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D-Dimer versus International Normalized Ratio of Prothrombin Time in Ischemic Stroke Patients Treated with Sufficient Warfarin
ARTICLE IN PRESS
D-Dimer versus International Normalized Ratio of Prothrombin Time in Ischemic Stroke Patients Treated with Sufficient Warfarin Ryoo Yamamoto,
MD, PhD,*
Yoshiharu Nakae, MD,* Fumiaki Tanaka, and Ken Johkura, MD, PhD*
MD, PhD,†
Background: In patients receiving chronic warfarin therapy, the international normalized ratio of prothrombin time (PT-INR) reportedly correlates with the incidence, size, severity, and outcome of ischemic stroke, and thus there are guidelines for the optimal PT-INR range that is to be maintained during secondary or primary prevention of ischemic stroke. However, the details of ischemic stroke in patients in whom an optimal PT-INR is maintained by warfarin therapy have not been thoroughly investigated. We conducted a retrospective study to determine the predictors of the size, severity, and outcome of ischemic stroke occurring in patients under chronic warfarin therapy and maintenance of an optimum PT-INR. Methods: The study group comprised 22 consecutive acute ischemic stroke patients who were receiving warfarin and whose PT-INR was within the optimal range on admission. The PT-INR and plasma D-dimer level of these patients on admission were analyzed in relation to infarction volume, National Institutes of Health Stroke Scale score on admission, and modified Rankin Scale score at discharge. Results: PT-INR did not correlate with infarction volume, severity, or outcome. The D-dimer level correlated positively and significantly with the volume (r = .49, P < .05), severity (r = .54, P < .05), and outcome of ischemic stroke (r = .61, P < .01) and did not correlate with the PT-INR (r = −.27, P = .23). Conclusions: When the PT-INR is within optimal range in patients receiving chronic warfarin therapy but who suffer an ischemic stroke, the admission D-dimer level, but not PT-INR, correlates with the size, severity, and outcome of the stroke. Thus, monitoring the D-dimer level in patients receiving long-term warfarin therapy is important, regardless of whether the optimal PT-INR is maintained. Key Words: Anticoagulant therapy—warfarin—D-dimer—atrial fibrillation—optimal therapy. © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.
Introduction From the *Department of Neurology and Stroke Center, Hiratsuka Kyosai Hospital, Hiratsuka, Japan; and †Department of Neurology, Yokohama City University Graduate School of Medicine, Yokohama, Japan. Received December 24, 2015; revision received March 11, 2016; accepted March 17, 2016. Source of funding: The study was supported by departmental resources only. Address correspondence to Ryoo Yamamoto, MD, PhD, Department of Neurology and Stroke Center, Hiratsuka Kyosai Hospital, 9-11 Oiwake, Hiratsuka 254-8502, Japan. E-mail: [email protected]. 1052-3057/$ - see front matter © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.03.037
Patients with nonvalvular atrial fibrillation (NVAF) have a four- to fivefold greater risk of ischemic stroke compared to the risk in patients without NVAF.1 Moreover, in comparison to other types of ischemic stroke, that resulting from NVAF is usually more severe and associated with higher short-term mortality.2 Anticoagulation is of proven efficacy for prevention of ischemic stroke in patients with NVAF,3 with warfarin being the most commonly prescribed antithrombin medication. The warfarin dosage is based on a target international normalized ratio of prothrombin time (PT-INR) of 2.0-3.0, as recommended by the ACC/AHA/ESC 2006 Practice Guidelines.4 These
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guidelines include a lower target INR of 2.0 (range, 1.62.5) for patients aged 75 years and older. In Japan, a target INR of 2.0-3.0, or 1.6-2.6 for patients aged 70 years and older, is recommended to prevent ischemic stroke due to NVAF.5,6 Ischemic stroke occurs in some patients who are treated with sufficient warfarin6,7; however, all factors predictive of such ischemic stroke have not been identified.8 Thus, we conducted a retrospective study to determine the predictors of the size, severity, and outcome of ischemic stroke in patients receiving chronic warfarin therapy and whose PT-INR was within optimal range.
Patients and Methods Study Patients During the period April 2011 through April 2015, up to 1268 patients were admitted to our hospital for acute ischemic stroke. From these patients’ records, we identified 22 consecutive NVAF patients who had been treated with warfarin and whose PT-INR was within the optimal therapeutic range upon admission. For the purpose of the study, the “optimal PT-INR range” was taken as 2.0-3.0 for patients aged less than 70 years and 1.6-2.6 for patients aged 70 years and older, according to the Japanese Guidelines for the Management of Stroke 2009.5 No patient with a malignant tumor was included in the study group because we felt that the pathologic mechanism of ischemic stroke might be different in these patients.9,10 Ischemic stroke was diagnosed in all study patients by a stroke neurologist, and the diagnosis was confirmed by magnetic resonance imaging (MRI).
Variables Studied The information we needed for the study was obtained from the patient’s hospital records. The following patient and clinical characteristics were evaluated: age and sex, PT-INR upon admission, time between the onset of symptoms and arrival at the hospital, the warfarin dosage, the plasma D-dimer level upon admission, the region of the ischemic stroke, total infarction volume, the preadmission CHADS2 score,11 the National Institutes of Health Stroke Scale (NIHSS) score12 upon admission, and the modified Rankin Scale (mRS) score13 at the time of discharge as a measure of outcome. Available data on the D-dimer level after admission were also analyzed. In addition, we noted whether patients had a history of ischemic stroke because we wished to know whether the warfarin therapy was intended for primary or secondary prevention of ischemic stroke. The PT-INR and plasma D-dimer level were measured as follows: Upon the patient’s arrival in the emergency room, venous blood was obtained from the antecubital vein of the nonparalyzed arm. The two-syringe
technique was used for the blood draw. The plasma D-dimer level was measured by latex immunity nephelometry with a commercially available kit (Sekisui Medical Co., Tokyo, Japan). Infarction volume was determined on MRI with the use of Image-J software (version 1.48; National Institutes of Health, Bethesda, MD).14 The ischemic lesion in each slice was traced manually so that the slice volume could be calculated. The volumes of all slices were summed to calculate the total infarction volume.
Statistical Analysis Data are shown as range and median values, where appropriate. Correlation between the PT-INR upon admission and infarction volume, NIHSS score, and mRS score, and correlation between the D-dimer level and infarction volume, NIHSS score, and mRS score were tested by Spearman’s rank correlation coefficient. The CHADS2 score was subjected to correlation analysis, and finally, correlation between the PT-INR and D-dimer level upon admission was tested. Data were analyzed using PRISM software (version 5.01; GraphPad Software Inc., La Jolla, California, USA). P < .05 was considered significant.
Ethical Considerations The study was approved by institutional ethics committee.
Results Clinical characteristics of the 22 study patients are summarized in Table 1. The male : female ratio was 11:11. Patients ranged in age from 59 to 97 years, with a median age of 81. Warfarin therapy was for secondary prevention in 12 patients and primary prevention in 10 patients. As mentioned, the PT-INR was within the optimal therapeutic range in all study patients upon admission. The time between onset of symptoms and admission ranged from 30 minutes to 72 hours, and was less than 12 hours for more than half of the patients. Thirteen of the 22 strokes involved the left or right middle cerebral artery. The NIHSS score and D-dimer level upon admission were available for 21 of the 22 patients. No correlation was found between PT-INR and infarction volume (P = .95), the NIHSS score on admission (P = .52), or mRS score at discharge (P = .55) (Fig 1, A-C). To the contrary, plasma D-dimer levels correlated positively and significantly with infarction volume (P = .023), the NIHSS score on admission (P = .012), and mRS score at discharge (P = .0034) (Fig 2, A-C). The CHADS2 score did not correlate with infarction volume (r = −.076, P = .74), the NIHSS score on admission (r = .20, P = .39), or mRS score at discharge (r = .35, P = .11), and the plasma D-dimer level did not correlate with PT-INR (r = −.27, P = .23).
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Table 1. Patient characteristics
Patient No.
Age/sex
1
76/male
2
94/female
3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
70/male 85/female 85/female 85/male 93/female 97/female 83/male 59/male 60/male 68/male 80/male 75/female 87/female 70/male 77/female 74/male 66/female 82/female 91/male 85/female
Region of infarction Lt. cerebellum, Lt. occipital, Lt. thalamus Lt. pons, Rt. cerebellum, Lt. occipital Lt. MCA Lt. capsule Lt. thalamus Lt. MCA Lt. MCA Lt. MCA Lt. MCA Rt. capsule Lt. MCA Lt. MCA Lt. MCA Rt. ACA Lt. MCA Rt. MCA Lt. MCA Lt. MCA Lt. cerebellum Bil. midbrain Rt. capsule Lt. MCA
Indication*
Time from onset to admission
1
Secondary
24 h
2
Secondary
40 min
3 1.5 1.75 3.5 2 1.25 1.5 2.25 2.25 1.5 2 2 1.5 1.5 2 2.75 2.5 2.25 1.25 1
Primary Primary Secondary Primary Secondary Secondary Primary Primary Primary Primary Secondary Primary Primary Secondary Primary Secondary Secondary Secondary Secondary Secondary
1h 12 h 3h 30 min 3h 4h 30 min 20 h 5h 16 h 3h 10 h 15 h 15 h 3h 6h 24 h 30 min 3 days 1h
Warfarin dosage (mg/day)
Abbreviations: ACA, anterior cerebral artery; Bil., bilateral; Lt., left; MCA, middle cerebral artery; Rt., right. *Primary or secondary prevention.
Figure 1. Scatter plots showing the relations between PT-INR and infarction volume (A), NIHSS score (B), and mRS score (C). Abbreviations: mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; PT-INR, international normalized ratio of prothrombin time.
Figure 2. Scatter plots showing the relations between the D-dimer level and infarction volume (A), NIHSS score (B), and mRS score (C). Abbreviations: mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale.
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Table 2. Changes in the D-dimer values after admission in patients 9, 13, 15, 18, 20, and 21 Day 0 (on admission) D-dimer (μg/mL) mean (SD)
1.78 (2.51)
Days 1-4
Days 5-8
1.30 (.95) 1.23 (.84)
Abbreviation: SD, standard deviation.
The D-dimer level was gradually decreased within a week after admission in 6 patients who were continuously treated with anticoagulant therapy (Table 2).
Discussion In our patients receiving chronic warfarin therapy, PTINR on admission did not correlate with the size, severity, or outcome of ischemic stroke, even when PT-INR was within the optimal range. This finding is contrary to reports that PT-INR correlates with the size, severity, and outcome of ischemic stroke.7,15,16 However, in the reported studies, patients with optimal PT-INRs and those with inadequate, low PT-INRs were compared, and the optimal anticoagulation therapy was shown to reduce not only the frequency of ischemic stroke but also the size, severity, and outcome of the new ischemic strokes that occurred. The CHADS2 score is a well-known predictor of stroke in patients with NVAF.11 In addition, association was reported between the preadmission CHADS2 score and the NIHSS score on admission and the mRS score at discharge in NVAF patients when most patients had not been treated with sufficient anticoagulant.17,18 However, in our patients with NVAF, when the PT-INR was within optimal range, the preadmission CHADS2 score did not correlate with the size, severity, or outcome of a new ischemic stroke. In our patients receiving long-term warfarin therapy, we found significant correlations between the plasma D-dimer level and the volume, severity, and outcome of the new ischemic stroke. The plasma D-dimer level is reported to predict thromboembolic events in patients with atrial fibrillation who are receiving oral anticoagulation therapy.19 Takano et al. suggested as early as 1991 that the D-dimer level may be an indicator of an acute cardioembolic stroke patients’ susceptibility to recurrent embolism.20 However, contradictory findings, i.e., absence of correlation between the plasma D-dimer level and stroke recurrence, have been reported.21,22 A high plasma D-dimer level in patients who have suffered an ischemic stroke may suggest a cardioembolic pathology, and thus an increased risk of death from stroke.23,24 To date, the relation between the plasma D-dimer level and stroke severity and outcome has been evaluated solely in a study group
in which only 15.3% of patients were treated with sufficient warfarin, and patients’ D-dimer levels were shown to correlate significantly with volume of infarction, NIHSS score on admission, and mRS score at discharge.25 The D-dimer level seems to predict the volume, severity, and outcome of ischemic stroke in patients with NVAF regardless of the PT-INR. The plasma D-dimer level may rise as a result of ischemic stroke; the D-dimer elevation associated with ischemic stroke peaks 1-2 weeks after the stroke onset.26,27 In patients with atrial fibrillation, however, the plasma D-dimer level is reported to increase just before the occurrence of the vascular event.28 The increased plasma D-dimer level in cardioembolic stroke patients gradually decreases during the first week after the stroke when anticoagulation therapy is given.29 In our study, blood sampling upon admission for D-dimer measurement was performed within 24 hours in almost all patients (mean time from stroke onset to blood sampling was 10.87 hours) and the plasma D-dimer level was gradually decreased after admission, as previously reported.29 Thus, the plasma D-dimer elevation in our patients was thought less likely to have been secondary to the initial ischemic stroke but rather to have occurred before the ischemic stroke. Our study showed that, when the PT-INR is maintained within the optimal range under warfarin therapy, the D-dimer level, but not PT-INR, correlates with the volume, severity, and outcome of a new ischemic stroke. This finding suggests that monitoring the D-dimer level may be important in patients who are treated with warfarin, even when the warfarin therapy is shown by the PT-INR to be sufficient. Whether decreasing the plasma D-dimer level improves stroke severity and outcome should be investigated in earnest.
Conclusion In patients treated with sufficient warfarin but who have suffered a new ischemic stroke, the plasma D-dimer level upon admission correlates with the severity and outcome of the stroke. Thus, monitoring the plasma D-dimer level may be necessary in patients on chronic warfarin therapy for secondary or primary prevention of ischemic stroke.
References 1. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22:983-988. 2. Steger C, Pratter A, Martinek-Bregel M, et al. Stroke patients with atrial fibrillation have a worse prognosis than patients without: data from the Austrian Stroke registry. Eur Heart J 2004;25:1734-1740. 3. Saxena R, Koudstaal PJ. Anticoagulants versus antiplatelet therapy for preventing stroke in patients with nonrheumatic atrial fibrillation and a history of stroke or transient ischemic attack. Cochrane Database Syst Rev 2004;(4):CD000187.
ARTICLE IN PRESS D-DIMER IN ISCHEMIC STROKE UNDER WARFARINIZATION 4. Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients with Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006;114:e257-e354. 5. Shinohara Y, Yanagihara T, Abe K, et al. I. Stroke in general. J Stroke Cerebrovasc Dis 2011;20(4 Suppl):S7-S30. 6. Yasaka M, Minematsu K, Yamaguchi T. Optimal intensity of international normalized ratio in warfarin therapy for secondary prevention of stroke in patients with nonvalvular atrial fibrillation. Intern Med 2001;40:11831188. 7. Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003;349:1019-1026. 8. Inoue Y, Inatomi Y, Yonehara T, et al. Ischemic stroke under anticoagulant therapy. Rinsho Shinkeigaku 2010;50:455-460. [in Japanese with English abstract]. 9. Varki A. Trousseau’s syndrome: multiple definitions and multiple mechanisms. Blood 2007;110:1723-1729. 10. Schwarzbach CJ, Schaefer A, Ebert A, et al. Stroke and cancer: the importance of cancer-associated hypercoagulation as a possible stroke etiology. Stroke 2012;43:3029-3034. 11. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001;285:2864-2870. 12. Lyden P, Brott T, Tilley B, et al. Improved reliability of the NIH Stroke Scale using video training. NINDS TPA Stroke Study Group. Stroke 1994;25:2220-2226. 13. Rankin J. Cerebral vascular accidents in patients over the age of 60.2. Prognosis. Scott Med J 1957;2:200-215. 14. Schneider CA, Rasband WS, Eliceiri KW. NIH image to Image-J: 25 years of image analysis. Nat Methods 2012;9:671-675. 15. Indredavik B, Rohweder G, Lydersen S. Frequency and effect of optimal anticoagulation before onset of ischaemic stroke in patients with known atrial fibrillation. J Intern Med 2005;258:133-144.
5 16. Wakita M, Yasaka M, Minematsu K, et al. Effects of anticoagulation on infarct size and clinical outcome in acute cardioembolic stroke. Angiology 2002;53:551-556. 17. Sato S, Yazawa Y, Itabashi R, et al. Pre-admission CHADS2 score is related to severity and outcome of stroke. J Neurol Sci 2011;307:149-152. 18. Hong HJ, Kim YD, Cha MJ, et al. Early neurological outcomes according to CHADS2 score in stroke patients with non-valvular atrial fibrillation. Eur J Neurol 2012;19:284-290. 19. Sadanaga T, Sadanaga M, Ogawa S. Evidence that D-dimer levels predict subsequent thromboembolic and cardiovascular events in patients with atrial fibrillation during oral anticoagulant therapy. J Am Coll Cardiol 2010;55:2225-2231. 20. Takano K, Yamaguchi T, Kato H, et al. Activation of coagulation in acute cardioembolic stroke. Stroke 1991;22:12-16. 21. Napoli MD, Papa F. Inflammation, hemostatic markers, and antithrombotic agents in relation to long-term risk of new cardiovascular events in first-ever ischemic stroke patients. Stroke 2002;33:1763-1771. 22. Bruno A, McConnell JP, Cohen SN, et al. Plasma thrombosis markers following cerebral infarction in African Americans. Thromb Res 2005;115:73-77. 23. Feinberg WM, Erickson LP, Bruck D, et al. Hemostatic markers in acute ischemic stroke. Association with stroke type, severity, and outcome. Stroke 1996;27:1296-1300. 24. Berge E, Friis P, Sandset PM. Hemostatic activation in acute ischemic stroke. Thromb Res 2001;101:13-21. 25. Matsumoto M, Sakaguchi M, Okazaki S, et al. Relationship between plasma D-dimer level and cerebral infarction volume in patients with nonvalvular atrial fibrillation. Cerebrovasc Dis 2013;35:64-72. 26. Smout J, Dyker A, Cleanthis M, et al. Platelet function following acute cerebral ischemia. Angiology 2009;60:362369. 27. Feinberg WM, Bruck DC, Ring ME, et al. Hemostatic markers in acute stroke. Stroke 1989;20:592-597. 28. Mahé I, Bergmann JF, Chassany O, et al. A multicentric prospective study in usual care: D-dimer and cardiovascular events in patients with atrial fibrillation. Thromb Res 2012;129:693-699. 29. Hirano K, Takashima S, Dougu N, et al. Study of hemostatic biomarkers in acute ischemic stroke by clinical subtype. J Stroke Cerebrovasc Dis 2012;21:404-410.
D-Dimer versus International Normalized Ratio of Prothrombin Time in Ischemic Stroke Patients Treated with Sufficient Warfarin Ryoo Yamamoto,
MD, PhD,*
Yoshiharu Nakae, MD,* Fumiaki Tanaka, and Ken Johkura, MD, PhD*
MD, PhD,†
Background: In patients receiving chronic warfarin therapy, the international normalized ratio of prothrombin time (PT-INR) reportedly correlates with the incidence, size, severity, and outcome of ischemic stroke, and thus there are guidelines for the optimal PT-INR range that is to be maintained during secondary or primary prevention of ischemic stroke. However, the details of ischemic stroke in patients in whom an optimal PT-INR is maintained by warfarin therapy have not been thoroughly investigated. We conducted a retrospective study to determine the predictors of the size, severity, and outcome of ischemic stroke occurring in patients under chronic warfarin therapy and maintenance of an optimum PT-INR. Methods: The study group comprised 22 consecutive acute ischemic stroke patients who were receiving warfarin and whose PT-INR was within the optimal range on admission. The PT-INR and plasma D-dimer level of these patients on admission were analyzed in relation to infarction volume, National Institutes of Health Stroke Scale score on admission, and modified Rankin Scale score at discharge. Results: PT-INR did not correlate with infarction volume, severity, or outcome. The D-dimer level correlated positively and significantly with the volume (r = .49, P < .05), severity (r = .54, P < .05), and outcome of ischemic stroke (r = .61, P < .01) and did not correlate with the PT-INR (r = −.27, P = .23). Conclusions: When the PT-INR is within optimal range in patients receiving chronic warfarin therapy but who suffer an ischemic stroke, the admission D-dimer level, but not PT-INR, correlates with the size, severity, and outcome of the stroke. Thus, monitoring the D-dimer level in patients receiving long-term warfarin therapy is important, regardless of whether the optimal PT-INR is maintained. Key Words: Anticoagulant therapy—warfarin—D-dimer—atrial fibrillation—optimal therapy. © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.
Introduction From the *Department of Neurology and Stroke Center, Hiratsuka Kyosai Hospital, Hiratsuka, Japan; and †Department of Neurology, Yokohama City University Graduate School of Medicine, Yokohama, Japan. Received December 24, 2015; revision received March 11, 2016; accepted March 17, 2016. Source of funding: The study was supported by departmental resources only. Address correspondence to Ryoo Yamamoto, MD, PhD, Department of Neurology and Stroke Center, Hiratsuka Kyosai Hospital, 9-11 Oiwake, Hiratsuka 254-8502, Japan. E-mail: [email protected]. 1052-3057/$ - see front matter © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.03.037
Patients with nonvalvular atrial fibrillation (NVAF) have a four- to fivefold greater risk of ischemic stroke compared to the risk in patients without NVAF.1 Moreover, in comparison to other types of ischemic stroke, that resulting from NVAF is usually more severe and associated with higher short-term mortality.2 Anticoagulation is of proven efficacy for prevention of ischemic stroke in patients with NVAF,3 with warfarin being the most commonly prescribed antithrombin medication. The warfarin dosage is based on a target international normalized ratio of prothrombin time (PT-INR) of 2.0-3.0, as recommended by the ACC/AHA/ESC 2006 Practice Guidelines.4 These
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guidelines include a lower target INR of 2.0 (range, 1.62.5) for patients aged 75 years and older. In Japan, a target INR of 2.0-3.0, or 1.6-2.6 for patients aged 70 years and older, is recommended to prevent ischemic stroke due to NVAF.5,6 Ischemic stroke occurs in some patients who are treated with sufficient warfarin6,7; however, all factors predictive of such ischemic stroke have not been identified.8 Thus, we conducted a retrospective study to determine the predictors of the size, severity, and outcome of ischemic stroke in patients receiving chronic warfarin therapy and whose PT-INR was within optimal range.
Patients and Methods Study Patients During the period April 2011 through April 2015, up to 1268 patients were admitted to our hospital for acute ischemic stroke. From these patients’ records, we identified 22 consecutive NVAF patients who had been treated with warfarin and whose PT-INR was within the optimal therapeutic range upon admission. For the purpose of the study, the “optimal PT-INR range” was taken as 2.0-3.0 for patients aged less than 70 years and 1.6-2.6 for patients aged 70 years and older, according to the Japanese Guidelines for the Management of Stroke 2009.5 No patient with a malignant tumor was included in the study group because we felt that the pathologic mechanism of ischemic stroke might be different in these patients.9,10 Ischemic stroke was diagnosed in all study patients by a stroke neurologist, and the diagnosis was confirmed by magnetic resonance imaging (MRI).
Variables Studied The information we needed for the study was obtained from the patient’s hospital records. The following patient and clinical characteristics were evaluated: age and sex, PT-INR upon admission, time between the onset of symptoms and arrival at the hospital, the warfarin dosage, the plasma D-dimer level upon admission, the region of the ischemic stroke, total infarction volume, the preadmission CHADS2 score,11 the National Institutes of Health Stroke Scale (NIHSS) score12 upon admission, and the modified Rankin Scale (mRS) score13 at the time of discharge as a measure of outcome. Available data on the D-dimer level after admission were also analyzed. In addition, we noted whether patients had a history of ischemic stroke because we wished to know whether the warfarin therapy was intended for primary or secondary prevention of ischemic stroke. The PT-INR and plasma D-dimer level were measured as follows: Upon the patient’s arrival in the emergency room, venous blood was obtained from the antecubital vein of the nonparalyzed arm. The two-syringe
technique was used for the blood draw. The plasma D-dimer level was measured by latex immunity nephelometry with a commercially available kit (Sekisui Medical Co., Tokyo, Japan). Infarction volume was determined on MRI with the use of Image-J software (version 1.48; National Institutes of Health, Bethesda, MD).14 The ischemic lesion in each slice was traced manually so that the slice volume could be calculated. The volumes of all slices were summed to calculate the total infarction volume.
Statistical Analysis Data are shown as range and median values, where appropriate. Correlation between the PT-INR upon admission and infarction volume, NIHSS score, and mRS score, and correlation between the D-dimer level and infarction volume, NIHSS score, and mRS score were tested by Spearman’s rank correlation coefficient. The CHADS2 score was subjected to correlation analysis, and finally, correlation between the PT-INR and D-dimer level upon admission was tested. Data were analyzed using PRISM software (version 5.01; GraphPad Software Inc., La Jolla, California, USA). P < .05 was considered significant.
Ethical Considerations The study was approved by institutional ethics committee.
Results Clinical characteristics of the 22 study patients are summarized in Table 1. The male : female ratio was 11:11. Patients ranged in age from 59 to 97 years, with a median age of 81. Warfarin therapy was for secondary prevention in 12 patients and primary prevention in 10 patients. As mentioned, the PT-INR was within the optimal therapeutic range in all study patients upon admission. The time between onset of symptoms and admission ranged from 30 minutes to 72 hours, and was less than 12 hours for more than half of the patients. Thirteen of the 22 strokes involved the left or right middle cerebral artery. The NIHSS score and D-dimer level upon admission were available for 21 of the 22 patients. No correlation was found between PT-INR and infarction volume (P = .95), the NIHSS score on admission (P = .52), or mRS score at discharge (P = .55) (Fig 1, A-C). To the contrary, plasma D-dimer levels correlated positively and significantly with infarction volume (P = .023), the NIHSS score on admission (P = .012), and mRS score at discharge (P = .0034) (Fig 2, A-C). The CHADS2 score did not correlate with infarction volume (r = −.076, P = .74), the NIHSS score on admission (r = .20, P = .39), or mRS score at discharge (r = .35, P = .11), and the plasma D-dimer level did not correlate with PT-INR (r = −.27, P = .23).
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Table 1. Patient characteristics
Patient No.
Age/sex
1
76/male
2
94/female
3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
70/male 85/female 85/female 85/male 93/female 97/female 83/male 59/male 60/male 68/male 80/male 75/female 87/female 70/male 77/female 74/male 66/female 82/female 91/male 85/female
Region of infarction Lt. cerebellum, Lt. occipital, Lt. thalamus Lt. pons, Rt. cerebellum, Lt. occipital Lt. MCA Lt. capsule Lt. thalamus Lt. MCA Lt. MCA Lt. MCA Lt. MCA Rt. capsule Lt. MCA Lt. MCA Lt. MCA Rt. ACA Lt. MCA Rt. MCA Lt. MCA Lt. MCA Lt. cerebellum Bil. midbrain Rt. capsule Lt. MCA
Indication*
Time from onset to admission
1
Secondary
24 h
2
Secondary
40 min
3 1.5 1.75 3.5 2 1.25 1.5 2.25 2.25 1.5 2 2 1.5 1.5 2 2.75 2.5 2.25 1.25 1
Primary Primary Secondary Primary Secondary Secondary Primary Primary Primary Primary Secondary Primary Primary Secondary Primary Secondary Secondary Secondary Secondary Secondary
1h 12 h 3h 30 min 3h 4h 30 min 20 h 5h 16 h 3h 10 h 15 h 15 h 3h 6h 24 h 30 min 3 days 1h
Warfarin dosage (mg/day)
Abbreviations: ACA, anterior cerebral artery; Bil., bilateral; Lt., left; MCA, middle cerebral artery; Rt., right. *Primary or secondary prevention.
Figure 1. Scatter plots showing the relations between PT-INR and infarction volume (A), NIHSS score (B), and mRS score (C). Abbreviations: mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; PT-INR, international normalized ratio of prothrombin time.
Figure 2. Scatter plots showing the relations between the D-dimer level and infarction volume (A), NIHSS score (B), and mRS score (C). Abbreviations: mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale.
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Table 2. Changes in the D-dimer values after admission in patients 9, 13, 15, 18, 20, and 21 Day 0 (on admission) D-dimer (μg/mL) mean (SD)
1.78 (2.51)
Days 1-4
Days 5-8
1.30 (.95) 1.23 (.84)
Abbreviation: SD, standard deviation.
The D-dimer level was gradually decreased within a week after admission in 6 patients who were continuously treated with anticoagulant therapy (Table 2).
Discussion In our patients receiving chronic warfarin therapy, PTINR on admission did not correlate with the size, severity, or outcome of ischemic stroke, even when PT-INR was within the optimal range. This finding is contrary to reports that PT-INR correlates with the size, severity, and outcome of ischemic stroke.7,15,16 However, in the reported studies, patients with optimal PT-INRs and those with inadequate, low PT-INRs were compared, and the optimal anticoagulation therapy was shown to reduce not only the frequency of ischemic stroke but also the size, severity, and outcome of the new ischemic strokes that occurred. The CHADS2 score is a well-known predictor of stroke in patients with NVAF.11 In addition, association was reported between the preadmission CHADS2 score and the NIHSS score on admission and the mRS score at discharge in NVAF patients when most patients had not been treated with sufficient anticoagulant.17,18 However, in our patients with NVAF, when the PT-INR was within optimal range, the preadmission CHADS2 score did not correlate with the size, severity, or outcome of a new ischemic stroke. In our patients receiving long-term warfarin therapy, we found significant correlations between the plasma D-dimer level and the volume, severity, and outcome of the new ischemic stroke. The plasma D-dimer level is reported to predict thromboembolic events in patients with atrial fibrillation who are receiving oral anticoagulation therapy.19 Takano et al. suggested as early as 1991 that the D-dimer level may be an indicator of an acute cardioembolic stroke patients’ susceptibility to recurrent embolism.20 However, contradictory findings, i.e., absence of correlation between the plasma D-dimer level and stroke recurrence, have been reported.21,22 A high plasma D-dimer level in patients who have suffered an ischemic stroke may suggest a cardioembolic pathology, and thus an increased risk of death from stroke.23,24 To date, the relation between the plasma D-dimer level and stroke severity and outcome has been evaluated solely in a study group
in which only 15.3% of patients were treated with sufficient warfarin, and patients’ D-dimer levels were shown to correlate significantly with volume of infarction, NIHSS score on admission, and mRS score at discharge.25 The D-dimer level seems to predict the volume, severity, and outcome of ischemic stroke in patients with NVAF regardless of the PT-INR. The plasma D-dimer level may rise as a result of ischemic stroke; the D-dimer elevation associated with ischemic stroke peaks 1-2 weeks after the stroke onset.26,27 In patients with atrial fibrillation, however, the plasma D-dimer level is reported to increase just before the occurrence of the vascular event.28 The increased plasma D-dimer level in cardioembolic stroke patients gradually decreases during the first week after the stroke when anticoagulation therapy is given.29 In our study, blood sampling upon admission for D-dimer measurement was performed within 24 hours in almost all patients (mean time from stroke onset to blood sampling was 10.87 hours) and the plasma D-dimer level was gradually decreased after admission, as previously reported.29 Thus, the plasma D-dimer elevation in our patients was thought less likely to have been secondary to the initial ischemic stroke but rather to have occurred before the ischemic stroke. Our study showed that, when the PT-INR is maintained within the optimal range under warfarin therapy, the D-dimer level, but not PT-INR, correlates with the volume, severity, and outcome of a new ischemic stroke. This finding suggests that monitoring the D-dimer level may be important in patients who are treated with warfarin, even when the warfarin therapy is shown by the PT-INR to be sufficient. Whether decreasing the plasma D-dimer level improves stroke severity and outcome should be investigated in earnest.
Conclusion In patients treated with sufficient warfarin but who have suffered a new ischemic stroke, the plasma D-dimer level upon admission correlates with the severity and outcome of the stroke. Thus, monitoring the plasma D-dimer level may be necessary in patients on chronic warfarin therapy for secondary or primary prevention of ischemic stroke.
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