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Combined anti-platelet therapy with aspirin and clopidogrel: Risk factor for thrombolysis-related intracerebral hemorrhage in acute ischemic stroke?
Journal of the Neurological Sciences 284 (2009) 155–157
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Combined anti-platelet therapy with aspirin and clopidogrel: Risk factor for thrombolysis-related intracerebral hemorrhage in acute ischemic stroke? Andreas Hermann a,b,1, Imanuel Dzialowski a,⁎,1, Roland Koch c, Georg Gahn d a
Department of Neurology, University of Technology Dresden, Fetscherstraβe 74, 01307, Dresden, Germany Center for Regenerative Therapies Dresden, Dresden, Germany Institute of Informatics and Biometrics, University of Technology Dresden, Dresden, Germany d Department of Neurology, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany b c
a r t i c l e
i n f o
Article history: Received 16 February 2009 Received in revised form 4 May 2009 Accepted 6 May 2009 Available online 26 May 2009 Keywords: Ischemic stroke Thrombolysis Antiplatelets Intracerebral hemorrhage
a b s t r a c t Background and purpose: To date, pre-treatment with anti-platelet agents does not constitute a contraindication for thrombolysis in acute ischemic stroke. We tested the hypothesis that combined pre-treatment with aspirin and clopidogrel is a risk factor for thrombolysis-related symptomatic intracerebral hemorrhage (sICH). Methods: We retrospectively studied patients with acute ischemic stroke receiving standard IV thrombolytic therapy with rt-PA in our institution. Exclusion criteria were thrombolysis initiated later than 3 h from symptom onset or with non-tPA-agents, no follow-up imaging was performed and data on prior medication was missing. We recorded clinical baseline variables including known risk factors for ICH. Our outcome measure was the incidence of ICH defined as parenchymal hematoma type 2 with ≥ 4 points deterioration on the National Institute of Health Stroke Scale score. We performed univariate analysis to determine risk factors for sICH. Results: We identified 102 patients receiving any thrombolysis of which 63 fulfilled the inclusion criteria. Mean age was 69 years, onset-to-treatment-time 138 min, 56% male, median NIHSS score was 10, and 3 patients received additional intra-arterial interventions. A total of 3 patients had received combined aspirin and clopidogrel treatment before thrombolysis. SICH occurred in 3/63 (4.7%) of patients. Out of these, 2 patients had received the combined anti-platelet treatment. In univariate analysis, only combined pretreatment with aspirin and clopidogrel treatment were associated with the occurrence of sICH. Conclusion: In our retrospective study, only pre-treatment with aspirin and clopidogrel was associated with thrombolysis-related intracerebral hemorrhage. This finding should be further validated in large prospective databases like the SITS-MOST registry. © 2009 Elsevier B.V. All rights reserved.
1. Introduction In acute ischemic stroke, symptomatic intracerebral hemorrhage (sICH) is the most feared complication after thrombolysis with recombinant tissue plasminogen activator (rt-PA), seen in approximately 5% of the treated patients, depending on the definition of sICH [1]. Several potential risk factors for sICH have been identified. Extent of hypoattenuation on pre-treatment CT, elevated serum glucose, history of diabetes, and symptom severity were independently associated with sICH after rt-PA in more than one study [2]. Data on the risk of pre-stroke treatment with antiplatelet agents (AP) are inconclusive. While being on aspirin (ASA) was not consistently found to be independently associated with sICH [2], pre-treatment with “other antiplatelet agents”, was an independent predictor of sICH ⁎ Corresponding author. Tel.: +49 351 458 18162; fax: +49 351 458 2060. E-mail address: [email protected] (I. Dzialowski). 1 A.H. and I.D. share 1st authorship since they equally contributed to the manuscript. 0022-510X/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2009.05.003
[3,4]. Very recently, multivariable analysis from the SITS-MOST database showed that ASA pre-treatment predicted sICH while “other AP agents” were associated with higher mortality at 3 months [5]. However, none of these studies systematically compared the risk of single non-ASA antiplatelet agents or AP combinations. From recent stroke prevention studies we have learned that combined AP therapy with ASA and clopidogrel carries a high annual risk (mean rate 1.7%) for major bleeding complications [6–10]. We thus studied the hypothesis that pre-treatment with clopidogrel and ASA is associated with an increased risk of sICH after thrombolysis for acute ischemic stroke. 2. Materials and methods We retrospectively studied patients with acute ischemic stroke receiving standard IV thrombolytic therapy with rt-PA in our institution from 01/2006–05/2007. Exclusion criteria were thrombolysis initiated later than 3 h from symptom onset or with non-tPA-agents, no follow-up
156
A. Hermann et al. / Journal of the Neurological Sciences 284 (2009) 155–157
imaging was performed and data on prior medication was missing. We recorded clinical baseline variables including known risk factors for sICH, onset-to-treatment-time (OTT), pre-hospital AP medication, admission National Institute of Health stroke Scale (NIHSS) score, blood pressure, serum glucose level, platelet count, INR, pTT and any additional intra-arterial intervention following IV thrombolysis. We rated the extent of hypoattenuation at cranial non-contrast CT (NCCT) on admission as absent, b or N than 1/3 of the middle cerebral artery territory using the Neuroradiology report. We assessed all 12–36 h follow-up NCCT for hemorrhagic transformation using criteria by Pessin et al [11]: hemorrhagic infarction and parenchymal hematoma (PH) types 1 and 2. Our single outcome measure was incidence of sICH according to the SITS-MOST criteria defined as PH-2 with deterioration ≥4 points on the NIHSS score [5]. We used standard descriptive statistics and performed a univariate analysis to determine risk factors for sICH. Distribution among groups were tested with the Chi-square test and Fisher`s exact test as appropriate. Level of significance was set at b0.05. 3. Results We identified 102 patients receiving any IV thrombolysis of which 63 fulfilled the inclusion criteria. Reasons for exclusion were OTT N 180 min in 24 patients (10 basilar artery occlusions, 4 receiving bridging IV thrombolysis and intra-arterial thrombolysis, 10 miscellaneous), no follow-up NCCT in 2, thrombolysis with abciximab in 2, and unavailable data in 11 patients. Mean age was 69 ± 11 years, OTT 138± 34, 56% male, median NIHSS score was 10 (range 1–30), 3 patients received additional Table 1 Univariate analysis of clinical, laboratory and imaging variables.
Age (years) b 50 50–59 60–69 70–79 ≥ 80 Gender (m) Arterial hypertension Coronary artery disease Smoking Diabetes Atrial fibrillation Any antiplatelet therapy ASA ASA/dipyridamol Clopidogrel ASA + clopidogrel NIHSS score on admission b 10 10–19 ≥ 20 Systolic BP pre tPA b 140 mmHg ≥ 140 mmHg Serum-glucose on admission b 7 mmol/l ≥ 7 mmol/l Platelet count b 100 G/l ≥ 100 G/l Elevated pTT (N 43 s) Elevated INR (N 1,4) Hypodensity at CT No b 33% MCA N 33% MCA Additional intra-arterial intervention
n (%)
SICH rate n (%)
p
4 (7) 7 (12) 21 (35) 16 (29) 12 (12) 35/63 (55) 45/63 (71) 16/63 (25) 8/61 (13) 21/63 (33) 16/63 (25) 36/63 (57) 26/63 (41) 1/63 (2) 6/63 (10) 3/63 (5)
– – 1/21 (5) 2/16 (11) – 3/35 (8) 2/45 (4) 3/16 (19) 1/8 (13) 2/21 (10) 1/16 (6) 3/36 (8) 0/26 0/1 1/6 (17) 2/3 (66)
0.16 0.16 1.0 0.01 0.34 0.21 0.74 0.20 1.0 1.0 0.10 0.005
26/63 (41) 35/63 (56) 2/63 (3)
2/26 (8) 1/35 (3) 0/2
12/57 (21) 45/57 (79)
2/12 (17) 1/45 (2)
0.1
15/63 (24) 48/63 (76)
1/15 (7) 2/482 (4)
0.69
1/62 58/62 0/62 0/63
(2) (94) (0) (0)
0/1 3/58 (5) – –
1.0 – –
37/62 22/62 3/62 3/63
(60) (35) (5) (5)
2/37 (5) 0/22 1/3 (33) 0/3 (0)
1.0 0.54 0.14 1.0
Table 2 Patient characteristics with symptomatic ICH. Patient
Age
Hx CAD
ASA
Clopidogrel
NIHSS score
BP pre tPA
OTT (min)
Early CT changes
1 2 3
76 70 69
+ + +
− + +
+ + +
8 7 14
180/94 120/70 130/80
180 120 180
No No N 33%
NIHSS, National Institute of health Stroke Scale, CAD, coronary artery disease, ASA, acetylic salicylic acid, BP, blood pressure, OTT, onset to treat time.
intra-arterial intervention (Table 1). Patients pre-treated with AP agents were older (71 ± 11 vs. 67 ± 11 years), and more frequently had a history of arterial hypertension (81% vs. 69%), atrial fibrillation (33% vs. 15%), diabetes mellitus (47% vs. 15%) and coronary artery disease (42% vs. 4%). A total of 29 patients had received ASA (standard dose 100 mg/day) and 9 patients had received clopidogrel (75 mg/day) before thrombolysis, respectively (Table 1). The combination of ASA and clopidogrel was present in 3 patients. SICH occurred in 3/63 (4.7%) of patients. Out of these, 2 patients had received the combined anti-platelet treatment, 1 was on clopidogrel alone (Table 2). In univariate analysis, only the pretreatment with combined ASA and clopidogrel was associated with the occurrence of sICH. 4. Discussion In our single-centre retrospective study, combined pre-treatment with ASA and clopidogrel was the only factor associated with sICH after standard thrombolysis with rt-PA. Pre-treatment with ASA as well as with “antiplatelet agents” has been identified as a potential risk factor for thrombolysis-related sICH [4]. However, to our knowledge, an increased risk for thrombolysis-related sICH after pretreatment with ASA and clopidogrel has not been previously reported. Of note, combined AP therapy with ASA and clopidogrel carries a significant increase in major bleeding complications when used in stroke prevention (Table 3) [6–10]. So far, combined ASA and clopidogrel treatment is neither widely recommended for primary nor for secondary prevention of stroke. Patients currently receiving this combined AP regimen usually have a history of coronary heart disease and recent coronary angioplasty or recent carotid angioplasty and stenting. However, this may change as indicated in the recent Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE-A), possibly leading to a much broader indication for this adjunction AP therapy [7]. Our results suggest that these patients might be at risk from thrombolysis in case they suffer an acute ischemic stroke.
Table 3 Annual bleeding risk with combined anti-platelet therapy using ASA + clopidogrel. 0.61
NIHSS, National Institute of health Stroke Scale; MCA, middle cerebral artery, ASA, acetylic salicylic acid, distribution among groups were tested using Chi-square test and Fisher`s exact test as appropriate.
CHARISMA MATCH ACTIVE ACTIVE W A ASA + Severe bleeding clopidogrel Fatal bleeding Primary intracranial bleeding Moderate/minor bleeding ASA Severe bleeding Fatal bleeding Primary intracranial bleeding Moderate bleeding
0.7% 0.1% 0.1% 0.8% 0.5% 0.1% 0.1% 0.5%
1.3% 0.3% 0.7% 2% n.a. n.a. n.a. n.a.
1.7% 0.2% 0.1% 13.5% n.a. n.a. n.a. n.a.
1.5% 0.3% 0.4% 3.5% 1.0% 0.2% 0.2% 1.4%
Shown is the annual risk for cerebral and non-cerebral bleedings in recently published stroke relevant studies which were investigating the dual AP therapy ASA and clopidogrel (for the CHARISMA and MATCH-study, annual bleeding risks were calculated from 30 and 18 months bleeding incidences, respectively). Note, these studies were designed as primary/secondary prevention studies, only the MATCHstudy investigated secondary prevention after ischemic stroke or TIA whereas in all other mentioned studies only approx. 10–15% of patients suffered from ischemic stroke/ TIA prior to randomization. Major bleedings are the sum of fatal bleeding (death of patient) and severe bleeding (patients survived but with major deterioration). n.a. means not applicable.
A. Hermann et al. / Journal of the Neurological Sciences 284 (2009) 155–157
Our study is limited by its retrospective design and the small number of patients and outcome events. However, our results support the need to specifically study the effect of different single and combined AP pretreatments on sICH and outcome in acute ischemic stroke thrombolysis. Such an analysis should be performed within a large prospective database like the SITS-MOST registry [5]. Acknowledgement The work was supported by the Deutsche Forschungsgemeinschaft through the DFG-Research Center for Regenerative Therapies Dresden (CRTD) to A.H. References [1] Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995, 333(24):1581–7. [2] Lansberg MG, Thijs VN, Bammer R, Kemp S, Wijman CA, Marks MP, et al. Risk factors of symptomatic intracerebral hemorrhage after tPA therapy for acute stroke. Stroke 2007;38(8):2275–8. [3] 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 (14):1679–85.
157
[4] 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(5):607–11. [5] Wahlgren N, Ahmed N, Eriksson N, Aichner F, Bluhmki E, Davalos 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 (12):3316–22. [6] Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, doubleblind, placebo-controlled trial. Lancet 2004;364(9431):331–7. [7] ACTIVE Investigators, Connolly SJ, Pogue J, Hart RG, Hohnloser SH, Pfeffer M, et al. Effect of Clopidogrel Added toAspirin in Patients with Atrial Fibrillation. N Engl J Med 2009;360(20):2127–9. [8] Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354(16):1706–17. [9] Connolly S, Pogue J, Hart R, Pfeffer M, Hohnloser S, Chrolavicius S, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006;367(9526):1903–12. [10] Usman MH, Notaro LA, Nagarakanti R, Brahin E, Dessain S, Gracely E, et al. Combination antiplatelet therapy for secondary stroke prevention: enhanced efficacy or double trouble? Am J Cardiol 2009;103(8):1107–12. [11] Pessin MS, Teal PA, Caplan LR. Hemorrhagic infarction: guilt by association? AJNR Am J Neuroradiol 1991;12(6):1123–6.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Combined anti-platelet therapy with aspirin and clopidogrel: Risk factor for thrombolysis-related intracerebral hemorrhage in acute ischemic stroke? Andreas Hermann a,b,1, Imanuel Dzialowski a,⁎,1, Roland Koch c, Georg Gahn d a
Department of Neurology, University of Technology Dresden, Fetscherstraβe 74, 01307, Dresden, Germany Center for Regenerative Therapies Dresden, Dresden, Germany Institute of Informatics and Biometrics, University of Technology Dresden, Dresden, Germany d Department of Neurology, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany b c
a r t i c l e
i n f o
Article history: Received 16 February 2009 Received in revised form 4 May 2009 Accepted 6 May 2009 Available online 26 May 2009 Keywords: Ischemic stroke Thrombolysis Antiplatelets Intracerebral hemorrhage
a b s t r a c t Background and purpose: To date, pre-treatment with anti-platelet agents does not constitute a contraindication for thrombolysis in acute ischemic stroke. We tested the hypothesis that combined pre-treatment with aspirin and clopidogrel is a risk factor for thrombolysis-related symptomatic intracerebral hemorrhage (sICH). Methods: We retrospectively studied patients with acute ischemic stroke receiving standard IV thrombolytic therapy with rt-PA in our institution. Exclusion criteria were thrombolysis initiated later than 3 h from symptom onset or with non-tPA-agents, no follow-up imaging was performed and data on prior medication was missing. We recorded clinical baseline variables including known risk factors for ICH. Our outcome measure was the incidence of ICH defined as parenchymal hematoma type 2 with ≥ 4 points deterioration on the National Institute of Health Stroke Scale score. We performed univariate analysis to determine risk factors for sICH. Results: We identified 102 patients receiving any thrombolysis of which 63 fulfilled the inclusion criteria. Mean age was 69 years, onset-to-treatment-time 138 min, 56% male, median NIHSS score was 10, and 3 patients received additional intra-arterial interventions. A total of 3 patients had received combined aspirin and clopidogrel treatment before thrombolysis. SICH occurred in 3/63 (4.7%) of patients. Out of these, 2 patients had received the combined anti-platelet treatment. In univariate analysis, only combined pretreatment with aspirin and clopidogrel treatment were associated with the occurrence of sICH. Conclusion: In our retrospective study, only pre-treatment with aspirin and clopidogrel was associated with thrombolysis-related intracerebral hemorrhage. This finding should be further validated in large prospective databases like the SITS-MOST registry. © 2009 Elsevier B.V. All rights reserved.
1. Introduction In acute ischemic stroke, symptomatic intracerebral hemorrhage (sICH) is the most feared complication after thrombolysis with recombinant tissue plasminogen activator (rt-PA), seen in approximately 5% of the treated patients, depending on the definition of sICH [1]. Several potential risk factors for sICH have been identified. Extent of hypoattenuation on pre-treatment CT, elevated serum glucose, history of diabetes, and symptom severity were independently associated with sICH after rt-PA in more than one study [2]. Data on the risk of pre-stroke treatment with antiplatelet agents (AP) are inconclusive. While being on aspirin (ASA) was not consistently found to be independently associated with sICH [2], pre-treatment with “other antiplatelet agents”, was an independent predictor of sICH ⁎ Corresponding author. Tel.: +49 351 458 18162; fax: +49 351 458 2060. E-mail address: [email protected] (I. Dzialowski). 1 A.H. and I.D. share 1st authorship since they equally contributed to the manuscript. 0022-510X/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2009.05.003
[3,4]. Very recently, multivariable analysis from the SITS-MOST database showed that ASA pre-treatment predicted sICH while “other AP agents” were associated with higher mortality at 3 months [5]. However, none of these studies systematically compared the risk of single non-ASA antiplatelet agents or AP combinations. From recent stroke prevention studies we have learned that combined AP therapy with ASA and clopidogrel carries a high annual risk (mean rate 1.7%) for major bleeding complications [6–10]. We thus studied the hypothesis that pre-treatment with clopidogrel and ASA is associated with an increased risk of sICH after thrombolysis for acute ischemic stroke. 2. Materials and methods We retrospectively studied patients with acute ischemic stroke receiving standard IV thrombolytic therapy with rt-PA in our institution from 01/2006–05/2007. Exclusion criteria were thrombolysis initiated later than 3 h from symptom onset or with non-tPA-agents, no follow-up
156
A. Hermann et al. / Journal of the Neurological Sciences 284 (2009) 155–157
imaging was performed and data on prior medication was missing. We recorded clinical baseline variables including known risk factors for sICH, onset-to-treatment-time (OTT), pre-hospital AP medication, admission National Institute of Health stroke Scale (NIHSS) score, blood pressure, serum glucose level, platelet count, INR, pTT and any additional intra-arterial intervention following IV thrombolysis. We rated the extent of hypoattenuation at cranial non-contrast CT (NCCT) on admission as absent, b or N than 1/3 of the middle cerebral artery territory using the Neuroradiology report. We assessed all 12–36 h follow-up NCCT for hemorrhagic transformation using criteria by Pessin et al [11]: hemorrhagic infarction and parenchymal hematoma (PH) types 1 and 2. Our single outcome measure was incidence of sICH according to the SITS-MOST criteria defined as PH-2 with deterioration ≥4 points on the NIHSS score [5]. We used standard descriptive statistics and performed a univariate analysis to determine risk factors for sICH. Distribution among groups were tested with the Chi-square test and Fisher`s exact test as appropriate. Level of significance was set at b0.05. 3. Results We identified 102 patients receiving any IV thrombolysis of which 63 fulfilled the inclusion criteria. Reasons for exclusion were OTT N 180 min in 24 patients (10 basilar artery occlusions, 4 receiving bridging IV thrombolysis and intra-arterial thrombolysis, 10 miscellaneous), no follow-up NCCT in 2, thrombolysis with abciximab in 2, and unavailable data in 11 patients. Mean age was 69 ± 11 years, OTT 138± 34, 56% male, median NIHSS score was 10 (range 1–30), 3 patients received additional Table 1 Univariate analysis of clinical, laboratory and imaging variables.
Age (years) b 50 50–59 60–69 70–79 ≥ 80 Gender (m) Arterial hypertension Coronary artery disease Smoking Diabetes Atrial fibrillation Any antiplatelet therapy ASA ASA/dipyridamol Clopidogrel ASA + clopidogrel NIHSS score on admission b 10 10–19 ≥ 20 Systolic BP pre tPA b 140 mmHg ≥ 140 mmHg Serum-glucose on admission b 7 mmol/l ≥ 7 mmol/l Platelet count b 100 G/l ≥ 100 G/l Elevated pTT (N 43 s) Elevated INR (N 1,4) Hypodensity at CT No b 33% MCA N 33% MCA Additional intra-arterial intervention
n (%)
SICH rate n (%)
p
4 (7) 7 (12) 21 (35) 16 (29) 12 (12) 35/63 (55) 45/63 (71) 16/63 (25) 8/61 (13) 21/63 (33) 16/63 (25) 36/63 (57) 26/63 (41) 1/63 (2) 6/63 (10) 3/63 (5)
– – 1/21 (5) 2/16 (11) – 3/35 (8) 2/45 (4) 3/16 (19) 1/8 (13) 2/21 (10) 1/16 (6) 3/36 (8) 0/26 0/1 1/6 (17) 2/3 (66)
0.16 0.16 1.0 0.01 0.34 0.21 0.74 0.20 1.0 1.0 0.10 0.005
26/63 (41) 35/63 (56) 2/63 (3)
2/26 (8) 1/35 (3) 0/2
12/57 (21) 45/57 (79)
2/12 (17) 1/45 (2)
0.1
15/63 (24) 48/63 (76)
1/15 (7) 2/482 (4)
0.69
1/62 58/62 0/62 0/63
(2) (94) (0) (0)
0/1 3/58 (5) – –
1.0 – –
37/62 22/62 3/62 3/63
(60) (35) (5) (5)
2/37 (5) 0/22 1/3 (33) 0/3 (0)
1.0 0.54 0.14 1.0
Table 2 Patient characteristics with symptomatic ICH. Patient
Age
Hx CAD
ASA
Clopidogrel
NIHSS score
BP pre tPA
OTT (min)
Early CT changes
1 2 3
76 70 69
+ + +
− + +
+ + +
8 7 14
180/94 120/70 130/80
180 120 180
No No N 33%
NIHSS, National Institute of health Stroke Scale, CAD, coronary artery disease, ASA, acetylic salicylic acid, BP, blood pressure, OTT, onset to treat time.
intra-arterial intervention (Table 1). Patients pre-treated with AP agents were older (71 ± 11 vs. 67 ± 11 years), and more frequently had a history of arterial hypertension (81% vs. 69%), atrial fibrillation (33% vs. 15%), diabetes mellitus (47% vs. 15%) and coronary artery disease (42% vs. 4%). A total of 29 patients had received ASA (standard dose 100 mg/day) and 9 patients had received clopidogrel (75 mg/day) before thrombolysis, respectively (Table 1). The combination of ASA and clopidogrel was present in 3 patients. SICH occurred in 3/63 (4.7%) of patients. Out of these, 2 patients had received the combined anti-platelet treatment, 1 was on clopidogrel alone (Table 2). In univariate analysis, only the pretreatment with combined ASA and clopidogrel was associated with the occurrence of sICH. 4. Discussion In our single-centre retrospective study, combined pre-treatment with ASA and clopidogrel was the only factor associated with sICH after standard thrombolysis with rt-PA. Pre-treatment with ASA as well as with “antiplatelet agents” has been identified as a potential risk factor for thrombolysis-related sICH [4]. However, to our knowledge, an increased risk for thrombolysis-related sICH after pretreatment with ASA and clopidogrel has not been previously reported. Of note, combined AP therapy with ASA and clopidogrel carries a significant increase in major bleeding complications when used in stroke prevention (Table 3) [6–10]. So far, combined ASA and clopidogrel treatment is neither widely recommended for primary nor for secondary prevention of stroke. Patients currently receiving this combined AP regimen usually have a history of coronary heart disease and recent coronary angioplasty or recent carotid angioplasty and stenting. However, this may change as indicated in the recent Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE-A), possibly leading to a much broader indication for this adjunction AP therapy [7]. Our results suggest that these patients might be at risk from thrombolysis in case they suffer an acute ischemic stroke.
Table 3 Annual bleeding risk with combined anti-platelet therapy using ASA + clopidogrel. 0.61
NIHSS, National Institute of health Stroke Scale; MCA, middle cerebral artery, ASA, acetylic salicylic acid, distribution among groups were tested using Chi-square test and Fisher`s exact test as appropriate.
CHARISMA MATCH ACTIVE ACTIVE W A ASA + Severe bleeding clopidogrel Fatal bleeding Primary intracranial bleeding Moderate/minor bleeding ASA Severe bleeding Fatal bleeding Primary intracranial bleeding Moderate bleeding
0.7% 0.1% 0.1% 0.8% 0.5% 0.1% 0.1% 0.5%
1.3% 0.3% 0.7% 2% n.a. n.a. n.a. n.a.
1.7% 0.2% 0.1% 13.5% n.a. n.a. n.a. n.a.
1.5% 0.3% 0.4% 3.5% 1.0% 0.2% 0.2% 1.4%
Shown is the annual risk for cerebral and non-cerebral bleedings in recently published stroke relevant studies which were investigating the dual AP therapy ASA and clopidogrel (for the CHARISMA and MATCH-study, annual bleeding risks were calculated from 30 and 18 months bleeding incidences, respectively). Note, these studies were designed as primary/secondary prevention studies, only the MATCHstudy investigated secondary prevention after ischemic stroke or TIA whereas in all other mentioned studies only approx. 10–15% of patients suffered from ischemic stroke/ TIA prior to randomization. Major bleedings are the sum of fatal bleeding (death of patient) and severe bleeding (patients survived but with major deterioration). n.a. means not applicable.
A. Hermann et al. / Journal of the Neurological Sciences 284 (2009) 155–157
Our study is limited by its retrospective design and the small number of patients and outcome events. However, our results support the need to specifically study the effect of different single and combined AP pretreatments on sICH and outcome in acute ischemic stroke thrombolysis. Such an analysis should be performed within a large prospective database like the SITS-MOST registry [5]. Acknowledgement The work was supported by the Deutsche Forschungsgemeinschaft through the DFG-Research Center for Regenerative Therapies Dresden (CRTD) to A.H. References [1] Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995, 333(24):1581–7. [2] Lansberg MG, Thijs VN, Bammer R, Kemp S, Wijman CA, Marks MP, et al. Risk factors of symptomatic intracerebral hemorrhage after tPA therapy for acute stroke. Stroke 2007;38(8):2275–8. [3] 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 (14):1679–85.
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[4] 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(5):607–11. [5] Wahlgren N, Ahmed N, Eriksson N, Aichner F, Bluhmki E, Davalos 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 (12):3316–22. [6] Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, doubleblind, placebo-controlled trial. Lancet 2004;364(9431):331–7. [7] ACTIVE Investigators, Connolly SJ, Pogue J, Hart RG, Hohnloser SH, Pfeffer M, et al. Effect of Clopidogrel Added toAspirin in Patients with Atrial Fibrillation. N Engl J Med 2009;360(20):2127–9. [8] Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354(16):1706–17. [9] Connolly S, Pogue J, Hart R, Pfeffer M, Hohnloser S, Chrolavicius S, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006;367(9526):1903–12. [10] Usman MH, Notaro LA, Nagarakanti R, Brahin E, Dessain S, Gracely E, et al. Combination antiplatelet therapy for secondary stroke prevention: enhanced efficacy or double trouble? Am J Cardiol 2009;103(8):1107–12. [11] Pessin MS, Teal PA, Caplan LR. Hemorrhagic infarction: guilt by association? AJNR Am J Neuroradiol 1991;12(6):1123–6.