinson B.,Walia J.,Kondo N.,Smiley N.,Blitz L.,Dale H.,Sulman S.,Szulawski I.,Modares F.,Martin R.,Nahhas A.,Renzi M.,Akyea‐Djamson 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Sebba Barroso,Braga J.,Alessi S.,Gomes M.,Silva R.,Teixeira M.,Costa F.,Motta M.,Sobral Filho D.,Reis G.,Garbelini B,Zimmermann S.,Pereira Barretto A.,Dohmann H.,Barreto Filho J.,Ghorayeb N.,Borelli F.,Rossi dos Santos F.,Lopes Prudente M.,Vejar M.,Lanas F.,Del Pino R.,Potthoff S.,Charme G.,Aguirre A.,Saldana A.,Garces E.,Bunster L.,Figueroa H.,Olivares C.,Raffo C.,Vergara E.,Sepulveda P.,Jano G.,Morales Alvarado J.,Suarez R.,Urina M.,Perez G.,Quintero A.,Pava L.,Botero Lopez R.,Luengas C.,Hernandez E.,Sanchez D.,Poveda C.,Coronel J.,Beltran R.,Jaramillo C.,Pardo J.,Ponte Negretti C.,Isea J.,Vergara G.,Morr I.,Sim K.,Wan Ahmad W.,Yusof Z.,Rosman A.,Basri H,Thompson P.,Jeffery I.,Purnell P.,Roberts‐Thomson P.,Heddle W.,Waites J.,Walters D.,Amerena J.,Challa P.,Karrasch J.,Lowy A.,Fitzpatrick D.,Parsons M.,Phan T.,Bladin C.,Donnan G.,Aroney G.,Gerraty R.,Anderson C.,Blombery P.,Martin P.,Tissa Wijeratne K.,Cross D.,Crimmins D.,Packham D.,Jackson D.,Chua W.,Merino R.,Magno M.,Tirador L.,Batalla E.,Manalo C.,Uy N.,Ebo G.,Reyes E.,Bernan A.,Richards M.,Hart H.,Mann S.,Fisher R.,Stewart R.,Wilkins G.,Barber A.,Tan R.,Ong H.,Singh R.,Sukonthasarn A.,Tanomsup S.,Krittayaphong R.,Piamsomboon C.,Piyayotai D.,Sunsaneewitayakul B.,Baek S.,Seo H.,Rim S.,Kim C.,Kim K.,Ryu K.,Jo S.,Tahk S.,Lee H.,Kim Y.,Shin D.,Choi Y.,Chung N.,Namgung J.,Hong T.,Shin W.,Jin S.,Yan X.,Fu G.,Lu G.,Yang K.,Xu D.,Chen J.,Liu J.,Wu S.,Song J.,Liao Y.,Xu B.,Li Z.,Ma S.,Yin Y.,Zhao Y.,Hu D.,Ma C.,Ma J.,Sun J.,Li H.,Hong X.,Yu B.,Lu Q.,Yang J.,Wu Z.,Li Y.,Huang Y.,Wang Y.,Liu M.,Cheng Y.,Yang T.,Chen K.,Wang H.,Yuan Z.,Wang J.,Zeng Z.,Chen Y.,Yavuzgil O.,Kozan O.,Etemoglu M.,Diker E.,Belgi A.,Ceyhan C.,Cin V.,Yilmaz O.,Ata N.,Altunkeser B.,Agacdiken Agir A.,Karadede A.,Topsakal R.,Gulati R.,Madhavan A.,Jain S.,Oomman A.,Janorkar S.,Kumar P.,Madhukar Naik A.,Thacker H.,Rajasekhar V.,Reddy R.,Keshavamurthy C.,Jain P.,Gowdappa B.,Gadkari M.,Abhyankar A.,Ramesh Babu B.,Vydianathan P.,Sinha S.,Garg N.,Rao S.,Gautam P.,Chockalingam K.,Kumbla M.,Panwar R.,Banker D.,Kaste M.,Jäkälä P.,Roine R.,Mihov A.,Raev D.,Yordanova V.,Dimitrova S.,Benov H.,Tsanova V.,Kyolean M.,Marchev S.,Stoikov A.,Zdravkov N.,Ramshev K.,Krastev A.,Stamenova P.,Angelova I.,Pencheva G.,Grigorova V.,Petrauskiene B.,Skripkauskiene I.,Raugaliene R.,Norkiene S.,Mazutavicius R.,Kavoliuniene A.,Aidietiene S.,Aganauskiene J.,Dailydkiene A.,Marcinkeviciene J.,Grigoniene L.,Anusauskiene J.,Kavaliauskiene R.,Lizogub V.,Rudenko L.,Tseluyko V.,Voronkov L.,Sychov O.,Svyshchenko Y.,Sirenko Y.,Serkova V.,Seredyuk N.,Pertseva T.,Netyazhenko V.,Lishnevska V.,Kupchynska O.,Koval O.,Koshukova G.,Karpenko O.,Grishyna O.,Faynyk A.,Dzyak G.,Dyadyk O.,Yena L.,Volkov V.,Rudyk I.,Kopytsya M.,Kononenko L.,Amosova K.,Zhurba S.,Kazimirko V.,Iuzkiv I.,Shershnyova O.,Khomazyuk T.,Batushkin V.,Vykhovanyuk I.,Popik G.,Skrebkov V.,Skurtov A.,Mishchenko T.,Lytvynenko N.,Sokolova L.,Vatutin M.,Shved M.,Rebrov B.,Kadina L.,Vajda M.,Ursol G.,Zheleznyy V.,Vysochanska T.,Gozhenko A.,Fan K.,Ho D.,Tse H.,Yu C.,Wong L.,Yeh H.,Pai P.,Hsieh I.,Huang C.,Hsieh Y.,Yin W.,Tsai L.,Huang T.,Chen C.,Chiang F.,Ueng K.,Charng M.,Marmor A.,Katz A.,Butnaru A.,Lewis B.,Eldar M.,Rosenhack S.,Elias N.,Koifman B.,Shochat M.,Swissa M.,Zimlichman R.,Bental T.,Weiss A.,Ganam R.,Elias M.,Nseir W.,Oliven A.,Brenner B.,Dayan M.,

Affiliation:

1. Duke Clinical Research Institute, Duke University Medical Center, Durham, NC

2. The Cardiovascular Institute, Mount Sinai Medical Center, New York, NY

3. Division of Electrophysiology, Department of Cardiovascular Medicine, Hospital of the University of Münster, Germany

4. Clinical Epidemiology Unit, General Medicine Division, Massachusetts General Hospital, and Harvard Medical School, Boston, MA

5. Department of Neurology, Royal Perth Hospital, Perth, Australia

6. Ruprecht‐Karls‐University, Heidelberg, Germany

7. Global Clinical Development, Bayer HealthCare Pharmaceuticals, Inc., Whippany, NJ

8. Janssen Research & Development, Raritan, NJ

9. Department of Medicine, Stanford University, Stanford, CA

10. University of Edinburgh, and Royal Infirmary of Edinburgh, UK

11. Duke Translational Medicine Institute, Duke University Medical Center, Durham, NC

Abstract

Background Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all‐cause mortality may guide interventions. Methods and Results In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose‐adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all‐cause mortality in the 14 171 participants in the intention‐to‐treat population. The median age was 73 years, and the mean CHADS 2 score was 3.5. Over 1.9 years of median follow‐up, 1214 (8.6%) patients died. Kaplan–Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all‐cause mortality was observed between the rivaroxaban and warfarin arms ( P =0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33–1.70, P <0.0001) and age ≥75 years (hazard ratio 1.69, 95% CI 1.51–1.90, P <0.0001) were associated with higher all‐cause mortality. Multiple additional characteristics were independently associated with higher mortality, with decreasing creatinine clearance, chronic obstructive pulmonary disease, male sex, peripheral vascular disease, and diabetes being among the most strongly associated (model C‐index 0.677). Conclusions In a large population of patients anticoagulated for nonvalvular atrial fibrillation, ≈7 in 10 deaths were cardiovascular, whereas <1 in 10 deaths were caused by nonhemorrhagic stroke or systemic embolism. Optimal prevention and treatment of heart failure, renal impairment, chronic obstructive pulmonary disease, and diabetes may improve survival. Clinical Trial Registration URL : https://www.clinicaltrials.gov/ . Unique identifier: NCT 00403767.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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