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Early initiation of new oral anticoagulants in acute stroke and TIA patients with nonvalvular atrial fibrillation
Journal of the Neurological Sciences 331 (2013) 90–93
Contents lists available at SciVerse ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Early initiation of new oral anticoagulants in acute stroke and TIA patients with nonvalvular atrial fibrillation Kensaku Shibazaki ⁎, Kazumi Kimura, Junya Aoki, Naoki Saji, Kenichiro Sakai Department of Stroke Medicine, Kawasaki Medical School, Japan
a r t i c l e
i n f o
Article history: Received 20 December 2012 Received in revised form 2 May 2013 Accepted 10 May 2013 Available online 3 June 2013 Keywords: New anticoagulants Stroke TIA Atrial fibrillation Intracerebral hemorrhage Hemorrhagic transformation
a b s t r a c t Background and purpose: The aim of this study was to investigate whether early initiation of new oral anticoagulants (NOAC) for acute stroke or transient ischemic attack (TIA) patients with nonvalvular atrial fibrillation (NVAF) are safe. Methods: Between March 2011 and September 2012, stroke or TIA patients with NVAF who started NOAC within 2 weeks were enrolled retrospectively. Symptomatic intracerebral hemorrhage (ICH), hemorrhagic transformation (HT) on T2⁎-weighted MRI, recurrence of stroke or TIA, systemic embolism and any bleeding complications after initiation of NOAC were evaluated. Results: 41 patients (25 males; mean age 76.2 years) started NOAC; of which, 39 (95%) patients had stroke, and 2 (5%) had TIA. The median (interquartile range) interval from onset to treatment with NOAC was 2 (1–6) days. Symptomatic ICH was not observed. HT on initial T2⁎ and new HT on follow-up T2⁎ were 5 (12%) and 11 (31%), but it was asymptomatic. Of 5 patients who had HT on the initial T2⁎, enlargement of hemorrhage on follow-up T2⁎ (hemorrhagic infarction (HI) Type 1 → HI Type 2) was observed in 1 patient, but it was asymptomatic. None of the patients had recurrent stroke or TIA, systemic embolism, and any bleeding complications. Conclusions: The NOAC may be safe in acute stroke or TIA patients with NVAF. A large, prospective study is needed to confirm this. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Atrial fibrillation (AF) is a common arrhythmia and a major risk for ischemic stroke [1]. Vitamin K antagonists reduce the risk of stroke but increase the risk of hemorrhage [2]. Several new oral anticoagulants (NOAC) have been developed over the last decade. Recently, the direct thrombin inhibitor dabigatran and the factor Xa inhibitor rivaroxaban have been studied in multicenter, prospective, randomized trials [3,4]. The results showed that dabigatran at the higher dose appears to be superior to warfarin, while dabigatran at the lower dose and rivaroxaban were only similarly effective. Both drugs reduced the tendency for severe intracerebral bleeding complications compared to the vitamin K antagonist. However, patients with acute stroke were not included into the RE-LY and ROCKET-AF study. Patients with stroke or transient ischemic stroke (TIA) and AF are at high risk of recurrent stroke [5], and anticoagulant therapy is needed to prevent further brain ischemia. However, a previous study demonstrated that early anticoagulation is associated with an increased risk of symptomatic intracranial hemorrhage (ICH) [6]. Moreover, hemorrhagic transformation (HT) often occurs within 2 weeks after ⁎ Corresponding author at: Department of Stroke Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki City, Okayama 701-0192, Japan. Tel.: +81 86 462 1111; fax: +81 86 464 1199. E-mail address: [email protected] (K. Shibazaki). 0022-510X/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2013.05.016
stroke, and it is more frequent in patients with acute cardioembolic stroke than in those with other stroke types [7]. Therefore, anticoagulation is not generally recommended in the acute phase of stroke. The aim of this study was to investigate whether early initiation of NOAC for acute stroke or TIA patients with nonvalvular AF (NVAF) are safe. 2. Subjects and methods Between March 2011 and September 2012, stroke or TIA patients with NVAF who started anticoagulant therapy within 2 weeks were enrolled retrospectively. All patients excluding three patients who could take medicine orally without renal failure (creatinine clearance b 30 ml/min) were treated with NOAC. Three patients suffered from TIA and they had warfarin before TIA. Remaining patients, in particular patients could not take medicine orally were treated with warfarin. AF was diagnosed by 12-lead electrocardiography (ECG), continuous electrocardiographic monitoring, or 24-hour Holter ECG. The diagnosis of acute stroke or TIA was made by stroke neurologists and confirmed by magnetic resonance imaging (MRI). The following factors were assessed: age, sex, type of AF, CHADS2 score [8], past history (stroke or TIA, myocardial infarction, heart failure, renal failure with hemodialysis), vascular risk factors, preadmission medication, National Institutes of Health Stroke Scale [9] score on admission, creatinine clearance, brain natriuretic peptide, ejection fraction, the use of thrombolysis or mechanical thrombectomy,
K. Shibazaki et al. / Journal of the Neurological Sciences 331 (2013) 90–93
type of NOAC, dosage of NOAC, symptomatic ICH, HT on T2⁎-weighted MRI, type of HT, recurrence of stroke or TIA, systemic embolism, any bleeding complications, renal failure and death during 3 months follow-up. This study complied with the Declaration of Helsinki with regard to investigations involving humans, and the study protocol was approved by the Ethics Committee of Kawasaki Medical School Hospital. MRI studies including T2⁎-gradient echo imaging were performed on admission and approximately 2 weeks after onset using a commercially available echo planar instrument operating at 1.5 T (Signa EXCITE XL version 11.0, GE Healthcare, Milwaukee, WI, USA). HT were classified according to the following European Cooperative Acute Stroke Study definitions with consensual evaluation based on the measured hypointense volumes: hemorrhagic infarction (HI) without space-occupying effects (HI1: small petechiae; HI2: more confluent) and parenchymal hemorrhage (PH) with space-occupying effects (PH1: b 30% of the infracted area with a mild space-occupying effect; PH2: >30% of the infracted area with a significant space-occupying effect) [10] on T2⁎. New HT was defined as the new appearance of low intensity lesions on the follow-up T2⁎ compared to the initial T2⁎. The experienced researcher (K.S.) who evaluated the MRI findings was blinded to the patients' clinical backgrounds. Symptomatic ICH was defined as an increase in the total NIHSS score of ≥4 when the ICH was the likely cause of the clinical deterioration. Stroke neurologists assessed the neurological deterioration during hospitalization. Patients were followed-up for 3 months after stroke or TIA. Recurrent stroke or TIA was defined as a new cerebrovascular event that met one of the following criteria: (1) the event resulted in a neurological deficit that was clearly different from that of the index stroke, and (2) the event involved a different anatomic site or vascular territory from that of the index stroke. Statistical analysis was performed using StatView version 5 statistical software. We divided the patients into two groups according the presence of new HT after initiation of NOAC (new HT group and non HT group). Their clinical characteristics were compared using chi-squared test or Fisher's exact test for categorical variables and the Mann–Whitney U test for continuous variables. Values of P b 0.05 were considered significant.
A total of 113 patients (58 males; mean age 79.0 years) with acute stroke or TIA and NVAF who started anticoagulant therapy within 2 weeks after onset were enrolled retrospectively. Thirty nine (36%) of 108 patients with stroke and two (40%) of five patients with TIA were treated NOAC. The median (interquartile range) interval from onset to treatment with NOAC was 2 (1–6) days. Dabigatran was used
Patients n=41
Initial T2*
Follow-up T2*
in 37 patients (90%) and rivaroxaban in 4 (10%). No patients received p-glykoprotein-modulating drugs such as itraconazole, quinidine, verapamil, and amiodaron. Blood tests such as prolongation of activated partial thromboplastin time (APTT) or prothrombin time-international normalized ratio were measured to assess adherence of the patients in taking NOAC. The baseline characteristics of the patients are shown in Table 1. Two patients stopped dabigatran during hospitalization: one patient, a 75-year-old female with low body weight, developed marked prolongation of activated partial thromboplastin time (APTT > 100 s) despite receiving the low dose of dabigatran; and the other patient, an 81-year-old male, developed renal impairment (creatinine clearance b 30 ml/min). No patients discontinued NOAC after discharge. Initial MRI was performed 8.5 (2.7–20.1) h after onset and follow-up MRI was performed 12 (7.8–14) days after onset. HT on initial T2⁎ and new HT on follow-up T2⁎ were 5 (12%) and 11 (31%), respectively (Fig. 1). Of the five patients who had HT on the initial T2⁎ in the NOAC group, enlargement of hemorrhage on follow-up T2⁎ (HI1 → HI2) was observed in one patient (Fig. 2). None of the patients had recurrent stroke or TIA, systemic embolism, any bleeding complications, renal failure and death during 3 months follow-up. Table 2 shows the characteristics of the new HT group and non HT group. The frequencies of persistent AF (82% for the new HT group vs. 32% for the non HT group, P = 0.0103), hypertension (100% vs. 60%, P = 0.0160), and the NIHSS score on admission (9.5 ± 6.9 vs. 3.8 ± 4.9, P = 0.0128) were significantly higher in the new HT group than in the non HT group. There was no difference in the rate of thrombolysis or mechanical thrombectomy between the two groups.
4. Discussion NOAC to prevent recurrence in acute stroke or TIA patients with NVAF were initiated at a median of 2 days. However, no patients had symptomatic ICH, PH on T2⁎, and recurrent stroke or TIA. Table 1 Baseline characteristics. Age
3. Results
hemorrhage n=5
HI 1 n=3
HI 2 n=2
HI 1 n=2
HI 2 n=3
No hemorrhage n=36
HI 1 n=6
Fig. 1. Patient flow chart.
HI 2 n=5
No hemorrhage n=25
91
>75 years Male sex Type of atrial fibrillation Paroxysmal Persistent CHADS2 score 0 or 1 2 3− Prior stroke or transient ischemic attack Prior myocardial infarction Prior Heart failure Diabetes mellitus Hypertension Prior medication Aspirin Anticoagulants ARB or ACE inhibitor Beta-blocker Statin NIHSS score on admission Creatinine clearance, ml/min Brain natriuretic peptide, pg/ml ≥100 pg/ml Ejection fraction, % b40% Thrombolysis or mechanical thrombectomy NOAC dosage Dabigatran 110 mg twice daily/150 mg twice daily Rivaroxaban 10 mg daily/15 mg daily
76.2 ± 9.5 24 (59) 25 (61) 20 (49) 21 (51) 2.0 ± 1.1 11 (27) 21 (51) 9 (22) 7 (17) 1 (2) 1 (2) 10 (24) 31 (76) 6 (15) 9 (22) 16 (39) 7 (17) 4 (10) 3 (1–9) 68.3 (57.5–78.7) 160.6 (108.1–249.2) 32 (78) 58.5 (52.7–64.7) 2 (5) 12 (29) 30 (73)/7 (17) 2 (5)/2 (5)
ARB indicates angiotensin receptor blockers; ACE, angiotensin-converting enzyme inhibitors; NIHSS, National Institutes of Health Stroke Scale; NOAC, new oral anticoagulants.
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K. Shibazaki et al. / Journal of the Neurological Sciences 331 (2013) 90–93
Fig. 2. On admission diffusion-weighted imaging (A) and T2⁎ (B) and follow-up T2⁎ (C). DWI shows a high intense lesion in the left middle cerebral artery area (A). T2⁎ (B) reveals the low intensity in the high intensity area (HI1). Follow-up T2⁎ (C) shows enlargement of hemorrhage (HI2).
ICH is the most devastating complication of anticoagulation; it increases the risks of mortality and severe disability and prolongs hospital stay. Warfarin broadly inhibits coagulation (inhibiting factors II, IX, VII, and X and proteins C and S), and it takes several days to reach a therapeutic international normalized ratio. In order to prevent a warfarin-related hypercoagulable state, heparin sodium is often administered before warfarin [11]. However, a previous study demonstrated that the incidence of symptomatic ICH after early anticoagulation in acute cardioembolic stroke is high, ranging from 2.1% to 10.6% [6]. On the other hand, NOAC are quickly absorbed and selectively inhibit coagulation, and multicenter, prospective, randomized trials demonstrated that NOAC reduced the tendency for severe intracerebral bleeding complications compared to the vitamin K antagonist. Therefore, in acute stroke or TIA patients with NVAF, NOAC may be safe and may help shorten hospital stay. HT is widely known in acute ischemic stroke and is detected in 40–70% of cases [7,12]. In the present study, of 36 patients without HT on initial T2⁎, 11 patients (31%) had new HT on follow-up T2⁎, which was lower than in a previous MRI-based study [12]. A recent study demonstrated that dabigatran had no effect on HT in an experimental model of ischemic stroke [13]. Furthermore, Gliem et al. reported that the lower risk of secondary ICH under dabigatran etexilate compared with vitamin K antagonist treatment may facilitate early initiation of oral anticoagulation after cardioembolism in an experimental study in mice [14]. To the best of our knowledge, no prior study has investigated the relationship between NOAC use
and HT in acute stroke or TIA patients with NVAF. Further prospective studies are needed to clarify this. Two patients stopped dabigatran during hospitalization, one because of marked prolongation of APTT and the other due to worsening of renal function. A high APTT might help screen for risks among patients on dabigatran. Progressive reduction in renal function is commonly seen in elderly patients. Renal insufficiency led to prolonged elimination of dabigatran, resulting in increased dabigatran plasma concentrations and overall exposure [15]. Therefore, serial blood tests after initiation of NOAC are needed to prevent hemorrhagic complications, especially in elderly patients with low body weight and in those with co-existing renal impairment. This study had limitation. The number of patients who received the NOAC was small. A large prospective study is needed to confirm the safety of NOAC for acute stroke or TIA. In conclusion, the NOAC may be safe in acute stroke or TIA patients with NVAF. Sources of funding None. Disclosures None.
Table 2 Characteristics between patients with or without hemorrhagic transformation.
Age, years >75 years Male gender Type of atrial fibrillation Persistent CHADS2 Prior stroke or transient ischemic attack Prior myocardial infarction Prior heart failure Diabetes mellitus Hypertension Prior medication Aspirin Anticoagulants NIHSS score on admission Brain natriuretic peptide, pg/ml Ejection fraction, % Thrombolysis or mechanical thrombectomy Dabigatran dosage 110 mg/150 mg twice daily
Non HT
New HT
n = 25
n = 11
75.3 (11.3) 14 (56) 13 (52)
77.2 (6.3) 6 (55) 8 (73)
0.8634 1 0.2951
8 (32) 1.7 (1.0) 4 (16)
9 (82) 2.5 (1.2) 3 (27)
0.0103 0.1002 0.6499
0 (0) 1 (4) 4 (16) 15 (60)
1 (9) 0 (0) 4 (36) 11 (100)
0.3056 1 0.2137 0.0160
1 (4) 3 (12) 3.8 (4.9) 151.5 (111.0– 243.7) 58.5 (53.5–64.8) 6 (24)
3 (27) 4 (36) 9.5 (6.9) 171.4 (69.4– 319.7) 58.5 (51.3–62.7) 5 (45)
0.0756 0.1665 0.0128 0.8772
17 (68%)/6 (24%)
9 (82%)/1 (9%)
0.3968
NIHSS indicates National Institutes of Health Stroke Scale.
P value
0.8907 0.2519
References [1] Jørgensen HS, Nakayama H, Reith J, Raaschou HO, Olsen TS. Acute stroke with atrial fibrillation. The Copenhagen Stroke Study. Stroke 1996;27:1765–9. [2] Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857–67. [3] Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51. [4] Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:83–91. [5] Moroney JT, Baqiella E, Paik MC, Sacco RL, Desmond DW. Risk factors for early recurrence after ischemic stroke: the role of stroke syndrome and subtype. Stroke 1998;29:2118–24. [6] Paciaroni M, Aqnelli G, Micheli S, Caso V. Efficacy and safety of anticoagulant treatment in acute cardioembolic stroke: a meta-analysis of randomized controlled trials. Stroke 2007;38:423–30. [7] Okada Y, Yamaguchi T, Minematsu K, Miyashita T, Sawada T, Sadoshima S, et al. Hemorrhagic transformation in cerebral embolism. Stroke 1989;20:598–603. [8] Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001;285:2864–70. [9] Lyden P, Brott T, Tilley B, Welch KM, Mascha EJ, Levine S, et al. Improved reliability of the NIH stroke scale using video training. NINDS TPA Stroke Study Group. Stroke 1994;25:2220–6. [10] Larrue V, von Kummer RR, Muller A, Bluhmki E. Risk factors for severe hemorrhagic transformation in ischemic stroke patients treated with recombinant tissue plasminogen activator: a secondary analysis of the European–Austrasian Acute Stroke Study (ECASS II). Stroke 2001;32:438–41. [11] Kelley RE, Berger JR, Alter M, Kovacs AG. Cerebral ischemia and atrial fibrillation: prospective study. Neurology 1984;34:1285–91.
K. Shibazaki et al. / Journal of the Neurological Sciences 331 (2013) 90–93 [12] Hornig CR, Bauer T, Simon C, Trittmacher S, Dorndorf W. Hemorrhagic transformation in cardioembolic cerebral infarction. Stroke 1993;24:465–8. [13] Bohmann F, Mirceska A, Pfeilschifter J, Lindhoff-Last E, Steinmetz H, Foerch C, et al. No influence of dabigatran anticoagulation on hemorrhagic transformation in an experimental model of ischemic stroke. PLoS One 2012;7: e40804.
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[14] Gliem M, Hermsen D, van Rooijen N, Hartung HP, Jander S. Secondary intracerebral hemorrhage due to early initiation of oral anticoagulation after ischemic stroke: an experimental study in mice. Stroke 2012;43:3352–7. [15] Stangier J, Rathgen K, Stahle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet 2010;49:259–68.
Contents lists available at SciVerse ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Early initiation of new oral anticoagulants in acute stroke and TIA patients with nonvalvular atrial fibrillation Kensaku Shibazaki ⁎, Kazumi Kimura, Junya Aoki, Naoki Saji, Kenichiro Sakai Department of Stroke Medicine, Kawasaki Medical School, Japan
a r t i c l e
i n f o
Article history: Received 20 December 2012 Received in revised form 2 May 2013 Accepted 10 May 2013 Available online 3 June 2013 Keywords: New anticoagulants Stroke TIA Atrial fibrillation Intracerebral hemorrhage Hemorrhagic transformation
a b s t r a c t Background and purpose: The aim of this study was to investigate whether early initiation of new oral anticoagulants (NOAC) for acute stroke or transient ischemic attack (TIA) patients with nonvalvular atrial fibrillation (NVAF) are safe. Methods: Between March 2011 and September 2012, stroke or TIA patients with NVAF who started NOAC within 2 weeks were enrolled retrospectively. Symptomatic intracerebral hemorrhage (ICH), hemorrhagic transformation (HT) on T2⁎-weighted MRI, recurrence of stroke or TIA, systemic embolism and any bleeding complications after initiation of NOAC were evaluated. Results: 41 patients (25 males; mean age 76.2 years) started NOAC; of which, 39 (95%) patients had stroke, and 2 (5%) had TIA. The median (interquartile range) interval from onset to treatment with NOAC was 2 (1–6) days. Symptomatic ICH was not observed. HT on initial T2⁎ and new HT on follow-up T2⁎ were 5 (12%) and 11 (31%), but it was asymptomatic. Of 5 patients who had HT on the initial T2⁎, enlargement of hemorrhage on follow-up T2⁎ (hemorrhagic infarction (HI) Type 1 → HI Type 2) was observed in 1 patient, but it was asymptomatic. None of the patients had recurrent stroke or TIA, systemic embolism, and any bleeding complications. Conclusions: The NOAC may be safe in acute stroke or TIA patients with NVAF. A large, prospective study is needed to confirm this. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Atrial fibrillation (AF) is a common arrhythmia and a major risk for ischemic stroke [1]. Vitamin K antagonists reduce the risk of stroke but increase the risk of hemorrhage [2]. Several new oral anticoagulants (NOAC) have been developed over the last decade. Recently, the direct thrombin inhibitor dabigatran and the factor Xa inhibitor rivaroxaban have been studied in multicenter, prospective, randomized trials [3,4]. The results showed that dabigatran at the higher dose appears to be superior to warfarin, while dabigatran at the lower dose and rivaroxaban were only similarly effective. Both drugs reduced the tendency for severe intracerebral bleeding complications compared to the vitamin K antagonist. However, patients with acute stroke were not included into the RE-LY and ROCKET-AF study. Patients with stroke or transient ischemic stroke (TIA) and AF are at high risk of recurrent stroke [5], and anticoagulant therapy is needed to prevent further brain ischemia. However, a previous study demonstrated that early anticoagulation is associated with an increased risk of symptomatic intracranial hemorrhage (ICH) [6]. Moreover, hemorrhagic transformation (HT) often occurs within 2 weeks after ⁎ Corresponding author at: Department of Stroke Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki City, Okayama 701-0192, Japan. Tel.: +81 86 462 1111; fax: +81 86 464 1199. E-mail address: [email protected] (K. Shibazaki). 0022-510X/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2013.05.016
stroke, and it is more frequent in patients with acute cardioembolic stroke than in those with other stroke types [7]. Therefore, anticoagulation is not generally recommended in the acute phase of stroke. The aim of this study was to investigate whether early initiation of NOAC for acute stroke or TIA patients with nonvalvular AF (NVAF) are safe. 2. Subjects and methods Between March 2011 and September 2012, stroke or TIA patients with NVAF who started anticoagulant therapy within 2 weeks were enrolled retrospectively. All patients excluding three patients who could take medicine orally without renal failure (creatinine clearance b 30 ml/min) were treated with NOAC. Three patients suffered from TIA and they had warfarin before TIA. Remaining patients, in particular patients could not take medicine orally were treated with warfarin. AF was diagnosed by 12-lead electrocardiography (ECG), continuous electrocardiographic monitoring, or 24-hour Holter ECG. The diagnosis of acute stroke or TIA was made by stroke neurologists and confirmed by magnetic resonance imaging (MRI). The following factors were assessed: age, sex, type of AF, CHADS2 score [8], past history (stroke or TIA, myocardial infarction, heart failure, renal failure with hemodialysis), vascular risk factors, preadmission medication, National Institutes of Health Stroke Scale [9] score on admission, creatinine clearance, brain natriuretic peptide, ejection fraction, the use of thrombolysis or mechanical thrombectomy,
K. Shibazaki et al. / Journal of the Neurological Sciences 331 (2013) 90–93
type of NOAC, dosage of NOAC, symptomatic ICH, HT on T2⁎-weighted MRI, type of HT, recurrence of stroke or TIA, systemic embolism, any bleeding complications, renal failure and death during 3 months follow-up. This study complied with the Declaration of Helsinki with regard to investigations involving humans, and the study protocol was approved by the Ethics Committee of Kawasaki Medical School Hospital. MRI studies including T2⁎-gradient echo imaging were performed on admission and approximately 2 weeks after onset using a commercially available echo planar instrument operating at 1.5 T (Signa EXCITE XL version 11.0, GE Healthcare, Milwaukee, WI, USA). HT were classified according to the following European Cooperative Acute Stroke Study definitions with consensual evaluation based on the measured hypointense volumes: hemorrhagic infarction (HI) without space-occupying effects (HI1: small petechiae; HI2: more confluent) and parenchymal hemorrhage (PH) with space-occupying effects (PH1: b 30% of the infracted area with a mild space-occupying effect; PH2: >30% of the infracted area with a significant space-occupying effect) [10] on T2⁎. New HT was defined as the new appearance of low intensity lesions on the follow-up T2⁎ compared to the initial T2⁎. The experienced researcher (K.S.) who evaluated the MRI findings was blinded to the patients' clinical backgrounds. Symptomatic ICH was defined as an increase in the total NIHSS score of ≥4 when the ICH was the likely cause of the clinical deterioration. Stroke neurologists assessed the neurological deterioration during hospitalization. Patients were followed-up for 3 months after stroke or TIA. Recurrent stroke or TIA was defined as a new cerebrovascular event that met one of the following criteria: (1) the event resulted in a neurological deficit that was clearly different from that of the index stroke, and (2) the event involved a different anatomic site or vascular territory from that of the index stroke. Statistical analysis was performed using StatView version 5 statistical software. We divided the patients into two groups according the presence of new HT after initiation of NOAC (new HT group and non HT group). Their clinical characteristics were compared using chi-squared test or Fisher's exact test for categorical variables and the Mann–Whitney U test for continuous variables. Values of P b 0.05 were considered significant.
A total of 113 patients (58 males; mean age 79.0 years) with acute stroke or TIA and NVAF who started anticoagulant therapy within 2 weeks after onset were enrolled retrospectively. Thirty nine (36%) of 108 patients with stroke and two (40%) of five patients with TIA were treated NOAC. The median (interquartile range) interval from onset to treatment with NOAC was 2 (1–6) days. Dabigatran was used
Patients n=41
Initial T2*
Follow-up T2*
in 37 patients (90%) and rivaroxaban in 4 (10%). No patients received p-glykoprotein-modulating drugs such as itraconazole, quinidine, verapamil, and amiodaron. Blood tests such as prolongation of activated partial thromboplastin time (APTT) or prothrombin time-international normalized ratio were measured to assess adherence of the patients in taking NOAC. The baseline characteristics of the patients are shown in Table 1. Two patients stopped dabigatran during hospitalization: one patient, a 75-year-old female with low body weight, developed marked prolongation of activated partial thromboplastin time (APTT > 100 s) despite receiving the low dose of dabigatran; and the other patient, an 81-year-old male, developed renal impairment (creatinine clearance b 30 ml/min). No patients discontinued NOAC after discharge. Initial MRI was performed 8.5 (2.7–20.1) h after onset and follow-up MRI was performed 12 (7.8–14) days after onset. HT on initial T2⁎ and new HT on follow-up T2⁎ were 5 (12%) and 11 (31%), respectively (Fig. 1). Of the five patients who had HT on the initial T2⁎ in the NOAC group, enlargement of hemorrhage on follow-up T2⁎ (HI1 → HI2) was observed in one patient (Fig. 2). None of the patients had recurrent stroke or TIA, systemic embolism, any bleeding complications, renal failure and death during 3 months follow-up. Table 2 shows the characteristics of the new HT group and non HT group. The frequencies of persistent AF (82% for the new HT group vs. 32% for the non HT group, P = 0.0103), hypertension (100% vs. 60%, P = 0.0160), and the NIHSS score on admission (9.5 ± 6.9 vs. 3.8 ± 4.9, P = 0.0128) were significantly higher in the new HT group than in the non HT group. There was no difference in the rate of thrombolysis or mechanical thrombectomy between the two groups.
4. Discussion NOAC to prevent recurrence in acute stroke or TIA patients with NVAF were initiated at a median of 2 days. However, no patients had symptomatic ICH, PH on T2⁎, and recurrent stroke or TIA. Table 1 Baseline characteristics. Age
3. Results
hemorrhage n=5
HI 1 n=3
HI 2 n=2
HI 1 n=2
HI 2 n=3
No hemorrhage n=36
HI 1 n=6
Fig. 1. Patient flow chart.
HI 2 n=5
No hemorrhage n=25
91
>75 years Male sex Type of atrial fibrillation Paroxysmal Persistent CHADS2 score 0 or 1 2 3− Prior stroke or transient ischemic attack Prior myocardial infarction Prior Heart failure Diabetes mellitus Hypertension Prior medication Aspirin Anticoagulants ARB or ACE inhibitor Beta-blocker Statin NIHSS score on admission Creatinine clearance, ml/min Brain natriuretic peptide, pg/ml ≥100 pg/ml Ejection fraction, % b40% Thrombolysis or mechanical thrombectomy NOAC dosage Dabigatran 110 mg twice daily/150 mg twice daily Rivaroxaban 10 mg daily/15 mg daily
76.2 ± 9.5 24 (59) 25 (61) 20 (49) 21 (51) 2.0 ± 1.1 11 (27) 21 (51) 9 (22) 7 (17) 1 (2) 1 (2) 10 (24) 31 (76) 6 (15) 9 (22) 16 (39) 7 (17) 4 (10) 3 (1–9) 68.3 (57.5–78.7) 160.6 (108.1–249.2) 32 (78) 58.5 (52.7–64.7) 2 (5) 12 (29) 30 (73)/7 (17) 2 (5)/2 (5)
ARB indicates angiotensin receptor blockers; ACE, angiotensin-converting enzyme inhibitors; NIHSS, National Institutes of Health Stroke Scale; NOAC, new oral anticoagulants.
92
K. Shibazaki et al. / Journal of the Neurological Sciences 331 (2013) 90–93
Fig. 2. On admission diffusion-weighted imaging (A) and T2⁎ (B) and follow-up T2⁎ (C). DWI shows a high intense lesion in the left middle cerebral artery area (A). T2⁎ (B) reveals the low intensity in the high intensity area (HI1). Follow-up T2⁎ (C) shows enlargement of hemorrhage (HI2).
ICH is the most devastating complication of anticoagulation; it increases the risks of mortality and severe disability and prolongs hospital stay. Warfarin broadly inhibits coagulation (inhibiting factors II, IX, VII, and X and proteins C and S), and it takes several days to reach a therapeutic international normalized ratio. In order to prevent a warfarin-related hypercoagulable state, heparin sodium is often administered before warfarin [11]. However, a previous study demonstrated that the incidence of symptomatic ICH after early anticoagulation in acute cardioembolic stroke is high, ranging from 2.1% to 10.6% [6]. On the other hand, NOAC are quickly absorbed and selectively inhibit coagulation, and multicenter, prospective, randomized trials demonstrated that NOAC reduced the tendency for severe intracerebral bleeding complications compared to the vitamin K antagonist. Therefore, in acute stroke or TIA patients with NVAF, NOAC may be safe and may help shorten hospital stay. HT is widely known in acute ischemic stroke and is detected in 40–70% of cases [7,12]. In the present study, of 36 patients without HT on initial T2⁎, 11 patients (31%) had new HT on follow-up T2⁎, which was lower than in a previous MRI-based study [12]. A recent study demonstrated that dabigatran had no effect on HT in an experimental model of ischemic stroke [13]. Furthermore, Gliem et al. reported that the lower risk of secondary ICH under dabigatran etexilate compared with vitamin K antagonist treatment may facilitate early initiation of oral anticoagulation after cardioembolism in an experimental study in mice [14]. To the best of our knowledge, no prior study has investigated the relationship between NOAC use
and HT in acute stroke or TIA patients with NVAF. Further prospective studies are needed to clarify this. Two patients stopped dabigatran during hospitalization, one because of marked prolongation of APTT and the other due to worsening of renal function. A high APTT might help screen for risks among patients on dabigatran. Progressive reduction in renal function is commonly seen in elderly patients. Renal insufficiency led to prolonged elimination of dabigatran, resulting in increased dabigatran plasma concentrations and overall exposure [15]. Therefore, serial blood tests after initiation of NOAC are needed to prevent hemorrhagic complications, especially in elderly patients with low body weight and in those with co-existing renal impairment. This study had limitation. The number of patients who received the NOAC was small. A large prospective study is needed to confirm the safety of NOAC for acute stroke or TIA. In conclusion, the NOAC may be safe in acute stroke or TIA patients with NVAF. Sources of funding None. Disclosures None.
Table 2 Characteristics between patients with or without hemorrhagic transformation.
Age, years >75 years Male gender Type of atrial fibrillation Persistent CHADS2 Prior stroke or transient ischemic attack Prior myocardial infarction Prior heart failure Diabetes mellitus Hypertension Prior medication Aspirin Anticoagulants NIHSS score on admission Brain natriuretic peptide, pg/ml Ejection fraction, % Thrombolysis or mechanical thrombectomy Dabigatran dosage 110 mg/150 mg twice daily
Non HT
New HT
n = 25
n = 11
75.3 (11.3) 14 (56) 13 (52)
77.2 (6.3) 6 (55) 8 (73)
0.8634 1 0.2951
8 (32) 1.7 (1.0) 4 (16)
9 (82) 2.5 (1.2) 3 (27)
0.0103 0.1002 0.6499
0 (0) 1 (4) 4 (16) 15 (60)
1 (9) 0 (0) 4 (36) 11 (100)
0.3056 1 0.2137 0.0160
1 (4) 3 (12) 3.8 (4.9) 151.5 (111.0– 243.7) 58.5 (53.5–64.8) 6 (24)
3 (27) 4 (36) 9.5 (6.9) 171.4 (69.4– 319.7) 58.5 (51.3–62.7) 5 (45)
0.0756 0.1665 0.0128 0.8772
17 (68%)/6 (24%)
9 (82%)/1 (9%)
0.3968
NIHSS indicates National Institutes of Health Stroke Scale.
P value
0.8907 0.2519
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