Original Article
http://dx.doi.org/10.3349/ymj.2015.56.2.410 pISSN: 0513-5796, eISSN: 1976-2437
Yonsei Med J 56(2):410-417, 2015
Factors Associated with Ischemic Stroke on Therapeutic Anticoagulation in Patients with Nonvalvular Atrial Fibrillation Young Dae Kim,1 Kyung Yul Lee,2 Hyo Suk Nam,1 Sang Won Han,3 Jong Yun Lee,4 Han-Jin Cho,5 Gyu Sik Kim,6 Seo Hyun Kim,7 Myoung-Jin Cha,8 Seong Hwan Ahn,9 Seung-Hun Oh,10 Kee Ook Lee,11 Yo Han Jung,12 Hye-Yeon Choi,13 Sang-Don Han,14 Hye Sun Lee,15 Chung Mo Nam,16 Eun Hye Kim,1 Ki Jeong Lee,1 Dongbeom Song,1 Hui-Nam Park,17 and Ji Hoe Heo1 Department of Neurology, Severance Hospital, Yonsei University College of Medicine, Seoul; 2Department of Neurology, Gangnam Severance Hospital, Severance Institute for Vascular and Metabolic Research, Yonsei University College of Medicine, Seoul; 3Department of Neurology, Sanggye Paik Hospital, Inje University College of Medicine, Seoul; 4Department of Neurology, National Medical Center, Seoul; 5Department of Neurology, Pusan National University Hospital, Pusan National University College of Medicine and Biomedical Research Institute, Busan; 6Department of Neurology, National Health Insurance Corporation Ilsan Hospital, Goyang; 7Department of Neurology, Yonsei University Wonju College of Medicine, Wonju; 8 Department of Neurology, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon; 9Department of Neurology, Chosun University School of Medicine, Gwangju; 10Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam; 11 Department of Neurology, Konyang University College of Medicine, Daejeon; 12Department of Neurology, Changwon Fatima Hospital, Changwon; 13 Department of Neurology, Kyung Hee University School of Medicine, Kyung Hee University Hospital at Gangdong, Seoul; 14 Department of Neurology, School of Medicine, Konkuk University, Chungju; 15 Departments of Biostatistics, 16Preventive Medicine, and 17Cardiology, Yonsei University College of Medicine, Seoul, Korea. 1
Received: April 11, 2014 Revised: June 13, 2014 Accepted: July 10, 2014 Corresponding author: Dr. Ji Hoe Heo, Department of Neurology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea. Tel: 82-2-2228-1605, Fax: 82-2-393-0705 E-mail: [email protected] ∙ The authors have no financial conflicts of interest.
© Copyright: Yonsei University College of Medicine 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution NonCommercial License (http://creativecommons.org/ licenses/by-nc/3.0) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
410
Purpose: In this study, we investigated the stroke mechanism and the factors associated with ischemic stroke in patients with nonvalvular atrial fibrillation (NVAF) who were on optimal oral anticoagulation with warfarin. Materials and Methods: This was a multicenter case-control study. The cases were consecutive patients with NVAF who developed cerebral infarction or transient ischemic attack (TIA) while on warfarin therapy with an international normalized ratio (INR) ≥2 between January 2007 and December 2011. The controls were patients with NVAF without ischemic stroke who were on warfarin therapy for more than 1 year with a mean INR ≥2 during the same time period. We also determined etiologic mechanisms of stroke in cases. Results: Among 3569 consecutive patients with cerebral infarction or TIA who had NVAF, 55 (1.5%) patients had INR ≥2 at admission. The most common stroke mechanism was cardioembolism (76.0%). Multivariate analysis demonstrated that smoking and history of previous ischemic stroke were independently associated with cases. High CHADS2 score (≥3) or CHA2DS2-VASc score (≥5), in particular, with previous ischemic stroke along with ≥1 point of other components of CHADS2 score or ≥3 points of other components of CHA2DS2-VASc score was a significant predictor for development of ischemic stroke. Conclusion: NVAF patients with high CHADS2/CHA2DS2-VASc scores and a previous ischemic stroke or smoking history are at high risk of stroke despite optimal warfarin treatment. Some other measures to reduce the risk of stroke would be necessary in those specific groups of patients. Key Words: Cardiac embolism, cerebral infarction, risk factors, atrial fibrillation, anticoagulation
Yonsei Med J http://www.eymj.org Volume 56 Number 2 March 2015
Ischemic Stroke during Therapeutic Anticoagulation
INTRODUCTION Nonvalvular atrial fibrillation (NVAF) is the most common cause of cardioembolic stroke.1,2 Warfarin (vitamin K antagonist) treatment with optimum intensity has been a standard treatment to prevent ischemic stroke or systemic embolism in patients with NVAF.3-5 However, despite having a therapeutic intensity of oral anticoagulation (OAC) therapy, some patients still suffer from ischemic stroke.6 Some patients may have a hypercoagulable state, and subsequently intractable to appropriate OAC therapy.7,8 Furthermore, noncardioembolic stroke such as atherothrombotic stroke or lacunar infarction can occur in patients with NVAF,9,10 and these types of ischemic stroke may not be successfully prevented with OAC. Until now, however, there has been limited information regarding the clinical determinants for development of ischemic stroke and the stroke mechanism in patients with NVAF who were on warfarin therapy in real clinical setting. In this study, we investigated which factors are associated with the development of ischemic stroke in patients with NVAF who are on optimal OAC therapy. We also determined the etiologic mechanisms of stroke in them.
MATERIALS AND METHODS Study population This study was a multicenter, case-control study with prospective case ascertainment and retrospective data collection between January 2007 and December 2011. Cases and controls were collected from total 14 hospitals in South Korea. This study was approved by the Institutional Review Board at each participating hospital and the requirement for informed consent was waived. Consecutive patients with cerebral infarction or transient ischemic attack (TIA) who were admitted to study hospitals during study period were investigated for eligibility for this study. All patients underwent brain CT/MRI, or both. During admission, demographic data, medical history, vascular risk factors, and clinical manifestations were collected for each patient. Among patients with cerebral infarction or TIA, a patient was eligible as the cases if they had NVAF with prior warfarin therapy and their international normalized ratio (INR) was ≥2 at presentation of ischemic stroke or TIA. Controls were selected from patients who were treated in
the department of neurology or cardiology at each study hospital during the same time period. We reviewed the medical records and results of laboratory tests. Patients were included as controls when they had NVAF and received warfarin for more than 1 year with a mean INR ≥2. Controls should not have a cerebral infarction or TIA for one year while they had been on warfarin therapy with their mean INR ≥2. Controls were matched 1:1 to cases on age and gender. Clinical variables We collected data for demographics, vascular risk factors, underlying cardiovascular diseases, and concurrent medications in cases and controls. Atrial fibrillation (AF) was categorized as paroxysmal or persistent/permanent AF. The CHADS2 score or CHA2DS2-VASc scores were calculated for all patients. The index cerebral infarction or TIA was not considered for calculating the CHADS2 score or CHA2DS2-VASc score. Concomitant potential cardiac sources of embolism was defined as having at least one of left atrial/atrial appendage thrombus, sick sinus syndrome, recent myocardial infarction (
http://dx.doi.org/10.3349/ymj.2015.56.2.410 pISSN: 0513-5796, eISSN: 1976-2437
Yonsei Med J 56(2):410-417, 2015
Factors Associated with Ischemic Stroke on Therapeutic Anticoagulation in Patients with Nonvalvular Atrial Fibrillation Young Dae Kim,1 Kyung Yul Lee,2 Hyo Suk Nam,1 Sang Won Han,3 Jong Yun Lee,4 Han-Jin Cho,5 Gyu Sik Kim,6 Seo Hyun Kim,7 Myoung-Jin Cha,8 Seong Hwan Ahn,9 Seung-Hun Oh,10 Kee Ook Lee,11 Yo Han Jung,12 Hye-Yeon Choi,13 Sang-Don Han,14 Hye Sun Lee,15 Chung Mo Nam,16 Eun Hye Kim,1 Ki Jeong Lee,1 Dongbeom Song,1 Hui-Nam Park,17 and Ji Hoe Heo1 Department of Neurology, Severance Hospital, Yonsei University College of Medicine, Seoul; 2Department of Neurology, Gangnam Severance Hospital, Severance Institute for Vascular and Metabolic Research, Yonsei University College of Medicine, Seoul; 3Department of Neurology, Sanggye Paik Hospital, Inje University College of Medicine, Seoul; 4Department of Neurology, National Medical Center, Seoul; 5Department of Neurology, Pusan National University Hospital, Pusan National University College of Medicine and Biomedical Research Institute, Busan; 6Department of Neurology, National Health Insurance Corporation Ilsan Hospital, Goyang; 7Department of Neurology, Yonsei University Wonju College of Medicine, Wonju; 8 Department of Neurology, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon; 9Department of Neurology, Chosun University School of Medicine, Gwangju; 10Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam; 11 Department of Neurology, Konyang University College of Medicine, Daejeon; 12Department of Neurology, Changwon Fatima Hospital, Changwon; 13 Department of Neurology, Kyung Hee University School of Medicine, Kyung Hee University Hospital at Gangdong, Seoul; 14 Department of Neurology, School of Medicine, Konkuk University, Chungju; 15 Departments of Biostatistics, 16Preventive Medicine, and 17Cardiology, Yonsei University College of Medicine, Seoul, Korea. 1
Received: April 11, 2014 Revised: June 13, 2014 Accepted: July 10, 2014 Corresponding author: Dr. Ji Hoe Heo, Department of Neurology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea. Tel: 82-2-2228-1605, Fax: 82-2-393-0705 E-mail: [email protected] ∙ The authors have no financial conflicts of interest.
© Copyright: Yonsei University College of Medicine 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution NonCommercial License (http://creativecommons.org/ licenses/by-nc/3.0) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
410
Purpose: In this study, we investigated the stroke mechanism and the factors associated with ischemic stroke in patients with nonvalvular atrial fibrillation (NVAF) who were on optimal oral anticoagulation with warfarin. Materials and Methods: This was a multicenter case-control study. The cases were consecutive patients with NVAF who developed cerebral infarction or transient ischemic attack (TIA) while on warfarin therapy with an international normalized ratio (INR) ≥2 between January 2007 and December 2011. The controls were patients with NVAF without ischemic stroke who were on warfarin therapy for more than 1 year with a mean INR ≥2 during the same time period. We also determined etiologic mechanisms of stroke in cases. Results: Among 3569 consecutive patients with cerebral infarction or TIA who had NVAF, 55 (1.5%) patients had INR ≥2 at admission. The most common stroke mechanism was cardioembolism (76.0%). Multivariate analysis demonstrated that smoking and history of previous ischemic stroke were independently associated with cases. High CHADS2 score (≥3) or CHA2DS2-VASc score (≥5), in particular, with previous ischemic stroke along with ≥1 point of other components of CHADS2 score or ≥3 points of other components of CHA2DS2-VASc score was a significant predictor for development of ischemic stroke. Conclusion: NVAF patients with high CHADS2/CHA2DS2-VASc scores and a previous ischemic stroke or smoking history are at high risk of stroke despite optimal warfarin treatment. Some other measures to reduce the risk of stroke would be necessary in those specific groups of patients. Key Words: Cardiac embolism, cerebral infarction, risk factors, atrial fibrillation, anticoagulation
Yonsei Med J http://www.eymj.org Volume 56 Number 2 March 2015
Ischemic Stroke during Therapeutic Anticoagulation
INTRODUCTION Nonvalvular atrial fibrillation (NVAF) is the most common cause of cardioembolic stroke.1,2 Warfarin (vitamin K antagonist) treatment with optimum intensity has been a standard treatment to prevent ischemic stroke or systemic embolism in patients with NVAF.3-5 However, despite having a therapeutic intensity of oral anticoagulation (OAC) therapy, some patients still suffer from ischemic stroke.6 Some patients may have a hypercoagulable state, and subsequently intractable to appropriate OAC therapy.7,8 Furthermore, noncardioembolic stroke such as atherothrombotic stroke or lacunar infarction can occur in patients with NVAF,9,10 and these types of ischemic stroke may not be successfully prevented with OAC. Until now, however, there has been limited information regarding the clinical determinants for development of ischemic stroke and the stroke mechanism in patients with NVAF who were on warfarin therapy in real clinical setting. In this study, we investigated which factors are associated with the development of ischemic stroke in patients with NVAF who are on optimal OAC therapy. We also determined the etiologic mechanisms of stroke in them.
MATERIALS AND METHODS Study population This study was a multicenter, case-control study with prospective case ascertainment and retrospective data collection between January 2007 and December 2011. Cases and controls were collected from total 14 hospitals in South Korea. This study was approved by the Institutional Review Board at each participating hospital and the requirement for informed consent was waived. Consecutive patients with cerebral infarction or transient ischemic attack (TIA) who were admitted to study hospitals during study period were investigated for eligibility for this study. All patients underwent brain CT/MRI, or both. During admission, demographic data, medical history, vascular risk factors, and clinical manifestations were collected for each patient. Among patients with cerebral infarction or TIA, a patient was eligible as the cases if they had NVAF with prior warfarin therapy and their international normalized ratio (INR) was ≥2 at presentation of ischemic stroke or TIA. Controls were selected from patients who were treated in
the department of neurology or cardiology at each study hospital during the same time period. We reviewed the medical records and results of laboratory tests. Patients were included as controls when they had NVAF and received warfarin for more than 1 year with a mean INR ≥2. Controls should not have a cerebral infarction or TIA for one year while they had been on warfarin therapy with their mean INR ≥2. Controls were matched 1:1 to cases on age and gender. Clinical variables We collected data for demographics, vascular risk factors, underlying cardiovascular diseases, and concurrent medications in cases and controls. Atrial fibrillation (AF) was categorized as paroxysmal or persistent/permanent AF. The CHADS2 score or CHA2DS2-VASc scores were calculated for all patients. The index cerebral infarction or TIA was not considered for calculating the CHADS2 score or CHA2DS2-VASc score. Concomitant potential cardiac sources of embolism was defined as having at least one of left atrial/atrial appendage thrombus, sick sinus syndrome, recent myocardial infarction (
