Jeff S Healey1, David J Gladstone2,3, Balakumar Swaminathan4, Jens Eckstein5, Hardi Mundl6, Andrew E Epstein7, Karl Georg Haeusler8, Robert Mikulik9, Scott E Kasner10, Danilo Toni11, Antonio Arauz12, George Ntaios13, Graeme J Hankey14, Kanjana Perera15, Jorge Pagola16, Ashfaq Shuaib17, Helmi Lutsep18, Xiaomeng Yang19, Shinichiro Uchiyama20, Matthias Endres21, Shelagh B Coutts22, Michal Karlinski23, Anna Czlonkowska24,25, Carlos A Molina25,26, Gustavo Santo27, Scott D Berkowitz28, Robert G Hart4, Stuart J Connolly1. 1. Division of Cardiology, Hamilton Health Sciences, Population Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada. 2. Division of Neurology and Hurvitz Brain Sciences Program, Sunnybrook Health Sciences Centre and Sunnybrook Research Institute, Toronto, Ontario, Canada. 3. Department of Medicine, University of Toronto, Toronto, Ontario, Canada. 4. Population Health Research Institute, Hamilton Health Sciences, Hamilton, Ontario, Canada. 5. Department of Internal Medicine, University Hospital Basel, Basel, Switzerland. 6. Bayer AG, Wuppertal, Germany. 7. Electrophysiology Section, Cardiovascular Division University of Pennsylvania, Cardiology Section, Philadelphia VA Medical Center, Philadelphia. 8. Department of Neurology, Universitätsklinikum Würzburg, Würzburg, Germany. 9. International Clinical Research Center and Neurology Department, St. Anne's University Hospital and Masaryk University, Brno, Czech Republic. 10. Department of Neurology, University of Pennsylvania, Philadelphia. 11. Department of Human Neurosciences, "Sapienza" University of Rome, Rome, Italy. 12. Instituto Nacional de Neurologia y Neurocirugia, Mexico D.F., Mexico City, Mexico. 13. Department of Medicine, University of Thesally, Larissa, Greece. 14. UWA Medical School, University of Western Australia, Sir Charles Gairdner Hospital, Perth, Australia. 15. McMaster University/Population Health Research Institute, Department of Medicine (Neurology), Hamilton, Ontario, Canada. 16. Unitat d'Ictus, Servei de Neurologia, Hospital Universitari Vall d'Hebrón, Barcelona, Spain. 17. Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. 18. Department of Neurology, OHSU, VA Portland Health Care System, Portland, Oregon. 19. Beijing Tiantan Hospital, Capital Medical University, Beijing, China. 20. International University of Health and Welfare, Sanno Hospital and Sanno Medical Center, Tokyo, Japan. 21. Klinik für Neurologie, Charité-Universitätsmedizin Berlin, Berlin, Germany. 22. Department of Clinical Neurosciences, Radiology, and Community Health Sciences, University of Calgary, Foothills Medical Centre, Calgary, Alberta, Canada. 23. Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland. 24. 2nd Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland. 25. Department of Pharmacology, Medical University of Warsaw, Warsaw, Poland. 26. Vall d'Hebron Stroke Unit. Hospital Universitari Vall d'Hebron, Barcelona, Spain. 27. Neurology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal. 28. Bayer US LLC, Pharmaceuticals Clinical Development Thrombosis, Whippany, New Jersey.
Abstract
Importance: The NAVIGATE ESUS randomized clinical trial found that 15 mg of rivaroxaban per day does not reduce stroke compared with aspirin in patients with embolic stroke of undetermined source (ESUS); however, it substantially reduces stroke risk in patients with atrial fibrillation (AF). Objective: To analyze whether rivaroxaban is associated with a reduction of recurrent stroke among patients with ESUS who have an increased risk of AF. Design, Setting, and Participants: Participants were stratified by predictors of AF, including left atrial diameter, frequency of premature atrial contractions, and HAVOC score, a validated scheme using clinical features. Treatment interactions with these predictors were assessed. Participants were enrolled between December 2014 and September 2017, and analysis began March 2018. Intervention: Rivaroxaban treatment vs aspirin. Main Outcomes and Measures: Risk of ischemic stroke. Results: Among 7112 patients with a mean (SD) age of 67 (9.8) years, the mean (SD) HAVOC score was 2.6 (1.8), the mean (SD) left atrial diameter was 3.8 (1.4) cm (n = 4022), and the median (interquartile range) daily frequency of premature atrial contractions was 48 (13-222). Detection of AF during follow-up increased for each tertile of HAVOC score: 2.3% (score, 0-2), 3.0% (score, 3), and 5.8% (score, >3); however, neither tertiles of the HAVOC score nor premature atrial contractions frequency impacted the association of rivaroxaban with recurrent ischemic stroke (P for interaction = .67 and .96, respectively). Atrial fibrillation annual incidence increased for each tertile of left atrial diameter (2.0%, 3.6%, and 5.2%) and for each tertile of premature atrial contractions frequency (1.3%, 2.9%, and 7.0%). Among the predefined subgroup of patients with a left atrial diameter of more than 4.6 cm (9% of overall population), the risk of ischemic stroke was lower among the rivaroxaban group (1.7% per year) compared with the aspirin group (6.5% per year) (hazard ratio, 0.26; 95% CI, 0.07-0.94; P for interaction = .02). Conclusions and Relevance: The HAVOC score, left atrial diameter, and premature atrial contraction frequency predicted subsequent clinical AF. Rivaroxaban was associated with a reduced risk of recurrent stroke among patients with ESUS and moderate or severe left atrial enlargement; however, this needs to be independently confirmed before influencing clinical practice.
RCT Entities:
Importance: The NAVIGATE ESUS randomized clinical trial found that 15 mg of rivaroxaban per day does not reduce stroke compared with aspirin in patients with embolic stroke of undetermined source (ESUS); however, it substantially reduces stroke risk in patients with atrial fibrillation (AF). Objective: To analyze whether rivaroxaban is associated with a reduction of recurrent stroke among patients with ESUS who have an increased risk of AF. Design, Setting, and Participants: Participants were stratified by predictors of AF, including left atrial diameter, frequency of premature atrial contractions, and HAVOC score, a validated scheme using clinical features. Treatment interactions with these predictors were assessed. Participants were enrolled between December 2014 and September 2017, and analysis began March 2018. Intervention: Rivaroxaban treatment vs aspirin. Main Outcomes and Measures: Risk of ischemic stroke. Results: Among 7112 patients with a mean (SD) age of 67 (9.8) years, the mean (SD) HAVOC score was 2.6 (1.8), the mean (SD) left atrial diameter was 3.8 (1.4) cm (n = 4022), and the median (interquartile range) daily frequency of premature atrial contractions was 48 (13-222). Detection of AF during follow-up increased for each tertile of HAVOC score: 2.3% (score, 0-2), 3.0% (score, 3), and 5.8% (score, >3); however, neither tertiles of the HAVOC score nor premature atrial contractions frequency impacted the association of rivaroxaban with recurrent ischemic stroke (P for interaction = .67 and .96, respectively). Atrial fibrillation annual incidence increased for each tertile of left atrial diameter (2.0%, 3.6%, and 5.2%) and for each tertile of premature atrial contractions frequency (1.3%, 2.9%, and 7.0%). Among the predefined subgroup of patients with a left atrial diameter of more than 4.6 cm (9% of overall population), the risk of ischemic stroke was lower among the rivaroxaban group (1.7% per year) compared with the aspirin group (6.5% per year) (hazard ratio, 0.26; 95% CI, 0.07-0.94; P for interaction = .02). Conclusions and Relevance: The HAVOC score, left atrial diameter, and premature atrial contraction frequency predicted subsequent clinical AF. Rivaroxaban was associated with a reduced risk of recurrent stroke among patients with ESUS and moderate or severe left atrial enlargement; however, this needs to be independently confirmed before influencing clinical practice.
Authors: Hooman Kamel; Wesley T O'Neal; Peter M Okin; Laura R Loehr; Alvaro Alonso; Elsayed Z Soliman Journal: Ann Neurol Date: 2015-08-31 Impact factor: 10.422
Authors: Hooman Kamel; Traci M Bartz; Mitchell S V Elkind; Peter M Okin; Evan L Thacker; Kristen K Patton; Phyllis K Stein; Christopher R deFilippi; Rebecca F Gottesman; Susan R Heckbert; Richard A Kronmal; Elsayed Z Soliman; W T Longstreth Journal: Stroke Date: 2018-03-13 Impact factor: 7.914
Authors: Christian T Ruff; Robert P Giugliano; Eugene Braunwald; Elaine B Hoffman; Naveen Deenadayalu; Michael D Ezekowitz; A John Camm; Jeffrey I Weitz; Basil S Lewis; Alexander Parkhomenko; Takeshi Yamashita; Elliott M Antman Journal: Lancet Date: 2013-12-04 Impact factor: 79.321
Authors: David J Gladstone; Paul Dorian; Melanie Spring; Val Panzov; Muhammad Mamdani; Jeff S Healey; Kevin E Thorpe Journal: Stroke Date: 2015-02-19 Impact factor: 7.914
Authors: David J Gladstone; Melanie Spring; Paul Dorian; Val Panzov; Kevin E Thorpe; Judith Hall; Haris Vaid; Martin O'Donnell; Andreas Laupacis; Robert Côté; Mukul Sharma; John A Blakely; Ashfaq Shuaib; Vladimir Hachinski; Shelagh B Coutts; Demetrios J Sahlas; Phil Teal; Samuel Yip; J David Spence; Brian Buck; Steve Verreault; Leanne K Casaubon; Andrew Penn; Daniel Selchen; Albert Jin; David Howse; Manu Mehdiratta; Karl Boyle; Richard Aviv; Moira K Kapral; Muhammad Mamdani Journal: N Engl J Med Date: 2014-06-26 Impact factor: 91.245
Authors: Kanjana S Perera; Thomas Vanassche; Jackie Bosch; Balakumar Swaminathan; Hardi Mundl; Mohana Giruparajah; Miguel A Barboza; Martin J O'Donnell; Maia Gomez-Schneider; Graeme J Hankey; Byung-Woo Yoon; Artemio Roxas; Philippa Lavallee; Joao Sargento-Freitas; Nikolay Shamalov; Raf Brouns; Rubens J Gagliardi; Scott E Kasner; Alessio Pieroni; Philipp Vermehren; Kazuo Kitagawa; Yongjun Wang; Keith Muir; Jonathan M Coutinho; Stuart J Connolly; Robert G Hart Journal: Stroke Date: 2016-08-09 Impact factor: 7.914
Authors: Hooman Kamel; Elsayed Z Soliman; Susan R Heckbert; Richard A Kronmal; W T Longstreth; Saman Nazarian; Peter M Okin Journal: Stroke Date: 2014-07-22 Impact factor: 7.914
Authors: Hooman Kamel; Lesly A Pearce; George Ntaios; David J Gladstone; Kanjana Perera; Risto O Roine; Elena Meseguer; Ashkan Shoamanesh; Scott D Berkowitz; Hardi Mundl; Mukul Sharma; Stuart J Connolly; Robert G Hart; Jeff S Healey Journal: Stroke Date: 2020-01-02 Impact factor: 7.914
Authors: Hooman Kamel; Babak B Navi; Neal S Parikh; Alexander E Merkler; Peter M Okin; Richard B Devereux; Jonathan W Weinsaft; Jiwon Kim; Jim W Cheung; Luke K Kim; Barbara Casadei; Costantino Iadecola; Mert R Sabuncu; Ajay Gupta; Iván Díaz Journal: Stroke Date: 2020-08-12 Impact factor: 7.914
Authors: Hooman Kamel; Kathleen Alwell; Brett M Kissela; Heidi J Sucharew; Daniel Woo; Matthew Flaherty; Simona Ferioli; Stacie L Demel; Charles J Moomaw; Kyle Walsh; Jason Mackey; De Los Rios La Rosa Felipe; Adam Jasne; Sabreena Slavin; Sharyl Martini; Opeolu Adeoye; Tehniyat Baig; Monica L Chen; Emily B Levitan; Elsayed Z Soliman; Dawn O Kleindorfer Journal: Neurology Date: 2020-11-25 Impact factor: 9.910
Authors: Emelia J Benjamin; Alan S Go; Patrice Desvigne-Nickens; Christopher D Anderson; Barbara Casadei; Lin Y Chen; Harry J G M Crijns; Ben Freedman; Mellanie True Hills; Jeff S Healey; Hooman Kamel; Dong-Yun Kim; Mark S Link; Renato D Lopes; Steven A Lubitz; David D McManus; Peter A Noseworthy; Marco V Perez; Jonathan P Piccini; Renate B Schnabel; Daniel E Singer; Robert G Tieleman; Mintu P Turakhia; Isabelle C Van Gelder; Lawton S Cooper; Sana M Al-Khatib Journal: Circulation Date: 2021-01-25 Impact factor: 29.690