Original Research Paper
Preexisting dual antiplatelet treatment increases the risk of post-thrombolysis intracranial hemorrhage in Chinese stroke patients Yuesong Pan1*, Qidong Chen1*, Xiaoling Liao1, Xingquan Zhao1, Chunjuan Wang1, Gaifen Liu1, Liping Liu1, Chunxue Wang1, David Wang2, Yilong Wang1, Yongjun Wang1, On Behalf of the TIMS-China Investigators 1
Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, China, 2INI Stroke Network, OSF Healthcare System, University of Illinois College of Medicine, Peoria, USA Objective: Previous studies have shown conflicting results on the use of antiplatelet (AP) agent and its risk of symptomatic intracerebral hemorrhage (sICH) following thrombolysis for acute ischemic stroke. Our study was to explore the safety of intravenous (IV) thrombolysis in Chinese stroke patients who were on AP prior to stroke. Methods: Data were collected from the thrombolysis implementation and monitor of acute ischemic stroke in China (TIMS-China) registry. Symptomatic ICH defined per SITS-MOST (safe implementation of treatments in stroke-monitoring study), ECASS II (second European-Australasian acute stroke study), and NINDS (National Institute of Neurological Disorders and Stroke) criteria, 90-day functional outcome, and 7day and 90-day mortalities were compared between the stroke patients who were on mono and dual AP therapy. Results: A total of 157 (14.2%) patients received at least one AP drug within 24 hours before thrombolysis. Patients with preexisting dual AP treatment had higher rate of sICH (14.3% (2/14) per SITS-MOST, 21.4% (3/14) per ECASS II definitions) than those on no AP treatment. No significant difference was found in the rate of sICH or 7-day or 90-day mortalities between the groups on aspirin (ASA) alone and on no AP treatment. Discussion: The risk of developing sICH is low when thrombolysis is given to patients who are on ASA alone. However, there is potential increased risk of sICH if a patient is on dual AP treatment.
Keywords: Antiplatelet, Ischemic stroke, Safety, Symptomatic intracerebral hemorrhage, Thrombolysis
Introduction Intravenous (IV) thrombolysis with recombinant tissue plasminogen activator (rtPA) is currently a routine treatment for patients with acute ischemic stroke. However, the potential increased risk of developing symptomatic intracranial hemorrhage (sICH), the most feared complication, limits its use.1–3 Antiplatelet (AP) drugs, which can impair platelet function, may potentiate the risk of developing thrombolysis-related ICH.4,5 Several studies have reported conflicting conclusions regarding the risk of developing ICH when patients were on AP therapy following thrombolysis.5–12 Our study therefore *Yuesong Pan and Qidong Chen contributed equally. Correspondence to: Yilong Wang, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, China. Email: yilong528@ gmail.com; Yongjun Wang, No. 6 Tiantanxili, Dongcheng District, Beijing, 100050, China. Email:[email protected]
ß W. S. Maney & Son Ltd 2014 DOI 10.1179/1743132814Y.0000000390
assessed the risk of developing ICH if a stroke patient was already on AP therapy prior to thrombolysis.
Subjects and Methods Study population and design Data were collected from the thrombolysis implementation and monitor of acute ischemic stroke in China (TIMS-China) registry,13 a national prospective stroke registry of thrombolytic therapy with IV rtPA in patients with acute ischemic stroke in China. Nationwide, 67 centers participated in this stroke registry between May 2007 and April 2012. Data on demographics, clinical characteristics, computer tomography (CT) or magnetic resonance imaging (MRI) scans of brain, medical therapy, and IV thrombolysis information were collected, and all patients were followed up for 3 months. The collection of data for
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TIMS-China was approved by ethics committees at all participating hospitals. All patients or his/her legal representatives gave written informed consents before being entered into the registry. Eligible patients were between ages 18 and 80, who had received rtPA treatment within the 4.5-hour time of onset. The TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria were used to classify stroke etiology.14 Treatment information of aspirin (ASA), clopidogrel (CLP), and other APs within 24 hours before thrombolysis was recorded in the TIMS-China case report form. Based on the available data, we have divided these patients into four groups: (1) no previous use of APs, (2) on ASA only, (3) combined ASA and CLP, and (4) any AP therapy (received at least one AP drug; patients may include those with ASA only and those with combined ASA and CLP).
Outcome measurements The primary outcome measurement was the incidence of sICH at 24–36 hours. Symptomatic ICH was defined according to three different definitions from previously published international trials. The definitions used were from the SITS-MOST (safe implementation of treatments in stroke-monitoring study) criteria2 (local or remote parenchymal hemorrhage type 2 on the 22–36-hour post-treatment imaging scan, combined with a neurological deterioration of four points or more on the NIHSS from baseline, or the lowest NIHSS value between baseline and 24 hours, or death), ECASS II (second EuropeanAustralasian acute stroke study) criteria15 (intracranial bleeding with four or more points worsening on NIHSS score), and NINDS (National Institute of Neurological Disorders and Stroke) definition1 (a hemorrhage that was not seen on a previous CT scan, and there had subsequently been either a suspicion of hemorrhage or any decline in neurologic status). The secondary outcome included 90-day functional outcome (functional independence was defined as a modified Rankin Scale (mRS) score of 0–2),2 and 7day and 90-day mortality rates.
Statistical analysis Categorical variables were presented as percentages, and continuous variables as mean ¡ SD or median (Q1–Q3). Pearson chi-square (x2) test was used for comparisons of categorical variables. When comparing any AP with no AP group, t-test or Mann– Whitney U test was used for continuous variables. When comparing ASA and ASA plus CLP with no AP group, one-way ANOVA or Kruskal–Wallis test was used for continuous variables. Percentage proportions of outcome events were calculated by dividing the number of events by the total number of patients. For each outcome variable, a separate
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multivariable logistic regression was performed. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by using the group without preexisting AP treatment as the reference. All potential risk factors shown in Table 1 were included in the multivariable analysis. The alpha level of significance was P , 0.05. All analyses were performed with SAS software version 9.3 (SAS Institute Inc, Cary, NC, USA).
Results A total of 1108 patients recorded in the TIMS-China registry database were entered into this analysis. Of these, 157 (14.2%) patients were on at least one AP drug within 24 hours before IV thrombolysis. Of the 157 patients who were on any AP, 14 (8.9%) were on ASA plus CLP, 8 (5.1%) were on ASA plus other AP, 115 (73.3%) were on ASA alone, 9 (5.7%) were on CLP alone, and 11 (7.0%) were on other AP drugs. Those on ASA plus other AP (N 5 8), CLP alone (N 5 9), or other AP (N 5 11) were not analyzed separately due to small sample sizes. Baseline characteristics of the patients who belong to different AP subgroups are shown in Table 1. Compared with those who were not on any AP treatment, patients on AP treatment within 24 hours before IV thrombolysis were significantly older, had higher NIHSS scores on admission, had more risk factors (hypertension, diabetes, atrial fibrillation), were more likely to be with stroke subtype of cardioembolism, and were more likely to be on antihypertensive and anticoagulant medications. There was no significant difference in patients with and without AP treatment in terms of their mRS scores before stroke, blood pressure and serum glucose on admission, and stroke onset to needle time. The rate of sICH at 24–36 hours, mortality on 7 and 90 days, and function outcome at 90 days are summarized in Table 2. The overall incidence of sICH was 2.0% according to the SITS-MOST definition, 3.8% as per ECASS II definition, and 5.3% as per NINDS criteria. After adjusting for potential confounders, those on preexisting ASA plus CLP treatment had higher rate of developing sICH than those on no AP treatment according to SITSMOST (14.3% (2/14); adjusted OR: 9.94, 95% CI: 1.55–63.71, P 5 0.02) and ECASS II (21.4% (3/14); adjusted OR: 5.92, 95% CI: 1.29–27.06, P 5 0.02) definitions. No such significant difference was seen per NINDS criteria (P 5 0.06). No significant difference of incidence of sICH was found between groups on any AP, ASA alone, and on no AP treatment (P.0.05). Furthermore, there was no significant increase in the risk for 7-day and 90-day mortalities or 90-day poor functional outcome for any group on AP treatment (P . 0.05).
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Table 1 Demographic and baseline characteristics of the patients
Variables Age (year) Gender (male) Hypertension Diabetes Atrial fibrillation mRS 0–2 before stroke NIHSS on admission SBP on admission (mmHg) DBP on admission (mmHg) Serum glucose on admission (mmol/l) Preexisting antihypertensive treatment Preexisting anticoagulant treatment Early infarct signs on admission CT head scan (Hyper)Dense middle cerebral artery sign on admission CT head scan Alteplase dose (mg/kg body weight) Onset to needle time (hours) Onset to needle time .3 hours Stroke subtype{ Large-artery atherosclerosis Small-vessel occlusion Cardioembolism Other
No AP (N 5 951)
ASA (N 5 115)
ASA plus CLP (N 5 14)
Any AP (N 5 157)
P*
P**
62.7 ¡ 11.2 587(61.7) 546(57.4) 153(16.1) 147(15.5) 932(98.3) 11(7–16) 148 ¡ 21 86 ¡ 13 7.7 ¡ 3.1 330(34.7) 12(1.3) 49(5.2)
66.1 ¡ 10.5 58(50.4) 89(77.4) 34(29.6) 41(35.7) 111(96.5) 12(8–17) 149 ¡ 21 85 ¡ 13 7.8 ¡ 3.1 76(66.1) 1(0.9) 10(8.7)
64.9 ¡ 10.8 10(71.4) 11(78.6) 4(28.6) 4(28.6) 14(100.0) 16(12–18) 144 ¡ 24 80 ¡ 10 7.5 ¡ 2.2 10(71.4) 2(14.3) 0(0.0)
66.0 ¡ 10.1 93(59.2) 113(72.0) 41(26.1) 50(31.9) 152(96.8) 12(8–18) 148 ¡ 21 85 ¡ 13 7.8 ¡ 2.9 94(59.9) 7(4.5) 12(7.6)
0.005 0.046 ,0.001 0.001 ,0.001 0.35 0.03 0.64 0.11 0.99 ,0.001 ,0.001 0.19
,0.001 0.55 ,0.001 0.002 ,0.001 0.34 0.01 0.99 0.20 0.98 ,0.001 0.01 0.20
0.46
0.98
0.40 0.39 0.89
0.10 0.08 0.48
0.004
0.001
66(6.9) 0.90(0.86–0.90) 2.8(2.3–3.3) 318(33.4) 512(54.2) 103(10.9) 172(18.2) 157(16.6)
10(8.7)
0(0.0)
0.90(0.83–0.90) 2.8(2.3–3.3) 40(34.8) 60(53.1) 9(8.0) 36(31.9) 8(7.1)
0.89(0.83–0.90) 2.6(2.3–3.1) 4(28.6) 7(50.0) 1(7.1) 5(35.7) 1(7.1)
11(7.0) 0.90(0.83–0.90) 2.8(2.2–3.3) 48(30.6) 86(55.8) 13(8.4) 44(28.6) 11(7.1)
For categorical variables, results are indicated by numbers (%), and for continuous variables, by mean ¡ SD or median (Q1–Q3). ASA: aspirin; CLP: clopidogrel; AP: antiplatelet; NIHSS: National Institutes of Health Stroke scale score; mRS: modified Rankin Scale. * P values indicate comparison of ASA and ASA plus CLP with no AP group (Pearson chi-square test for categorical and one-way ANOVA or Kruskal–Wallis test for continuous variables). ** P values indicate comparison of any AP with no AP group (Pearson chi-square test for categorical and t-test or Mann–Whitney U test for continuous variables). { Stroke subtype was defined by the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification.
Discussion This multi-center prospective study in China suggested that stroke patients who were on one AP agent had no increased risk of developing sICH if given IV rtPA. However, stroke patients who were on ASA plus CLP would have increased risk of having sICH when treated with IV rtPA. Our study found that there was no significant difference of incidence of sICH between groups on any AP, ASA alone, and those on no AP treatment. This result is similar to several previously published studies,6,7,10–12 but is different from others.8,9 Analysis of SITS-MOST data revealed that patients who were on ASA but not other APs at stroke onset had a significantly higher rate of developing sICH.2 Recent meta-analysis showed that the pooled adjusted OR for the association of AP drug use to the development of sICH was about 1.6 (95% CI 5 1.1–2.4).12 Our study also found that patients who were on ASA plus CLP had higher rate of developing sICH than those who were on no AP treatment by SITSMOST and ECASS II definition, but not by NINDS definition. This result was confirmatory to findings reported in two previous studies.5,10 SITS-ISTR (safe implementation of treatments in stroke international stroke thrombolysis register) showed that ASA plus CLP was a significant predictor for developing sICH
compared with those being on no AP therapy by NINDS and ECASS II definitions but not by SITSMOST criteria.5 Additionally, that study showed that being on any AP therapy would have an increased risk of developing sICH per SITS-MOST definition, but not per NINDS or ECASS II definition. Patients on AP agents before thrombolysis were older, had higher NIHSS scores, had more risk factors (hypertension, diabetes, and atrial fibrillation), and were more likely to be with stroke subtype of cardioembolism and on anticoagulant medications. It is an evidence of confounding by indication that stroke patients on AP agents may have been a marker for those patients who may have more risk factors.16 Patients took AP agents for more risk factors, such as older age, higher NIHSS scores, hypertension, diabetes, and atrial fibrillation. Antiplatelet therapy could indicate higher risk of stroke recurrence. Older age, higher NIHSS scores, and higher glycemia were common predictors of post-thrombolysis sICH.17–21 Although several studies reported warfarin treatment was not associated with increased sICH risk,22–24 concerns regarding risk of post-thrombolysis sICH raised for anticoagulant-treated stroke patients with atrial fibrillation.25,26 These baseline characteristics of patients on AP agents could indicate high risk of postthrombolysis sICH. We performed multivariable regression analysis adjusted for these baseline variables.
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Table 2 Association between preexisting antiplatelet (AP) therapy and safety and function outcomes Multivariable analysis{
Univariable analysis OR(95% CI)
P
Adjusted OR(95% CI)
P
(1.7) (2.6) (14.3) (3.8)
1 1.57(0.45–5.46) 9.74(2.01–47.12) 2.32(0.90–6.03)
0.48 0.005 0.08
1 1.44(0.34–6.18) 9.94(1.55–63.71) 2.04(0.60–6.96)
0.62 0.02 0.26
32/951(3.4) 6/115 (5.2) 3/14 (21.4) 10/157 (6.4)
1 1.58(0.65–3.87) 7.83(2.08–29.45) 1.95(0.94–4.06)
0.32 0.002 0.07
1 1.02(0.35–3.03) 5.92(1.29–27.06) 1.31(0.53–3.25)
0.97 0.02 0.56
48/951 7/115 3/14 11/157
(5.0) (5.1) (21.4) (7.0)
1 1.22(0.54–2.76) 5.13(1.39–19.00) 1.42(0.72–2.79)
0.63 0.01 0.31
1 0.83(0.32–2.16) 4.07(0.95–17.40) 0.92(0.41–2.08)
0.70 0.06 0.85
46/950 7/115 3/14 14/157
(4.8) (6.1) (21.4) (8.9)
1 1.27(0.56–2.89) 5.36(1.45–19.87) 1.92(1.03–3.59)
0.56 0.01 0.04
1 1.10(0.44–2.77) 4.35(0.98–19.34) 1.68(0.81–3.48)
0.83 0.053 0.17
91/933 12/112 4/14 22/154
(9.8) (10.7) (28.6) (14.3)
1 1.11(0.59–2.10) 3.70(1.14–12.05) 1.54(0.94–2.54)
0.75 0.03 0.09
1 0.93(0.45–1.94) 2.75(0.71–10.57) 1.19(0.66–2.17)
0.85 0.14 0.56
388/933 47/111 7/14 66/153
(41.6) (42.3) (50.0) (43.1)
1 1.03(0.69–1.54) 1.41(0.49–4.04) 1.07(0.76–1.51)
0.88 0.53 0.72
1 0.90(0.56–1.44) 1.05(0.31–3.58) 0.84(0.56–1.27)
0.65 0.94 0.41
n/N (%) sICH per SITS-MOST No AP ASA ASA plus CLP Any AP sICH per ECASS II No AP ASA ASA plus CLP Any AP sICH per NINDS No AP ASA ASA plus CLP Any AP 7-day death No AP ASA ASA plus CLP Any AP 90-day death No AP ASA ASA plus CLP Any AP 90-day mRS 3–6 No AP ASA ASA plus CLP Any AP
16/951 3/115 2/14 6/157
ASA: aspirin; CLP: clopidogrel; AP: antiplatelet; sICH: symptomatic intracerebral hemorrhage; SITS-MOST: safe implementation of thrombolysis in stroke-monitoring study; ECASS: European cooperative acute stroke study; NINDS: National Institute of Neurological Disorders and Stroke; mRS: modified Rankin scale; CT: computer tomography; CI: confidence interval. { Adjusted for age, gender, hypertension, diabetes, atrial fibrillation, mRS before stroke, NIHSS on admission, blood pressure on admission, serum glucose on admission, preexisting antihypertensive treatment, preexisting anticoagulant treatment, early infarct signs on admission CT head scan, (hyper)dense middle cerebral artery sign on admission CT head scan, alteplase dose per body weight, onset to needle time, and stroke subtype.
Two previous studies used strictly the 3-hour time window,5,10 whereas others extended the rtPA treatment to 4.5 hours9 or did not restrict the time window of using thrombolysis at all.11,12 We used the time window of ,4.5 hours. No significant difference of developing sICH was found in factors such as onset to needle time between groups on AP and no AP. This study has several limitations. First, this study was based on a registry database, not a prospective study. The conclusion needs further verification by randomized controlled clinical trials. Second, our study contains a small sample size. There were only 14 patients in the ASA plus CLP group, resulting in a large OR and wider CI (adjusted OR: 9.94 (95% CI: 1.55–63.71) per SITS-MOST; 5.92 (95% CI: 1.29– 27.06) per ECASS II). There were only 8 patients who were on ASA plus other AP, 9 on CLP alone, and 11 on other AP. These groups were not analyzed separately because the sample size was small.
However, the risk of developing sICH is higher in those patients who are on ASA plus CLP and considered for IV rtPA.
Disclaimer Statements Contributors All authors have contributed significantly, and are in agreement with the content of the manuscript. Funding This study was funded by the State Key Development Program of Basic Research of China (2009CB521905), and National Science and Technology Major Project of China (2011BAI08B02). Conflicts of interest The authors declare no conflict of interest. Ethics approval The collection of data for the TIMS-China was approved by ethics committees at all participating hospitals. All patients or his/her legal representatives gave written informed consent before being entered in the registry.
Acknowledgements Conclusion The risk of developing sICH is low when giving IV rtPA to patients who are already on AP therapy.
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We thank all participating hospitals, relevant clinicians and patients, and imaging and laboratory technicians.
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References 1 The National Institute of Neurological Disorders and stroke rtPA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581–1587. 2 Wahlgren N, Ahmed N, Da´valos A, Ford GA, Grond M, Hacke W, et al. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in StrokeMonitoring Study (SITS-MOST): an observational study. Lancet. 2007;369:275–82. 3 Bluhmki E, Chamorro A, Da´valos A, Machnig T, Sauce C, Wahlgren N, et al. Stroke treatment with alteplase given 3.0– 4.5 h after onset of acute ischaemic stroke (ECASS III): additional outcomes and subgroup analysis of a randomised controlled trial. Lancet Neurol. 2009;8:1095–102. 4 Diener HC, Foerch C, Riess H, Ro¨ther J, Schroth G, Weber R. Treatment of acute ischaemic stroke with thrombolysis or thrombectomy in patients receiving anti-thrombotic treatment. Lancet Neurol. 2013;12:677–88. 5 Diedler J, Ahmed N, Sykora M, Uyttenboogaart M, Overgaard K, Luijckx GJ, et al. Safety of intravenous thrombolysis for acute ischemic stroke in patients receiving antiplatelet therapy at stroke onset. Stroke. 2010;41:288–94. 6 Tanne D, Kasner SE, Demchuk AM, Koren-Morag N, Hanson S, Grond M, et al. Markers of increased risk of intracerebral hemorrhage after intravenous recombinant tissue plasminogen activator therapy for acute ischemic stroke in clinical practice: the Multicenter rt-PA Stroke Survey. Circulation. 2002;105:1679–85. 7 Schmu¨lling S, Rudolf J, Strotmann-Tack T, Grond M, Schneweis S, Sobesky J, et al. Acetylsalicylic acid pretreatment, concomitant heparin therapy and the risk of early intracranial hemorrhage following systemic thrombolysis for acute ischemic stroke. Cerebrovasc Dis. 2003;16:183–90. 8 Wahlgren N, Ahmed N, Eriksson N, Aichner F, Bluhmki E, Da´valos A, et al. Multivariable analysis of outcome predictors and adjustment of main outcome results to baseline data profile in randomized controlled trials: Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy (SITS-MOST). Stroke. 2008;39:3316–22. 9 Uyttenboogaart M, Koch MW, Koopman K, Vroomen PC, De Keyser J, Luijckx GJ. Safety of antiplatelet therapy prior to intravenous thrombolysis in acute ischemic stroke. Arch Neurol. 2008;65:607–11. 10 Hermann A, Dzialowski I, Koch R, Gahn G. Combined antiplatelet therapy with aspirin and clopidogrel: risk factor for thrombolysis-related intracerebral hemorrhage in acute ischemic stroke? J Neurol Sci. 2009;284:155–7. 11 Dorado L, Milla´n M, de la Ossa NP, Guerrero C, Gomis M, Lo´pez-Cancio E, et al. Influence of antiplatelet pre-treatment on the risk of intracranial haemorrhage in acute ischaemic stroke after intravenous thrombolysis. Eur J Neurol. 2010;17:301–6. 12 Meurer WJ, Kwok H, Skolarus LE, Adelman EE, Kade AM, Kalbfleisch J, et al. Does preexisting antiplatelet treatment influence postthrombolysis intracranial hemorrhage in community-treated ischemic stroke patients? An observational study. Acad Emerg Med. 2013;20:146–54. 13 Liao XL, Wang CX, Wang YL, Wang CJ, Zhao XQ, Zhang LQ, et al. Implementation and outcome of thrombolysis with
14
15
16
17
18
19
20
21
22
23
24
25
26
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alteplase 3 to 4.5 h after acute stroke in Chinese patients. CNS Neurosci Ther. 2013;19:43–7. Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993;24:35–41. Larrue V, von Kummer RR, Mu¨ller 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-Australasian Acute Stroke Study (ECASS II). Stroke. 2001;32:438–41. Stu¨rmer T, Glynn RJ, Rothman KJ, Avorn J, Schneeweiss S. Adjustments for unmeasured confounders in pharmacoepidemiologic database studies using external information. Med Care. 2007;45:S158–65. Strbian D, Engelter S, Michel P, Meretoja A, Sekoranja L, Ahlhelm FJ, et al. Symptomatic intracranial hemorrhage after stroke thrombolysis: the SEDAN score. Ann Neurol. 2012;71:634–41. Saposnik G, Guzik AK, Reeves M, Ovbiagele B, Johnston SC. Stroke prognostication using age and NIH Stroke Scale: SPAN-100. Neurology. 2013;80:21–8. Mazya M, Egido JA, Ford GA, Lees KR, Mikulik R, Toni D, et al. Predicting the risk of symptomatic intracerebral hemorrhage in ischemic stroke treated with intravenous alteplase: safe Implementation of Treatments in Stroke (SITS) symptomatic intracerebral hemorrhage risk score. Stroke. 2012;43:1524–31. Lou M, Safdar A, Mehdiratta M, Kumar S, Schlaug G, Caplan L, et al. The HAT Score: a simple grading scale for predicting hemorrhage after thrombolysis. Neurology. 2008;71:1417–23. Echouffo-Tcheugui JB, Woodward M, Kengne AP. Predicting a post-thrombolysis intracerebral hemorrhage: a systematic review. J Thromb Haemost. 2013;11:862–71. Xian Y, Liang L, Smith EE, Schwamm LH, Reeves MJ, Olson DM, et al. Risks of intracranial hemorrhage among patients with acute ischemic stroke receiving warfarin and treated with intravenous tissue plasminogen activator. JAMA. 2012;307: 2600–8. Vergouwen MD, Casaubon LK, Swartz RH, Fang J, Stamplecoski M, Kapral MK, et al. Subtherapeutic warfarin is not associated with increased hemorrhage rates in ischemic strokes treated with tissue plasminogen activator. Stroke. 2011;42:1041–5. Meretoja A, Putaala J, Tatlisumak T, Atula S, Artto V, Curtze S, et al. Off-label thrombolysis is not associated with poor outcome in patients with stroke. Stroke. 2010;41:1450–8. Seet RC, Zhang Y, Moore SA, Wijdicks EF, Rabinstein AA. Subtherapeutic international normalized ratio in warfarintreated patients increases the risk for symptomatic intracerebral hemorrhage after intravenous thrombolysis. Stroke. 2011;42: 2333–5. Prabhakaran S, Rivolta J, Vieira JR, Rincon F, Stillman J, Marshall RS, et al. Symptomatic intracerebral hemorrhage among eligible warfarin-treated patients receiving intravenous tissue plasminogen activator for acute ischemic stroke. Arch Neurol. 2010;67:559–63.
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Preexisting dual antiplatelet treatment increases the risk of post-thrombolysis intracranial hemorrhage in Chinese stroke patients Yuesong Pan1*, Qidong Chen1*, Xiaoling Liao1, Xingquan Zhao1, Chunjuan Wang1, Gaifen Liu1, Liping Liu1, Chunxue Wang1, David Wang2, Yilong Wang1, Yongjun Wang1, On Behalf of the TIMS-China Investigators 1
Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, China, 2INI Stroke Network, OSF Healthcare System, University of Illinois College of Medicine, Peoria, USA Objective: Previous studies have shown conflicting results on the use of antiplatelet (AP) agent and its risk of symptomatic intracerebral hemorrhage (sICH) following thrombolysis for acute ischemic stroke. Our study was to explore the safety of intravenous (IV) thrombolysis in Chinese stroke patients who were on AP prior to stroke. Methods: Data were collected from the thrombolysis implementation and monitor of acute ischemic stroke in China (TIMS-China) registry. Symptomatic ICH defined per SITS-MOST (safe implementation of treatments in stroke-monitoring study), ECASS II (second European-Australasian acute stroke study), and NINDS (National Institute of Neurological Disorders and Stroke) criteria, 90-day functional outcome, and 7day and 90-day mortalities were compared between the stroke patients who were on mono and dual AP therapy. Results: A total of 157 (14.2%) patients received at least one AP drug within 24 hours before thrombolysis. Patients with preexisting dual AP treatment had higher rate of sICH (14.3% (2/14) per SITS-MOST, 21.4% (3/14) per ECASS II definitions) than those on no AP treatment. No significant difference was found in the rate of sICH or 7-day or 90-day mortalities between the groups on aspirin (ASA) alone and on no AP treatment. Discussion: The risk of developing sICH is low when thrombolysis is given to patients who are on ASA alone. However, there is potential increased risk of sICH if a patient is on dual AP treatment.
Keywords: Antiplatelet, Ischemic stroke, Safety, Symptomatic intracerebral hemorrhage, Thrombolysis
Introduction Intravenous (IV) thrombolysis with recombinant tissue plasminogen activator (rtPA) is currently a routine treatment for patients with acute ischemic stroke. However, the potential increased risk of developing symptomatic intracranial hemorrhage (sICH), the most feared complication, limits its use.1–3 Antiplatelet (AP) drugs, which can impair platelet function, may potentiate the risk of developing thrombolysis-related ICH.4,5 Several studies have reported conflicting conclusions regarding the risk of developing ICH when patients were on AP therapy following thrombolysis.5–12 Our study therefore *Yuesong Pan and Qidong Chen contributed equally. Correspondence to: Yilong Wang, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, China. Email: yilong528@ gmail.com; Yongjun Wang, No. 6 Tiantanxili, Dongcheng District, Beijing, 100050, China. Email:[email protected]
ß W. S. Maney & Son Ltd 2014 DOI 10.1179/1743132814Y.0000000390
assessed the risk of developing ICH if a stroke patient was already on AP therapy prior to thrombolysis.
Subjects and Methods Study population and design Data were collected from the thrombolysis implementation and monitor of acute ischemic stroke in China (TIMS-China) registry,13 a national prospective stroke registry of thrombolytic therapy with IV rtPA in patients with acute ischemic stroke in China. Nationwide, 67 centers participated in this stroke registry between May 2007 and April 2012. Data on demographics, clinical characteristics, computer tomography (CT) or magnetic resonance imaging (MRI) scans of brain, medical therapy, and IV thrombolysis information were collected, and all patients were followed up for 3 months. The collection of data for
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Dual AP increases post-thrombolysis sICH
TIMS-China was approved by ethics committees at all participating hospitals. All patients or his/her legal representatives gave written informed consents before being entered into the registry. Eligible patients were between ages 18 and 80, who had received rtPA treatment within the 4.5-hour time of onset. The TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria were used to classify stroke etiology.14 Treatment information of aspirin (ASA), clopidogrel (CLP), and other APs within 24 hours before thrombolysis was recorded in the TIMS-China case report form. Based on the available data, we have divided these patients into four groups: (1) no previous use of APs, (2) on ASA only, (3) combined ASA and CLP, and (4) any AP therapy (received at least one AP drug; patients may include those with ASA only and those with combined ASA and CLP).
Outcome measurements The primary outcome measurement was the incidence of sICH at 24–36 hours. Symptomatic ICH was defined according to three different definitions from previously published international trials. The definitions used were from the SITS-MOST (safe implementation of treatments in stroke-monitoring study) criteria2 (local or remote parenchymal hemorrhage type 2 on the 22–36-hour post-treatment imaging scan, combined with a neurological deterioration of four points or more on the NIHSS from baseline, or the lowest NIHSS value between baseline and 24 hours, or death), ECASS II (second EuropeanAustralasian acute stroke study) criteria15 (intracranial bleeding with four or more points worsening on NIHSS score), and NINDS (National Institute of Neurological Disorders and Stroke) definition1 (a hemorrhage that was not seen on a previous CT scan, and there had subsequently been either a suspicion of hemorrhage or any decline in neurologic status). The secondary outcome included 90-day functional outcome (functional independence was defined as a modified Rankin Scale (mRS) score of 0–2),2 and 7day and 90-day mortality rates.
Statistical analysis Categorical variables were presented as percentages, and continuous variables as mean ¡ SD or median (Q1–Q3). Pearson chi-square (x2) test was used for comparisons of categorical variables. When comparing any AP with no AP group, t-test or Mann– Whitney U test was used for continuous variables. When comparing ASA and ASA plus CLP with no AP group, one-way ANOVA or Kruskal–Wallis test was used for continuous variables. Percentage proportions of outcome events were calculated by dividing the number of events by the total number of patients. For each outcome variable, a separate
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multivariable logistic regression was performed. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by using the group without preexisting AP treatment as the reference. All potential risk factors shown in Table 1 were included in the multivariable analysis. The alpha level of significance was P , 0.05. All analyses were performed with SAS software version 9.3 (SAS Institute Inc, Cary, NC, USA).
Results A total of 1108 patients recorded in the TIMS-China registry database were entered into this analysis. Of these, 157 (14.2%) patients were on at least one AP drug within 24 hours before IV thrombolysis. Of the 157 patients who were on any AP, 14 (8.9%) were on ASA plus CLP, 8 (5.1%) were on ASA plus other AP, 115 (73.3%) were on ASA alone, 9 (5.7%) were on CLP alone, and 11 (7.0%) were on other AP drugs. Those on ASA plus other AP (N 5 8), CLP alone (N 5 9), or other AP (N 5 11) were not analyzed separately due to small sample sizes. Baseline characteristics of the patients who belong to different AP subgroups are shown in Table 1. Compared with those who were not on any AP treatment, patients on AP treatment within 24 hours before IV thrombolysis were significantly older, had higher NIHSS scores on admission, had more risk factors (hypertension, diabetes, atrial fibrillation), were more likely to be with stroke subtype of cardioembolism, and were more likely to be on antihypertensive and anticoagulant medications. There was no significant difference in patients with and without AP treatment in terms of their mRS scores before stroke, blood pressure and serum glucose on admission, and stroke onset to needle time. The rate of sICH at 24–36 hours, mortality on 7 and 90 days, and function outcome at 90 days are summarized in Table 2. The overall incidence of sICH was 2.0% according to the SITS-MOST definition, 3.8% as per ECASS II definition, and 5.3% as per NINDS criteria. After adjusting for potential confounders, those on preexisting ASA plus CLP treatment had higher rate of developing sICH than those on no AP treatment according to SITSMOST (14.3% (2/14); adjusted OR: 9.94, 95% CI: 1.55–63.71, P 5 0.02) and ECASS II (21.4% (3/14); adjusted OR: 5.92, 95% CI: 1.29–27.06, P 5 0.02) definitions. No such significant difference was seen per NINDS criteria (P 5 0.06). No significant difference of incidence of sICH was found between groups on any AP, ASA alone, and on no AP treatment (P.0.05). Furthermore, there was no significant increase in the risk for 7-day and 90-day mortalities or 90-day poor functional outcome for any group on AP treatment (P . 0.05).
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Table 1 Demographic and baseline characteristics of the patients
Variables Age (year) Gender (male) Hypertension Diabetes Atrial fibrillation mRS 0–2 before stroke NIHSS on admission SBP on admission (mmHg) DBP on admission (mmHg) Serum glucose on admission (mmol/l) Preexisting antihypertensive treatment Preexisting anticoagulant treatment Early infarct signs on admission CT head scan (Hyper)Dense middle cerebral artery sign on admission CT head scan Alteplase dose (mg/kg body weight) Onset to needle time (hours) Onset to needle time .3 hours Stroke subtype{ Large-artery atherosclerosis Small-vessel occlusion Cardioembolism Other
No AP (N 5 951)
ASA (N 5 115)
ASA plus CLP (N 5 14)
Any AP (N 5 157)
P*
P**
62.7 ¡ 11.2 587(61.7) 546(57.4) 153(16.1) 147(15.5) 932(98.3) 11(7–16) 148 ¡ 21 86 ¡ 13 7.7 ¡ 3.1 330(34.7) 12(1.3) 49(5.2)
66.1 ¡ 10.5 58(50.4) 89(77.4) 34(29.6) 41(35.7) 111(96.5) 12(8–17) 149 ¡ 21 85 ¡ 13 7.8 ¡ 3.1 76(66.1) 1(0.9) 10(8.7)
64.9 ¡ 10.8 10(71.4) 11(78.6) 4(28.6) 4(28.6) 14(100.0) 16(12–18) 144 ¡ 24 80 ¡ 10 7.5 ¡ 2.2 10(71.4) 2(14.3) 0(0.0)
66.0 ¡ 10.1 93(59.2) 113(72.0) 41(26.1) 50(31.9) 152(96.8) 12(8–18) 148 ¡ 21 85 ¡ 13 7.8 ¡ 2.9 94(59.9) 7(4.5) 12(7.6)
0.005 0.046 ,0.001 0.001 ,0.001 0.35 0.03 0.64 0.11 0.99 ,0.001 ,0.001 0.19
,0.001 0.55 ,0.001 0.002 ,0.001 0.34 0.01 0.99 0.20 0.98 ,0.001 0.01 0.20
0.46
0.98
0.40 0.39 0.89
0.10 0.08 0.48
0.004
0.001
66(6.9) 0.90(0.86–0.90) 2.8(2.3–3.3) 318(33.4) 512(54.2) 103(10.9) 172(18.2) 157(16.6)
10(8.7)
0(0.0)
0.90(0.83–0.90) 2.8(2.3–3.3) 40(34.8) 60(53.1) 9(8.0) 36(31.9) 8(7.1)
0.89(0.83–0.90) 2.6(2.3–3.1) 4(28.6) 7(50.0) 1(7.1) 5(35.7) 1(7.1)
11(7.0) 0.90(0.83–0.90) 2.8(2.2–3.3) 48(30.6) 86(55.8) 13(8.4) 44(28.6) 11(7.1)
For categorical variables, results are indicated by numbers (%), and for continuous variables, by mean ¡ SD or median (Q1–Q3). ASA: aspirin; CLP: clopidogrel; AP: antiplatelet; NIHSS: National Institutes of Health Stroke scale score; mRS: modified Rankin Scale. * P values indicate comparison of ASA and ASA plus CLP with no AP group (Pearson chi-square test for categorical and one-way ANOVA or Kruskal–Wallis test for continuous variables). ** P values indicate comparison of any AP with no AP group (Pearson chi-square test for categorical and t-test or Mann–Whitney U test for continuous variables). { Stroke subtype was defined by the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification.
Discussion This multi-center prospective study in China suggested that stroke patients who were on one AP agent had no increased risk of developing sICH if given IV rtPA. However, stroke patients who were on ASA plus CLP would have increased risk of having sICH when treated with IV rtPA. Our study found that there was no significant difference of incidence of sICH between groups on any AP, ASA alone, and those on no AP treatment. This result is similar to several previously published studies,6,7,10–12 but is different from others.8,9 Analysis of SITS-MOST data revealed that patients who were on ASA but not other APs at stroke onset had a significantly higher rate of developing sICH.2 Recent meta-analysis showed that the pooled adjusted OR for the association of AP drug use to the development of sICH was about 1.6 (95% CI 5 1.1–2.4).12 Our study also found that patients who were on ASA plus CLP had higher rate of developing sICH than those who were on no AP treatment by SITSMOST and ECASS II definition, but not by NINDS definition. This result was confirmatory to findings reported in two previous studies.5,10 SITS-ISTR (safe implementation of treatments in stroke international stroke thrombolysis register) showed that ASA plus CLP was a significant predictor for developing sICH
compared with those being on no AP therapy by NINDS and ECASS II definitions but not by SITSMOST criteria.5 Additionally, that study showed that being on any AP therapy would have an increased risk of developing sICH per SITS-MOST definition, but not per NINDS or ECASS II definition. Patients on AP agents before thrombolysis were older, had higher NIHSS scores, had more risk factors (hypertension, diabetes, and atrial fibrillation), and were more likely to be with stroke subtype of cardioembolism and on anticoagulant medications. It is an evidence of confounding by indication that stroke patients on AP agents may have been a marker for those patients who may have more risk factors.16 Patients took AP agents for more risk factors, such as older age, higher NIHSS scores, hypertension, diabetes, and atrial fibrillation. Antiplatelet therapy could indicate higher risk of stroke recurrence. Older age, higher NIHSS scores, and higher glycemia were common predictors of post-thrombolysis sICH.17–21 Although several studies reported warfarin treatment was not associated with increased sICH risk,22–24 concerns regarding risk of post-thrombolysis sICH raised for anticoagulant-treated stroke patients with atrial fibrillation.25,26 These baseline characteristics of patients on AP agents could indicate high risk of postthrombolysis sICH. We performed multivariable regression analysis adjusted for these baseline variables.
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Table 2 Association between preexisting antiplatelet (AP) therapy and safety and function outcomes Multivariable analysis{
Univariable analysis OR(95% CI)
P
Adjusted OR(95% CI)
P
(1.7) (2.6) (14.3) (3.8)
1 1.57(0.45–5.46) 9.74(2.01–47.12) 2.32(0.90–6.03)
0.48 0.005 0.08
1 1.44(0.34–6.18) 9.94(1.55–63.71) 2.04(0.60–6.96)
0.62 0.02 0.26
32/951(3.4) 6/115 (5.2) 3/14 (21.4) 10/157 (6.4)
1 1.58(0.65–3.87) 7.83(2.08–29.45) 1.95(0.94–4.06)
0.32 0.002 0.07
1 1.02(0.35–3.03) 5.92(1.29–27.06) 1.31(0.53–3.25)
0.97 0.02 0.56
48/951 7/115 3/14 11/157
(5.0) (5.1) (21.4) (7.0)
1 1.22(0.54–2.76) 5.13(1.39–19.00) 1.42(0.72–2.79)
0.63 0.01 0.31
1 0.83(0.32–2.16) 4.07(0.95–17.40) 0.92(0.41–2.08)
0.70 0.06 0.85
46/950 7/115 3/14 14/157
(4.8) (6.1) (21.4) (8.9)
1 1.27(0.56–2.89) 5.36(1.45–19.87) 1.92(1.03–3.59)
0.56 0.01 0.04
1 1.10(0.44–2.77) 4.35(0.98–19.34) 1.68(0.81–3.48)
0.83 0.053 0.17
91/933 12/112 4/14 22/154
(9.8) (10.7) (28.6) (14.3)
1 1.11(0.59–2.10) 3.70(1.14–12.05) 1.54(0.94–2.54)
0.75 0.03 0.09
1 0.93(0.45–1.94) 2.75(0.71–10.57) 1.19(0.66–2.17)
0.85 0.14 0.56
388/933 47/111 7/14 66/153
(41.6) (42.3) (50.0) (43.1)
1 1.03(0.69–1.54) 1.41(0.49–4.04) 1.07(0.76–1.51)
0.88 0.53 0.72
1 0.90(0.56–1.44) 1.05(0.31–3.58) 0.84(0.56–1.27)
0.65 0.94 0.41
n/N (%) sICH per SITS-MOST No AP ASA ASA plus CLP Any AP sICH per ECASS II No AP ASA ASA plus CLP Any AP sICH per NINDS No AP ASA ASA plus CLP Any AP 7-day death No AP ASA ASA plus CLP Any AP 90-day death No AP ASA ASA plus CLP Any AP 90-day mRS 3–6 No AP ASA ASA plus CLP Any AP
16/951 3/115 2/14 6/157
ASA: aspirin; CLP: clopidogrel; AP: antiplatelet; sICH: symptomatic intracerebral hemorrhage; SITS-MOST: safe implementation of thrombolysis in stroke-monitoring study; ECASS: European cooperative acute stroke study; NINDS: National Institute of Neurological Disorders and Stroke; mRS: modified Rankin scale; CT: computer tomography; CI: confidence interval. { Adjusted for age, gender, hypertension, diabetes, atrial fibrillation, mRS before stroke, NIHSS on admission, blood pressure on admission, serum glucose on admission, preexisting antihypertensive treatment, preexisting anticoagulant treatment, early infarct signs on admission CT head scan, (hyper)dense middle cerebral artery sign on admission CT head scan, alteplase dose per body weight, onset to needle time, and stroke subtype.
Two previous studies used strictly the 3-hour time window,5,10 whereas others extended the rtPA treatment to 4.5 hours9 or did not restrict the time window of using thrombolysis at all.11,12 We used the time window of ,4.5 hours. No significant difference of developing sICH was found in factors such as onset to needle time between groups on AP and no AP. This study has several limitations. First, this study was based on a registry database, not a prospective study. The conclusion needs further verification by randomized controlled clinical trials. Second, our study contains a small sample size. There were only 14 patients in the ASA plus CLP group, resulting in a large OR and wider CI (adjusted OR: 9.94 (95% CI: 1.55–63.71) per SITS-MOST; 5.92 (95% CI: 1.29– 27.06) per ECASS II). There were only 8 patients who were on ASA plus other AP, 9 on CLP alone, and 11 on other AP. These groups were not analyzed separately because the sample size was small.
However, the risk of developing sICH is higher in those patients who are on ASA plus CLP and considered for IV rtPA.
Disclaimer Statements Contributors All authors have contributed significantly, and are in agreement with the content of the manuscript. Funding This study was funded by the State Key Development Program of Basic Research of China (2009CB521905), and National Science and Technology Major Project of China (2011BAI08B02). Conflicts of interest The authors declare no conflict of interest. Ethics approval The collection of data for the TIMS-China was approved by ethics committees at all participating hospitals. All patients or his/her legal representatives gave written informed consent before being entered in the registry.
Acknowledgements Conclusion The risk of developing sICH is low when giving IV rtPA to patients who are already on AP therapy.
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We thank all participating hospitals, relevant clinicians and patients, and imaging and laboratory technicians.
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References 1 The National Institute of Neurological Disorders and stroke rtPA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581–1587. 2 Wahlgren N, Ahmed N, Da´valos A, Ford GA, Grond M, Hacke W, et al. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in StrokeMonitoring Study (SITS-MOST): an observational study. Lancet. 2007;369:275–82. 3 Bluhmki E, Chamorro A, Da´valos A, Machnig T, Sauce C, Wahlgren N, et al. Stroke treatment with alteplase given 3.0– 4.5 h after onset of acute ischaemic stroke (ECASS III): additional outcomes and subgroup analysis of a randomised controlled trial. Lancet Neurol. 2009;8:1095–102. 4 Diener HC, Foerch C, Riess H, Ro¨ther J, Schroth G, Weber R. Treatment of acute ischaemic stroke with thrombolysis or thrombectomy in patients receiving anti-thrombotic treatment. Lancet Neurol. 2013;12:677–88. 5 Diedler J, Ahmed N, Sykora M, Uyttenboogaart M, Overgaard K, Luijckx GJ, et al. Safety of intravenous thrombolysis for acute ischemic stroke in patients receiving antiplatelet therapy at stroke onset. Stroke. 2010;41:288–94. 6 Tanne D, Kasner SE, Demchuk AM, Koren-Morag N, Hanson S, Grond M, et al. Markers of increased risk of intracerebral hemorrhage after intravenous recombinant tissue plasminogen activator therapy for acute ischemic stroke in clinical practice: the Multicenter rt-PA Stroke Survey. Circulation. 2002;105:1679–85. 7 Schmu¨lling S, Rudolf J, Strotmann-Tack T, Grond M, Schneweis S, Sobesky J, et al. Acetylsalicylic acid pretreatment, concomitant heparin therapy and the risk of early intracranial hemorrhage following systemic thrombolysis for acute ischemic stroke. Cerebrovasc Dis. 2003;16:183–90. 8 Wahlgren N, Ahmed N, Eriksson N, Aichner F, Bluhmki E, Da´valos A, et al. Multivariable analysis of outcome predictors and adjustment of main outcome results to baseline data profile in randomized controlled trials: Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy (SITS-MOST). Stroke. 2008;39:3316–22. 9 Uyttenboogaart M, Koch MW, Koopman K, Vroomen PC, De Keyser J, Luijckx GJ. Safety of antiplatelet therapy prior to intravenous thrombolysis in acute ischemic stroke. Arch Neurol. 2008;65:607–11. 10 Hermann A, Dzialowski I, Koch R, Gahn G. Combined antiplatelet therapy with aspirin and clopidogrel: risk factor for thrombolysis-related intracerebral hemorrhage in acute ischemic stroke? J Neurol Sci. 2009;284:155–7. 11 Dorado L, Milla´n M, de la Ossa NP, Guerrero C, Gomis M, Lo´pez-Cancio E, et al. Influence of antiplatelet pre-treatment on the risk of intracranial haemorrhage in acute ischaemic stroke after intravenous thrombolysis. Eur J Neurol. 2010;17:301–6. 12 Meurer WJ, Kwok H, Skolarus LE, Adelman EE, Kade AM, Kalbfleisch J, et al. Does preexisting antiplatelet treatment influence postthrombolysis intracranial hemorrhage in community-treated ischemic stroke patients? An observational study. Acad Emerg Med. 2013;20:146–54. 13 Liao XL, Wang CX, Wang YL, Wang CJ, Zhao XQ, Zhang LQ, et al. Implementation and outcome of thrombolysis with
14
15
16
17
18
19
20
21
22
23
24
25
26
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alteplase 3 to 4.5 h after acute stroke in Chinese patients. CNS Neurosci Ther. 2013;19:43–7. Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993;24:35–41. Larrue V, von Kummer RR, Mu¨ller 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-Australasian Acute Stroke Study (ECASS II). Stroke. 2001;32:438–41. Stu¨rmer T, Glynn RJ, Rothman KJ, Avorn J, Schneeweiss S. Adjustments for unmeasured confounders in pharmacoepidemiologic database studies using external information. Med Care. 2007;45:S158–65. Strbian D, Engelter S, Michel P, Meretoja A, Sekoranja L, Ahlhelm FJ, et al. Symptomatic intracranial hemorrhage after stroke thrombolysis: the SEDAN score. Ann Neurol. 2012;71:634–41. Saposnik G, Guzik AK, Reeves M, Ovbiagele B, Johnston SC. Stroke prognostication using age and NIH Stroke Scale: SPAN-100. Neurology. 2013;80:21–8. Mazya M, Egido JA, Ford GA, Lees KR, Mikulik R, Toni D, et al. Predicting the risk of symptomatic intracerebral hemorrhage in ischemic stroke treated with intravenous alteplase: safe Implementation of Treatments in Stroke (SITS) symptomatic intracerebral hemorrhage risk score. Stroke. 2012;43:1524–31. Lou M, Safdar A, Mehdiratta M, Kumar S, Schlaug G, Caplan L, et al. The HAT Score: a simple grading scale for predicting hemorrhage after thrombolysis. Neurology. 2008;71:1417–23. Echouffo-Tcheugui JB, Woodward M, Kengne AP. Predicting a post-thrombolysis intracerebral hemorrhage: a systematic review. J Thromb Haemost. 2013;11:862–71. Xian Y, Liang L, Smith EE, Schwamm LH, Reeves MJ, Olson DM, et al. Risks of intracranial hemorrhage among patients with acute ischemic stroke receiving warfarin and treated with intravenous tissue plasminogen activator. JAMA. 2012;307: 2600–8. Vergouwen MD, Casaubon LK, Swartz RH, Fang J, Stamplecoski M, Kapral MK, et al. Subtherapeutic warfarin is not associated with increased hemorrhage rates in ischemic strokes treated with tissue plasminogen activator. Stroke. 2011;42:1041–5. Meretoja A, Putaala J, Tatlisumak T, Atula S, Artto V, Curtze S, et al. Off-label thrombolysis is not associated with poor outcome in patients with stroke. Stroke. 2010;41:1450–8. Seet RC, Zhang Y, Moore SA, Wijdicks EF, Rabinstein AA. Subtherapeutic international normalized ratio in warfarintreated patients increases the risk for symptomatic intracerebral hemorrhage after intravenous thrombolysis. Stroke. 2011;42: 2333–5. Prabhakaran S, Rivolta J, Vieira JR, Rincon F, Stillman J, Marshall RS, et al. Symptomatic intracerebral hemorrhage among eligible warfarin-treated patients receiving intravenous tissue plasminogen activator for acute ischemic stroke. Arch Neurol. 2010;67:559–63.
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