Journal of Clinical Neuroscience 22 (2015) 83–86
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Clopidogrel plus aspirin versus aspirin alone for preventing early neurological deterioration in patients with acute ischemic stroke Fan He 1, Cheng Xia 1, Jing-Hua Zhang, Xiao-Qiu Li, Zhong-He Zhou, Feng-Peng Li, Wei Li, Yan Lv, Hui-Sheng Chen ⇑ Department of Neurology, General Hospital of Shen-Yang Military Region, 83 Wen Hua Road, Shen He District, Shen Yang 110840, PR China
a r t i c l e
i n f o
Article history: Received 4 July 2013 Accepted 25 May 2014
Keywords: Acute ischemic stroke Antiplatelet Deterioration of stroke
a b s t r a c t Recent studies have suggested that combination antiplatelet therapy may be superior to monotherapy in the treatment of acute stroke. However, additional prospective studies are needed to confirm this finding. The present trial compared the efficacy and safety of clopidogrel plus aspirin versus aspirin alone in the treatment of non-cardioembolic ischemic stroke within 72 hours of onset. Six hundred and ninety patients aged P40 years with minor stroke or transient ischemic attack (TIA) were identified for enrollment. Experienced physicians determined baseline National Institutes of Health Stroke Scale scores at the time of admission. All patients were randomly allocated (1:1) to receive aspirin alone (300 mg/day) or clopidogrel (300 mg for the first day, 75 mg/day thereafter) plus aspirin (100 mg/day). The main endpoints were neurological deterioration, recurrent stroke, and development of stroke in patients with TIA within 14 days of admission. After 43 patients were excluded, 321 patients in the dual therapy group and 326 patients in the monotherapy group completed the treatment. Baseline characteristics were similar between groups. During the 2 week period, stroke deterioration occurred in nine patients in the dual therapy group and 19 patients in the monotherapy group. Stroke occurred after TIA in one patient in the dual therapy group and three patients in the monotherapy group. Similar numbers of adverse events occurred in both groups. This study showed that early dual antiplatelet treatment reduced early neurological deterioration in patients with acute ischemic stroke, compared with antiplatelet monotherapy. These results imply that dual antiplatelet therapy is superior to monotherapy in the early treatment of acute ischemic stroke. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction In the acute stages of transient ischemic attack (TIA) and minor ischemic stroke, patients are at high risk of an unstable clinical course, including recurrence or deterioration of stroke. Most of these unfavorable events occur in the initial 48–72 hours after symptom onset and have deleterious effects on the recovery of neurological functions [1–4]. Thrombolysis has been demonstrated to be an effective method of treating acute ischemic stroke, but it cannot be used in most patients due to strict indications, such as the limited time window after the onset of stroke. Thus, guidelines recommend early antiplatelet treatment for most patients with acute ischemic stroke [5,6]. Two large trials established the efficacy
⇑ Corresponding author. Tel.: +86 24 2889 7511; fax: +86 24 2885 6448. 1
E-mail address: [email protected] (H.-S. Chen). These authors have contributed equally to the manuscript.
http://dx.doi.org/10.1016/j.jocn.2014.05.038 0967-5868/Ó 2014 Elsevier Ltd. All rights reserved.
of aspirin in the treatment of acute ischemic stroke [7,8], and guidelines currently recommend the use of aspirin in the acute stage [5,6]. A recent study comparing the efficacy and safety of cilostazol to aspirin found that cilostazol use was feasible for the treatment of acute ischemic stroke [9]. A recent review and meta-analysis showed that dual antiplatelet therapy appears to safely and effectively reduce stroke recurrence and combined vascular events in patients with acute ischemic stroke or TIA, compared with monotherapy [10]. In addition, two recent studies showed trends towards reduced ischemic stroke recurrence with dual antiplatelet therapy in the acute stage compared with monotherapy [11,12]. However, additional prospective studies are needed to further test this apparent superiority of combination antiplatelet therapy over antiplatelet monotherapy in the treatment of acute stroke. The present study aimed to assess whether combination therapy with clopidogrel and aspirin reduced the recurrence or deterioration of stroke more effectively than aspirin monotherapy in northern Han Chinese patients.
84
F. He et al. / Journal of Clinical Neuroscience 22 (2015) 83–86
2. Methods
atorvastatin-specific safety outcomes were mainly muscle pain and myositis.
2.1. Participants 2.3. Statistical analysis Between September 2010 and October 2012, 690 patients aged P40 years with minor stroke or TIA (672 hours of onset) were identified as eligible for enrollment in this study. Minor stroke was defined by a National Institutes of Health Stroke Scale (NIHSS) score 67 at the time of randomization. TIA was defined as the complete recovery of neurological deficit within 1 hour of onset. The exclusion criteria were (1) cardioembolic stroke, (2) anticoagulation therapy before stroke onset or definite indication for anticoagulation, (3) current peptic ulceration or history of systemic bleeding, (4) platelet count 8. Our institutional ethics committee approved the study protocol and all patients or family members provided written informed consent. 2.2. Procedures The patients were randomly allocated (1:1) to receive aspirin alone (300 mg/day) or clopidogrel (300 mg for the first day, 75 mg/day thereafter) plus aspirin (100 mg/day). Randomization was performed by blindly choosing a table tennis ball from a box with the number 1 or 2 written on it to represent dual or single antiplatelet therapy. In addition to antiplatelet treatment, routine management of arterial blood pressure and blood glucose and lipid levels (atorvastatin, 40 mg/day) was conducted according to published guidelines [5,6]. At baseline, all patients underwent electrocardiography, chest radiographs, and brain MRI and magnetic resonance angiography (MRA). Demographic characteristics and vascular risk factors were also collected. Blood samples were collected at baseline for biochemical and hematological measurements, to identify patients with clear contraindications to the trial medications, and to provide baseline data to monitor the safety profiles of the medications over the course of the trial. Acute ischemic stroke or TIA was confirmed by clinical symptoms and brain MRI (including diffusion-weighted imaging [DWI]) and MRA findings. Experienced physicians determined baseline NIHSS scores at the time of admission. Drugs were administered to enrolled patients immediately after neurological evaluation. The NIHSS was administered twice each day (morning and evening) until the 14th day after admission. The main study endpoints were neurological deterioration, recurrent stroke, and development of stroke in patients with TIA within 14 days after admission. Neurological deterioration, including recurrent stroke, was defined as an increase of P2 points in NIHSS score. Stroke recurrence was defined as additional neurological deficit and corresponding positive lesions on DWI. The development of stroke in patients with TIA was defined as continued neurological deficit and corresponding positive lesions on DWI. The causes of ischemic stroke were determined using the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification [13]. All patients with the main endpoints underwent brain CT scan to exclude intracranial hemorrhage. Intracranial or extracranial hemorrhagic events were monitored due to safety concerns. Other safety outcomes were those known to be associated with the trial medications. Clopidogrel-specific safety outcomes were the incidence of thrombotic thrombocytopenic purpura and granulocytopenia, and
Differences in baseline factors (sex, age, vascular risk factors, stroke subtypes) between groups were compared using the v2 test. Changes in NIHSS scores were examined using analysis of covariance, adjusted for baseline scores. 3. Results Between September 2010 and October 2012, 690 patients were randomly assigned to the two groups. Forty-three of these patients were subsequently excluded from the study because they refused participation, had an adverse event, or met at least one exclusion criterion (Fig. 1). A total of 321 patients in the dual therapy group and 326 patients in the monotherapy group completed the treatment. Table 1 shows the patients’ baseline demographic characteristics. Baseline characteristics were similar between the groups. Mean time to randomization was 22.35 hours after stroke or TIA onset in the dual therapy group and 24.59 hours after onset in the monotherapy group. According to the TOAST classification system, the principal causes of stroke were small vessel occlusion (dual therapy, 45.79%; monotherapy, 46.63%) and large artery atherosclerosis (dual therapy, 31.46%; monotherapy, 31.9%). The most prevalent risk factors in both groups were hypertension, smoking, and diabetes mellitus. Nearly one-third of patients had experienced previous ischemic stroke or TIA (dual therapy, 32.4%; monotherapy, 35.89%). During the 2 week treatment period, deterioration of stroke occurred in nine patients in the dual therapy group and 19 patients in the monotherapy group (Table 2). Stroke occurred after TIA in one patient in the dual therapy group and three patients in the monotherapy group. NIHSS scores on admission (not including patients with TIA) were similar in the two groups (Table 3). Both antiplatelet therapeutic approaches produced an obvious decrease in NIHSS scores after 2 weeks of treatment (p < 0.001, Table 3). Excluding patients with stroke deterioration, mean NIHSS scores at 2 weeks after admission were 0.84 and 0.98 in the dual therapy and monotherapy groups, respectively, representing decreases of 77.24% and 70.48%, respectively. Similar numbers of adverse events occurred in the two groups (Table 4). No severe intracranial hemorrhage or severe systemic bleeding event occurred. Two patients in the dual therapy group and one in the monotherapy group showed minor hemorrhagic transformation (presenting as slight capillary hemorrhage). Six patients in the dual therapy group and two patients in the monotherapy group had minor systemic bleeding events (Table 4). 4. Discussion In this study, we compared the efficacy of aspirin plus clopidogrel versus aspirin alone in preventing or reducing the recurrence or deterioration of acute ischemic stroke. The results showed that early dual antiplatelet treatment reduced early neurological deterioration of acute ischemic stroke compared with antiplatelet monotherapy. These results imply that dual antiplatelet therapy is superior to monotherapy in the early treatment of acute ischemic stroke. Antiplatelet treatment is an important therapeutic strategy for acute ischemic stroke because thrombolysis cannot be used widely due its strict indications. Many studies of antiplatelet therapy have focused on its role in the secondary prevention of ischemic stroke
85
F. He et al. / Journal of Clinical Neuroscience 22 (2015) 83–86
Fig. 1. Profile of the clinical trial.
Table 1 Patient demographic and baseline characteristics Aspirin + clopidogrel (n = 321)
Aspirin (n = 326)
p value
62.92 ± 8.96
61.52 ± 10.21
0.655
183 138
185 141
0.947
22 (6.85) 299 (93.15) 22.35 ± 0.67
16 (4.91) 310 (95.09) 24.59 ± 0.76
0.239 0.415
Risk factors and medical history Smoking Alcohol consumption Hypertension Diabetes mellitus Heart disease Ischemic stroke or TIA
161 (50.16) 121 (37.69) 213 (66.36) 138 (42.99) 88 (27.41) 104 (32.40)
165 (50.61) 113 (34.66) 224 (68.71) 128 (39.26) 92 (28.22) 117 (35.89)
0.907 0.422 0.522 0.335 0.819 0.349
Blood examination findings on admission LDL cholesterol, mmol/L Total cholesterol, mmol/L Triglycerides, mmol/L Fibrinogen, g/L
2.47 ± 0.21 4.59 ± 0.26 1.81 ± 0.31 3.51 ± 0.16
2.42 ± 0.26 4.56 ± 0.24 1.82 ± 0.29 3.49 ± 0.12
0.862 0.817 0.923 0.889
TOAST classification Large artery atherosclerosis Small vessel occlusion Other determined cause Undetermined cause
101 (31.46) 147 (45.79) 8 (2.49) 65 (20.25)
104 (31.9) 152 (46.63) 9 (2.76) 61 (18.71)
0.905 0.797 0.831 0.816
Age, years Sex, n Male Female Qualifying events TIA Ischemic stroke Mean time from onset to randomization, hours
LDL = low-density lipoprotein, TIA = transient ischemic attack, TOAST = Trial of Org 10172 in Acute Stroke Treatment. Data are presented as number (%) or mean ± standard deviation.
Table 2 Deterioration of stroke or development of stroke from transient ischemic attack
Deterioration of stroke From TIA to stroke
Aspirin + clopidogrel
Aspirin
9 1
19 3
TIA = transient ischemic attack.
Table 3 Changes in National Institutes of Health Stroke Scale scores
NIHSS score on admission NIHSS score on day 14 Decrease
Aspirin + clopidogrel
Aspirin
p value
3.69 ± 0.85 0.84 ± 0.23 77.24%
3.32 ± 1.13 0.98 ± 0.27 70.48%
0.439 0.519
NIHSS = National Institutes of Health Stroke Scale. Data are presented as mean ± standard deviation.
[14–17], but few studies have investigated the efficacy and safety of early antiplatelet administration in the treatment of acute ischemic stroke. Two important clinical trials have demonstrated the efficacy of aspirin in the treatment of acute ischemic stroke [7,8],
and several subsequent studies sought to identify a better antiplatelet strategy for this condition. The FASTER trial compared the use of aspirin plus clopidogrel with aspirin monotherapy (with
86
F. He et al. / Journal of Clinical Neuroscience 22 (2015) 83–86
Table 4 Number of adverse events within 2 weeks of stroke onset
Conflicts of Interest/Disclosures
Aspirin + clopidogrel
Aspirin
Intracranial hemorrhage or hemorrhagic transformation Mild Moderate Severe Other severe bleeding event Other minor bleeding event
2 0 0 0 6
1 0 0 0 2
All adverse events Mild Moderate Severe
2 0 0
3 0 0
and without simvastatin) in patients with TIA or minor stroke within 24 hours of symptom onset [11], and the EARLY trial compared the safety and efficacy of aspirin plus dipyridamole initiated within 24 hours of stroke or TIA with the same therapy initiated after 7 days of aspirin monotherapy [12]. Furthermore, a transcranial Doppler embolic signal study provided supporting evidence for the superiority of dual antiplatelet therapy to monotherapy [18]. In the acute stage of ischemic stroke, dual antiplatelet therapy reduced the amounts of microembolic signals in patients with predominantly intracranial symptomatic stenosis, compared with antiplatelet monotherapy. A recent review and meta-analysis [10], as well as the results of the present study, also support the superiority of dual antiplatelet therapy to a monotherapeutic strategy in the early treatment of acute stroke. On the other hand, these data suggest that the number, rather than type, of antiplatelet drugs may play a key role in reducing stroke recurrence or deterioration. This proposal seems reasonable because different antiplatelet combinations have synergistic effects due to differences in antiplatelet mechanisms. When considering the use of more intensive antiplatelet therapy, the balance between reducing stroke recurrence and increasing the risk of major bleeding events must be taken into account. In the present study, few patients in both groups developed bleeding events, and no other obvious side effects occurred. The incidence of bleeding events was lower than reported in a previous study [11], perhaps due to differences in the duration of antiplatelet therapy (2 weeks in the present study compared with 90 days in the previous study). The present study also has many limitations, such as the small sample size, open-label design, and short observation period (2 weeks). Thus, randomized, double-blinded clinical trials with larger samples patient numbers are needed. Research focusing on the identification of the safest and most effective combination of antiplatelet drugs for the treatment of acute ischemic stroke is also necessary. In conclusion, the present data and those from previous studies confirm the advantages of dual antiplatelet therapy over monotherapy to reduce the recurrence or deterioration of ischemic stroke in the acute phase. The demonstrated safety and efficacy of this treatment may increase clinicians’ confidence in choosing a dual antiplatelet strategy to treat acute ischemic stroke.
The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgments The work was supported by grants to Prof. Hui-Sheng Chen from the Science and Technology Project Plan of Liao Ning Province (No. 2011225021) and the Key Project of the 12th National FiveYear Research Program of China (No. 2012ZX09303016-002). References [1] Johnston SC, Gress DR, Browner WS, et al. Short-term prognosis after emergency department diagnosis of TIA. JAMA 2000;284:2901–6. [2] Lovett JK, Dennis MS, Sandercock PA, et al. Very early risk of stroke after a first transient ischemic attack. Stroke 2003;34:e138–40. [3] Hill MD, Yiannakoulias N, Jeerakathil T, et al. The high risk of stroke immediately after transient ischemic attack: a population-based study. Neurology 2004;62:2015–20. [4] Coull AJ, Lovett JK, Rothwell PM. Population based study of early risk of stroke after transient ischaemic attack or minor stroke: implications for public education and organisation of services. BMJ 2004;328:326. [5] Adams RJ, Albers G, Alberts MJ, et al. Update to the AHA/ASA recommendations for the prevention of stroke in patients with stroke and transient ischemic attack. Stroke 2008;39:1647–52. [6] European Stroke Organisation (ESO); Executive Committee and the ESO Writing Committee. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis 2008;25:457–507. [7] International Stroke Trial Collaborative Group. The international stroke trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19,435 patients with acute ischaemic stroke. Lancet 1997;349: 1569–81. [8] CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. Lancet 1997;349:1641–9. [9] Lee YS, Bae HJ, Kang DW, et al. Cilostazol in Acute Ischemic Stroke Treatment (CAIST Trial): a randomized double-blind non-inferiority trial. Cerebrovasc Dis 2011;32:65–71. [10] Geeganage CM, Diener HC, Algra A, et al. Dual or mono antiplatelet therapy for patients with acute ischemic stroke or transient ischemic attack: systematic review and meta-analysis of randomized controlled trials. Stroke 2012;43: 1058–66. [11] Kennedy J, Hill MD, Ryckborst KJ, et al. Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial. Lancet Neurol 2007;6:961–9. [12] Dengler R, Diener HC, Schwartz A, et al. Early treatment with aspirin plus extended-release dipyridamole for transient ischaemic attack or ischaemic stroke within 24 h of symptom onset (EARLY trial): a randomised, open-label, blinded-endpoint trial. Lancet Neurol 2010;9:159–66. [13] Adams HP Jr, Bendixen BH, Kappelle LJ, 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. [14] Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, doubleblind, placebocontrolled trial. Lancet 2004;364:331–7. [15] Sacco RL, Diener HC, Yusuf S, et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med 2008;359:1238–51. [16] SPS3 Investigators, Benavente OR, Hart RG, et al. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med 2012;367:817–25. [17] Tanne D. Stroke: secondary stroke prevention–personalized antiplatelet therapy. Nat Rev Neurol 2012;8:536–7. [18] Wong KS, Chen C, Fu J, et al. Clopidogrel plus aspirin versus aspirin alone for reducing embolisation inpatients with acute symptomatic cerebral or carotid artery stenosis (CLAIR study): randomised, open-label, blinded-endpoint trial. Lancet Neurol 2010;9:489–97.
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Clopidogrel plus aspirin versus aspirin alone for preventing early neurological deterioration in patients with acute ischemic stroke Fan He 1, Cheng Xia 1, Jing-Hua Zhang, Xiao-Qiu Li, Zhong-He Zhou, Feng-Peng Li, Wei Li, Yan Lv, Hui-Sheng Chen ⇑ Department of Neurology, General Hospital of Shen-Yang Military Region, 83 Wen Hua Road, Shen He District, Shen Yang 110840, PR China
a r t i c l e
i n f o
Article history: Received 4 July 2013 Accepted 25 May 2014
Keywords: Acute ischemic stroke Antiplatelet Deterioration of stroke
a b s t r a c t Recent studies have suggested that combination antiplatelet therapy may be superior to monotherapy in the treatment of acute stroke. However, additional prospective studies are needed to confirm this finding. The present trial compared the efficacy and safety of clopidogrel plus aspirin versus aspirin alone in the treatment of non-cardioembolic ischemic stroke within 72 hours of onset. Six hundred and ninety patients aged P40 years with minor stroke or transient ischemic attack (TIA) were identified for enrollment. Experienced physicians determined baseline National Institutes of Health Stroke Scale scores at the time of admission. All patients were randomly allocated (1:1) to receive aspirin alone (300 mg/day) or clopidogrel (300 mg for the first day, 75 mg/day thereafter) plus aspirin (100 mg/day). The main endpoints were neurological deterioration, recurrent stroke, and development of stroke in patients with TIA within 14 days of admission. After 43 patients were excluded, 321 patients in the dual therapy group and 326 patients in the monotherapy group completed the treatment. Baseline characteristics were similar between groups. During the 2 week period, stroke deterioration occurred in nine patients in the dual therapy group and 19 patients in the monotherapy group. Stroke occurred after TIA in one patient in the dual therapy group and three patients in the monotherapy group. Similar numbers of adverse events occurred in both groups. This study showed that early dual antiplatelet treatment reduced early neurological deterioration in patients with acute ischemic stroke, compared with antiplatelet monotherapy. These results imply that dual antiplatelet therapy is superior to monotherapy in the early treatment of acute ischemic stroke. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction In the acute stages of transient ischemic attack (TIA) and minor ischemic stroke, patients are at high risk of an unstable clinical course, including recurrence or deterioration of stroke. Most of these unfavorable events occur in the initial 48–72 hours after symptom onset and have deleterious effects on the recovery of neurological functions [1–4]. Thrombolysis has been demonstrated to be an effective method of treating acute ischemic stroke, but it cannot be used in most patients due to strict indications, such as the limited time window after the onset of stroke. Thus, guidelines recommend early antiplatelet treatment for most patients with acute ischemic stroke [5,6]. Two large trials established the efficacy
⇑ Corresponding author. Tel.: +86 24 2889 7511; fax: +86 24 2885 6448. 1
E-mail address: [email protected] (H.-S. Chen). These authors have contributed equally to the manuscript.
http://dx.doi.org/10.1016/j.jocn.2014.05.038 0967-5868/Ó 2014 Elsevier Ltd. All rights reserved.
of aspirin in the treatment of acute ischemic stroke [7,8], and guidelines currently recommend the use of aspirin in the acute stage [5,6]. A recent study comparing the efficacy and safety of cilostazol to aspirin found that cilostazol use was feasible for the treatment of acute ischemic stroke [9]. A recent review and meta-analysis showed that dual antiplatelet therapy appears to safely and effectively reduce stroke recurrence and combined vascular events in patients with acute ischemic stroke or TIA, compared with monotherapy [10]. In addition, two recent studies showed trends towards reduced ischemic stroke recurrence with dual antiplatelet therapy in the acute stage compared with monotherapy [11,12]. However, additional prospective studies are needed to further test this apparent superiority of combination antiplatelet therapy over antiplatelet monotherapy in the treatment of acute stroke. The present study aimed to assess whether combination therapy with clopidogrel and aspirin reduced the recurrence or deterioration of stroke more effectively than aspirin monotherapy in northern Han Chinese patients.
84
F. He et al. / Journal of Clinical Neuroscience 22 (2015) 83–86
2. Methods
atorvastatin-specific safety outcomes were mainly muscle pain and myositis.
2.1. Participants 2.3. Statistical analysis Between September 2010 and October 2012, 690 patients aged P40 years with minor stroke or TIA (672 hours of onset) were identified as eligible for enrollment in this study. Minor stroke was defined by a National Institutes of Health Stroke Scale (NIHSS) score 67 at the time of randomization. TIA was defined as the complete recovery of neurological deficit within 1 hour of onset. The exclusion criteria were (1) cardioembolic stroke, (2) anticoagulation therapy before stroke onset or definite indication for anticoagulation, (3) current peptic ulceration or history of systemic bleeding, (4) platelet count 8. Our institutional ethics committee approved the study protocol and all patients or family members provided written informed consent. 2.2. Procedures The patients were randomly allocated (1:1) to receive aspirin alone (300 mg/day) or clopidogrel (300 mg for the first day, 75 mg/day thereafter) plus aspirin (100 mg/day). Randomization was performed by blindly choosing a table tennis ball from a box with the number 1 or 2 written on it to represent dual or single antiplatelet therapy. In addition to antiplatelet treatment, routine management of arterial blood pressure and blood glucose and lipid levels (atorvastatin, 40 mg/day) was conducted according to published guidelines [5,6]. At baseline, all patients underwent electrocardiography, chest radiographs, and brain MRI and magnetic resonance angiography (MRA). Demographic characteristics and vascular risk factors were also collected. Blood samples were collected at baseline for biochemical and hematological measurements, to identify patients with clear contraindications to the trial medications, and to provide baseline data to monitor the safety profiles of the medications over the course of the trial. Acute ischemic stroke or TIA was confirmed by clinical symptoms and brain MRI (including diffusion-weighted imaging [DWI]) and MRA findings. Experienced physicians determined baseline NIHSS scores at the time of admission. Drugs were administered to enrolled patients immediately after neurological evaluation. The NIHSS was administered twice each day (morning and evening) until the 14th day after admission. The main study endpoints were neurological deterioration, recurrent stroke, and development of stroke in patients with TIA within 14 days after admission. Neurological deterioration, including recurrent stroke, was defined as an increase of P2 points in NIHSS score. Stroke recurrence was defined as additional neurological deficit and corresponding positive lesions on DWI. The development of stroke in patients with TIA was defined as continued neurological deficit and corresponding positive lesions on DWI. The causes of ischemic stroke were determined using the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification [13]. All patients with the main endpoints underwent brain CT scan to exclude intracranial hemorrhage. Intracranial or extracranial hemorrhagic events were monitored due to safety concerns. Other safety outcomes were those known to be associated with the trial medications. Clopidogrel-specific safety outcomes were the incidence of thrombotic thrombocytopenic purpura and granulocytopenia, and
Differences in baseline factors (sex, age, vascular risk factors, stroke subtypes) between groups were compared using the v2 test. Changes in NIHSS scores were examined using analysis of covariance, adjusted for baseline scores. 3. Results Between September 2010 and October 2012, 690 patients were randomly assigned to the two groups. Forty-three of these patients were subsequently excluded from the study because they refused participation, had an adverse event, or met at least one exclusion criterion (Fig. 1). A total of 321 patients in the dual therapy group and 326 patients in the monotherapy group completed the treatment. Table 1 shows the patients’ baseline demographic characteristics. Baseline characteristics were similar between the groups. Mean time to randomization was 22.35 hours after stroke or TIA onset in the dual therapy group and 24.59 hours after onset in the monotherapy group. According to the TOAST classification system, the principal causes of stroke were small vessel occlusion (dual therapy, 45.79%; monotherapy, 46.63%) and large artery atherosclerosis (dual therapy, 31.46%; monotherapy, 31.9%). The most prevalent risk factors in both groups were hypertension, smoking, and diabetes mellitus. Nearly one-third of patients had experienced previous ischemic stroke or TIA (dual therapy, 32.4%; monotherapy, 35.89%). During the 2 week treatment period, deterioration of stroke occurred in nine patients in the dual therapy group and 19 patients in the monotherapy group (Table 2). Stroke occurred after TIA in one patient in the dual therapy group and three patients in the monotherapy group. NIHSS scores on admission (not including patients with TIA) were similar in the two groups (Table 3). Both antiplatelet therapeutic approaches produced an obvious decrease in NIHSS scores after 2 weeks of treatment (p < 0.001, Table 3). Excluding patients with stroke deterioration, mean NIHSS scores at 2 weeks after admission were 0.84 and 0.98 in the dual therapy and monotherapy groups, respectively, representing decreases of 77.24% and 70.48%, respectively. Similar numbers of adverse events occurred in the two groups (Table 4). No severe intracranial hemorrhage or severe systemic bleeding event occurred. Two patients in the dual therapy group and one in the monotherapy group showed minor hemorrhagic transformation (presenting as slight capillary hemorrhage). Six patients in the dual therapy group and two patients in the monotherapy group had minor systemic bleeding events (Table 4). 4. Discussion In this study, we compared the efficacy of aspirin plus clopidogrel versus aspirin alone in preventing or reducing the recurrence or deterioration of acute ischemic stroke. The results showed that early dual antiplatelet treatment reduced early neurological deterioration of acute ischemic stroke compared with antiplatelet monotherapy. These results imply that dual antiplatelet therapy is superior to monotherapy in the early treatment of acute ischemic stroke. Antiplatelet treatment is an important therapeutic strategy for acute ischemic stroke because thrombolysis cannot be used widely due its strict indications. Many studies of antiplatelet therapy have focused on its role in the secondary prevention of ischemic stroke
85
F. He et al. / Journal of Clinical Neuroscience 22 (2015) 83–86
Fig. 1. Profile of the clinical trial.
Table 1 Patient demographic and baseline characteristics Aspirin + clopidogrel (n = 321)
Aspirin (n = 326)
p value
62.92 ± 8.96
61.52 ± 10.21
0.655
183 138
185 141
0.947
22 (6.85) 299 (93.15) 22.35 ± 0.67
16 (4.91) 310 (95.09) 24.59 ± 0.76
0.239 0.415
Risk factors and medical history Smoking Alcohol consumption Hypertension Diabetes mellitus Heart disease Ischemic stroke or TIA
161 (50.16) 121 (37.69) 213 (66.36) 138 (42.99) 88 (27.41) 104 (32.40)
165 (50.61) 113 (34.66) 224 (68.71) 128 (39.26) 92 (28.22) 117 (35.89)
0.907 0.422 0.522 0.335 0.819 0.349
Blood examination findings on admission LDL cholesterol, mmol/L Total cholesterol, mmol/L Triglycerides, mmol/L Fibrinogen, g/L
2.47 ± 0.21 4.59 ± 0.26 1.81 ± 0.31 3.51 ± 0.16
2.42 ± 0.26 4.56 ± 0.24 1.82 ± 0.29 3.49 ± 0.12
0.862 0.817 0.923 0.889
TOAST classification Large artery atherosclerosis Small vessel occlusion Other determined cause Undetermined cause
101 (31.46) 147 (45.79) 8 (2.49) 65 (20.25)
104 (31.9) 152 (46.63) 9 (2.76) 61 (18.71)
0.905 0.797 0.831 0.816
Age, years Sex, n Male Female Qualifying events TIA Ischemic stroke Mean time from onset to randomization, hours
LDL = low-density lipoprotein, TIA = transient ischemic attack, TOAST = Trial of Org 10172 in Acute Stroke Treatment. Data are presented as number (%) or mean ± standard deviation.
Table 2 Deterioration of stroke or development of stroke from transient ischemic attack
Deterioration of stroke From TIA to stroke
Aspirin + clopidogrel
Aspirin
9 1
19 3
TIA = transient ischemic attack.
Table 3 Changes in National Institutes of Health Stroke Scale scores
NIHSS score on admission NIHSS score on day 14 Decrease
Aspirin + clopidogrel
Aspirin
p value
3.69 ± 0.85 0.84 ± 0.23 77.24%
3.32 ± 1.13 0.98 ± 0.27 70.48%
0.439 0.519
NIHSS = National Institutes of Health Stroke Scale. Data are presented as mean ± standard deviation.
[14–17], but few studies have investigated the efficacy and safety of early antiplatelet administration in the treatment of acute ischemic stroke. Two important clinical trials have demonstrated the efficacy of aspirin in the treatment of acute ischemic stroke [7,8],
and several subsequent studies sought to identify a better antiplatelet strategy for this condition. The FASTER trial compared the use of aspirin plus clopidogrel with aspirin monotherapy (with
86
F. He et al. / Journal of Clinical Neuroscience 22 (2015) 83–86
Table 4 Number of adverse events within 2 weeks of stroke onset
Conflicts of Interest/Disclosures
Aspirin + clopidogrel
Aspirin
Intracranial hemorrhage or hemorrhagic transformation Mild Moderate Severe Other severe bleeding event Other minor bleeding event
2 0 0 0 6
1 0 0 0 2
All adverse events Mild Moderate Severe
2 0 0
3 0 0
and without simvastatin) in patients with TIA or minor stroke within 24 hours of symptom onset [11], and the EARLY trial compared the safety and efficacy of aspirin plus dipyridamole initiated within 24 hours of stroke or TIA with the same therapy initiated after 7 days of aspirin monotherapy [12]. Furthermore, a transcranial Doppler embolic signal study provided supporting evidence for the superiority of dual antiplatelet therapy to monotherapy [18]. In the acute stage of ischemic stroke, dual antiplatelet therapy reduced the amounts of microembolic signals in patients with predominantly intracranial symptomatic stenosis, compared with antiplatelet monotherapy. A recent review and meta-analysis [10], as well as the results of the present study, also support the superiority of dual antiplatelet therapy to a monotherapeutic strategy in the early treatment of acute stroke. On the other hand, these data suggest that the number, rather than type, of antiplatelet drugs may play a key role in reducing stroke recurrence or deterioration. This proposal seems reasonable because different antiplatelet combinations have synergistic effects due to differences in antiplatelet mechanisms. When considering the use of more intensive antiplatelet therapy, the balance between reducing stroke recurrence and increasing the risk of major bleeding events must be taken into account. In the present study, few patients in both groups developed bleeding events, and no other obvious side effects occurred. The incidence of bleeding events was lower than reported in a previous study [11], perhaps due to differences in the duration of antiplatelet therapy (2 weeks in the present study compared with 90 days in the previous study). The present study also has many limitations, such as the small sample size, open-label design, and short observation period (2 weeks). Thus, randomized, double-blinded clinical trials with larger samples patient numbers are needed. Research focusing on the identification of the safest and most effective combination of antiplatelet drugs for the treatment of acute ischemic stroke is also necessary. In conclusion, the present data and those from previous studies confirm the advantages of dual antiplatelet therapy over monotherapy to reduce the recurrence or deterioration of ischemic stroke in the acute phase. The demonstrated safety and efficacy of this treatment may increase clinicians’ confidence in choosing a dual antiplatelet strategy to treat acute ischemic stroke.
The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgments The work was supported by grants to Prof. Hui-Sheng Chen from the Science and Technology Project Plan of Liao Ning Province (No. 2011225021) and the Key Project of the 12th National FiveYear Research Program of China (No. 2012ZX09303016-002). References [1] Johnston SC, Gress DR, Browner WS, et al. Short-term prognosis after emergency department diagnosis of TIA. JAMA 2000;284:2901–6. [2] Lovett JK, Dennis MS, Sandercock PA, et al. Very early risk of stroke after a first transient ischemic attack. Stroke 2003;34:e138–40. [3] Hill MD, Yiannakoulias N, Jeerakathil T, et al. The high risk of stroke immediately after transient ischemic attack: a population-based study. Neurology 2004;62:2015–20. [4] Coull AJ, Lovett JK, Rothwell PM. Population based study of early risk of stroke after transient ischaemic attack or minor stroke: implications for public education and organisation of services. BMJ 2004;328:326. [5] Adams RJ, Albers G, Alberts MJ, et al. Update to the AHA/ASA recommendations for the prevention of stroke in patients with stroke and transient ischemic attack. Stroke 2008;39:1647–52. [6] European Stroke Organisation (ESO); Executive Committee and the ESO Writing Committee. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis 2008;25:457–507. [7] International Stroke Trial Collaborative Group. The international stroke trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19,435 patients with acute ischaemic stroke. Lancet 1997;349: 1569–81. [8] CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. Lancet 1997;349:1641–9. [9] Lee YS, Bae HJ, Kang DW, et al. Cilostazol in Acute Ischemic Stroke Treatment (CAIST Trial): a randomized double-blind non-inferiority trial. Cerebrovasc Dis 2011;32:65–71. [10] Geeganage CM, Diener HC, Algra A, et al. Dual or mono antiplatelet therapy for patients with acute ischemic stroke or transient ischemic attack: systematic review and meta-analysis of randomized controlled trials. Stroke 2012;43: 1058–66. [11] Kennedy J, Hill MD, Ryckborst KJ, et al. Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial. Lancet Neurol 2007;6:961–9. [12] Dengler R, Diener HC, Schwartz A, et al. Early treatment with aspirin plus extended-release dipyridamole for transient ischaemic attack or ischaemic stroke within 24 h of symptom onset (EARLY trial): a randomised, open-label, blinded-endpoint trial. Lancet Neurol 2010;9:159–66. [13] Adams HP Jr, Bendixen BH, Kappelle LJ, 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. [14] Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, doubleblind, placebocontrolled trial. Lancet 2004;364:331–7. [15] Sacco RL, Diener HC, Yusuf S, et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med 2008;359:1238–51. [16] SPS3 Investigators, Benavente OR, Hart RG, et al. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med 2012;367:817–25. [17] Tanne D. Stroke: secondary stroke prevention–personalized antiplatelet therapy. Nat Rev Neurol 2012;8:536–7. [18] Wong KS, Chen C, Fu J, et al. Clopidogrel plus aspirin versus aspirin alone for reducing embolisation inpatients with acute symptomatic cerebral or carotid artery stenosis (CLAIR study): randomised, open-label, blinded-endpoint trial. Lancet Neurol 2010;9:489–97.
