A Comparative Study of Dual versus Monoantiplatelet Therapy in Patients with Acute Large-Artery Atherosclerosis Stroke Xingyang Yi, MD,* Jing Lin, MD,† Chun Wang, MSc,* Biao Zhang, MD,* and Wanzhang Chi, MSc†
Background: Antiplatelet drugs are recommended for patients with acute noncardioembolic stroke. However, few randomized clinical trials have investigated the safety and efficacy of dual antiplatelet therapy for these patients. The aim of this study was to evaluate the effects of treatment with clopidogrel and aspirin (combination therapy) and aspirin alone (monotherapy) on neurologic deterioration, platelet activation, and other short-term outcomes in patients with acute largeartery atherosclerosis stroke. Materials and Methods: Altogether 574 patients with acute (#2 days) large-artery atherosclerosis stroke were randomly assigned to receive either combined clopidogrel and aspirin or aspirin alone. Platelet aggregation and platelet–leukocyte aggregation studies were performed at days 1 and 30. Primary outcomes including recurrent ischemic stroke, neurologic deterioration, periphery vascular events, and myocardial infarction were monitored. Safety endpoints were hemorrhagic episodes and death. Results: The prevalence of neurologic deterioration and recurrent ischemic stroke were lower in patients in the combination therapy group than in those of the monotherapy group (3.52% versus 9.78% and 1.76% versus 6.29%, respectively). At day 30 of treatment, the platelet aggregations and platelet–leukocyte aggregates were lower in patients who were treated with clopidogrel and aspirin than in patients given aspirin alone (P , .001). Conclusions: For patients with acute large-artery atherosclerosis stroke, treatment with clopidogrel and aspirin for 1 month provided significantly greater inhibition of platelet activity than aspirin alone. Thus, dual therapy can be safer and more effective in reducing ischemic stroke recurrence and neurologic deterioration. Key Words: Acute ischemic stroke—stroke recurrence—dual antiplatelet therapy—monoantiplatelet therapy—neurologic degeneration. Ó 2014 by National Stroke Association
Introduction Aspirin (acetylsalicylic acid [ASA]) is the most commonly used antiplatelet drug worldwide for both From the *Department of Neurology, People’s Hospital of Deyang City, Deyang, Sichuan; and †Department of Neurology, Third Affiliated Hospital of Wenzhou Medical College, Wenzhou, Zhejiang, China. Received December 24, 2013; revision received January 28, 2014; accepted January 30, 2014. This study was supported by Scientific Research Foundation of Zhejiang Province Health Department (2007A178). Address correspondence to Jing Lin, Department of Neurology, People’s Hospital of Deyang City, Deyang 618000, Sichuan, China. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.01.022
primary and secondary prevention of cardiovascular disease and stroke. Compared with placebo, aspirin reduces the relative risk (RR) of vascular events by 13% according to 2 meta-analyses,1,2 and stroke risk by 18% in the European Stroke Prevention Study 2.3 In a large trial, it was found that clopidogrel was marginally, although significantly, more effective than aspirin; in reducing the risk of an outcome cluster of stroke, myocardial infarction, and vascular death in patients with atherosclerotic vascular disease, stroke, however, clopidogrel alone was not significant in reducing the risk of stroke.4 However, recent observations have suggested that drug resistance contributes to the failure of therapy in as many as 40% of patients using aspirin or clopidogrel treated for the secondary prevention of cerebrovascular incidents.5-7
Journal of Stroke and Cerebrovascular Diseases, Vol. -, No. - (---), 2014: pp 1-7
1
X. YI ET AL.
2
Aspirin prohibits platelet aggregation by inhibiting cyclooxygenase, whereas clopidogrel reduces platelet activation via adenosine diphosphate (ADP) receptor– dependent pathways. Because aspirin and clopidogrel have different modes of action, it is attractive to hypothesize that their combination may have additive effects on platelet inhibition. Combination antiplatelet treatment with clopidogrel and aspirin has been found to reduce the risk of recurrent cardiac ischemia in acute cardiac ischemic patients.8,9 Many large and influential stroke studies have not differentiated early from long-term secondary prevention. For example, the MATCH (Management of Atherothrombosis with Clopidogrel in High-risk Patients with Recent Transient Ischaemic Attack or Ischaemic Stroke) trial followed patients with stroke through 18 months of treatment to find that the combination of clopidogrel and aspirin was not more effective than clopidogrel alone in preventing recurrent ischemic events.10 Yet, data in the acute setting have suggested that the combination might be more effective than aspirin alone in reducing microembolic signals and for the prevention of early recurrent stroke and transient ischemic attack.11-14 Researchers of the latter studies maintain, however, that more data are required before any firm conclusion can be drawn. Neurologic deterioration and recurrent stroke are very common events in acute stroke patients, and both have severe prognoses.15,16 To prevent these occurrences, it is important to delineate the underlying mechanisms of their pathogenesis. Platelet activation, such as platelet aggregation and platelet–leukocyte aggregation, has a crucial role in arterial thrombogenesis and in the pathophysiology of ischemic stroke,17,18 consequently antiplatelet therapy is considered standard in the prevention of ischemic stroke. However, it is not known conclusively whether platelet activation is involved in neurologic deterioration and recurrent stroke. Our hypothesis is that platelet activation may lead to neurologic deterioration, recurrent stroke, or both. Furthermore, clopidogrel and aspirin in combination may be more effective than aspirin alone in reducing the risk of these terrible events by more efficiently inhibiting platelet activity. Herein, we describe a randomized controlled study, which evaluated the effects of combined clopidogrel and aspirin therapy relative to aspirin monotherapy on platelet activation, neurologic deterioration, and stroke recurrence in patients within 30 days of acute large-artery atherosclerosis stroke.
Materials and Methods Study Populations The Ethics Committee of our hospital reviewed and approved this study. Each patient or a family member gave their informed consent in writing before enrollment. We prospectively enrolled 574 patients (mean age,
69.4 6 10.3 years) who were admitted within 48 hours of their index stroke. The patients were selected from the People’s Hospital of Deyang City and the Third Affiliated Hospital of Wenzhou Medical College. For inclusion in the study, all subjects were aged 18 years or older, with a diagnosis of ischemic stroke by cranial computed tomography and magnetic resonance imaging scanning. Stroke in all cases was because of large-artery atherosclerosis according to the Trial of ORG 10172 in the Acute Stroke Treatment classification system.19 All the patients had no history of carotid endarterectomy or carotid stent therapy, and during the 30 days of treatment none underwent carotid endarterectomy or carotid stent therapy. Patients who presented or had experienced any of the following were excluded from the study: coma or National Institutes of Health Stroke Scale (NIHSS) score of 13 or more11; any clinically relevant arrhythmia on admission including atrial fibrillation; any major concurrent illness including renal failure and malignancies; fever, hypoxia, alterations in consciousness, or any relevant hemodynamic compromise on admission; use of ticlopidine, dipyridamole, other nonsteroidal anti-inflammatory drugs, or other aspirincontaining drugs previously or at the time of the index stroke; administration of heparin or low-molecularweight heparin within 24 hours before their enrollment in the study; any major surgical procedure within 1 week before enrollment; malignant paraproteinemias or a family or personal history of bleeding disorders; platelet count less than 100 3 109/L or greater than 450 3 109/L and hemoglobin less than 8 g/dL; any history of myeloproliferative disorders or of heparin-induced thrombocytopenia; or conditions such as sensitivity to aspirin, asthma, or severe cardiovascular, liver, or renal disease. Neurologic functions of the patients were scored using the NIHSS on admission and on days 3, 7, 14, and 30 after the onset. All enrolled patients were randomly assigned to either of the 2 treatment groups: clopidogrel and aspirin in combination (C 1 ASA group; n 5 286) or aspirin alone (ASA group; n 5 288). Randomization into the trial was done through the randomization office in our hospital by means of sealed envelopes or allocation via the Internet.
Treatment For patients in the ASA group, aspirin (Bayer Healthcare, Beijing, China) was administered daily beginning on the day of admission (200 mg/day for 30 days and 100 mg/ day thereafter). Patients in the C 1 ASA group received 200 mg aspirin and 75 mg clopidogrel (Sanofi, Hangzhou, China) daily from the day of admission and continuing for 30 days, and 75 mg/day clopidogrel thereafter.
Platelet Aggregation Tests Blood samples were collected before the initial dose of aspirin or clopidogrel and at day 30 of therapy.
A RANDOMIZED TRIAL
Platelet-rich plasma (PRP) and platelet-poor plasma (PPP) were obtained from citrated blood samples (.129 mol/L citrate-containing tubes, Vacutainer; Becton Dickinson, Meylon, France) when needed. Functional studies were performed with PRP or whole blood within 2 hours of extraction. Platelet aggregation was measured by optical platelet aggregometry (OPA).20 In brief, whole-blood specimens were centrifuged at 200g for 10 minutes to obtain PRP. PPP was obtained from the remaining specimens by centrifugation at 4000g for 10 minutes. Classical OPA in PRP was performed using a PAP-4D aggregometer (Bio/Data Corporation, Alpha Laboratories Limited, Horsham, PA). Platelet aggregation was recorded as changes in light transmission. The recorder was adjusted to make sure that the difference in light transmission between PRP and PPP was 100%. The results of OPA are presented as the amplitude of light transmittance at 5 minutes after addition of the agonist .5 mM of arachidonic acid (AA) and 10 mM of ADP (Helena Laboratories, Beaumont, TX).
Platelet–leukocyte Aggregates Venous blood was drawn from an antecubital vein before the administration of the initial dose of aspirin or clopidogrel and again at day 30. This was anticoagulated with 3.8% sodium citrate and processed after 10 minutes of resting time without further manipulation. Blood samples were kept at body temperature at all times. Platelet–leukocyte aggregates were measured by flow cytometry,21 we used direct fluorescent markers (all commercially available; Coulter Immunotech, Krefeld, Germany). Whole blood was diluted 1:10 with warmed hydroxyethyl-piperazineethane-sulfonic acid (HEPES) buffer. Two aliquots of 50 mL were incubated with CD61-phycoerythrin (an activation-independent subunit of the glycoprotein IIb/IIIa complex) to immunologically identify all platelets. Simultaneously, in a 1-step procedure, the sample for measuring platelet activation was stained with anti-CD62P. The other sample was double stained with the pan-leukocyte marker CD45 to identify leukocytes. After incubation for 5 minutes, the process was stopped using cold buffer and immediately followed by flow cytometry.
Study Endpoints The primary efficacy outcome was neurologic deterioration. Neurologic deterioration was defined as an increase of 4 or more in the NIHSS score occurring within 7 days after the index stroke, except recurrent stroke or hemorrhagic transformation after acute ischemic stroke.22 The secondary efficacy outcomes included the recurrence of stroke and peripheral vascular event (deep venous thrombosis, periphery arterial embolisms, or myocardial infarction) during the 30 days of treatment. Recurrent stroke was defined as a newly acute neurologic vascular
3
event with focal signs that persisted for more than 24 hours. The safety outcomes included hemorrhagic episodes and deaths occurring during the 30 days of treatment. Hemorrhagic episodes were defined as hemorrhagic transformation of the cerebral infarction, intracerebral hemorrhage not associated with cerebral infarction, or extracranial hemorrhage (eg, gastrointestinal bleeding or hematuria). All deaths and information on the causes of death were recorded, whether myocardial infarction, ischemic cerebrovascular accident, or any other vascular or nonvascular cause. Any symptomatic intracranial hemorrhage or any hemorrhage requiring blood transfusion or prolonged hospitalization was considered as serious hemorrhage. All reported efficacy and safety outcomes were confirmed by our central adjudication committee that was unaware of the study group assignments.
Statistical Analyses We speculated that a sample of 574 patients would provide 90% power to detect a RR reduction of 15% in the percentage of neurologic deterioration in the combination therapy group, with a 2-sided type I error of .05, assuming an event rate of 15% in the monotherapy group. SPSS 16.0 statistical software (SPSS, Chicago, IL) was used to perform statistical analyses. Categorical variables are presented as frequencies and percentages. For the categorical variables, patient demographics between the groups were compared using chi-squared tests or, when expected cell frequencies were small, exact tests were conducted. Continuous variables are presented as the mean 6 standard deviation and were compared with the Student t test. Differences in outcome parameters between the groups were assessed by the RR and their associated 95% confidence intervals (CIs). All analyses were done by an investigator masked to both patient identity and the day the recording was taken.
Results Between August 2009 and December 2011, altogether 574 patients were enrolled of which 286 were randomly assigned to the dual therapy (C 1 ASA group) and 288 to the monotherapy (ASA group). During the 30 days, 1 patient was withdrawn because of a drug eruption and 1 was withdrawn because of a change in physician in both the C 1 ASA and ASA groups. Thus, altogether 570 patients (284 in the C 1 ASA group and 286 in the ASA group) were selected for the study. There were no significant differences in demographic or baseline clinicopathologic features of the C 1 ASA and ASA groups (Table 1). The average times from stroke onset to randomization were 26 6 13 and 24 6 14 hours in the C 1 ASA and the ASA groups, respectively. There was no significant difference between the 2 groups.
X. YI ET AL.
4
Table 1. Demographics and clinicopathologic features of patients in the C 1 ASA (n 5 284) and ASA (n 5 286) groups on admission Characteristic
C 1 ASA
ASA
P value*
Age, y Gender, female, n (%) Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Stroke onset to antiplatelet therapy, d Smoking, n (%) Hypertension, n (%) Diabetes, n (%) Previous myocardial infarction, n (%) Previous angina, n (%) Total cholesterol, mmol/L Triglyceride, mmol/L High-density lipoprotein, mmol/L Low-density lipoprotein, mmol/L Admission NIHSS score Previous or ongoing drug treatments, n (%) Antihypertensive drugs Hypoglycemic drugs Statins Antiplatelet drugs
69.2 6 10.1 128 (45.1) 137.6 6 21.2 80.5 6 12.4 2.1 6 .91 112 (39.4) 204 (71.8) 105 (37.0) 4 (1.41) 6 (2.11) 4.9 6 4.7 1.8 6 .9 1.29 6 .38 3.10 6 .75 11.2 6 2.1
70.1 6 10.4 129 (45.1) 135.9 6 23.2 81.6 6 11.8 2.2 6 .9 116 (40.6) 210 (73.4) 110 (38.5) 3 (1.0) 7 (2.4) 5.0 6 1.05 1.8 6 .8 1.28 6 .3 3.13 6 .81 11.5 6 2.2
.46 .94 .75 .89 .89 .83 .44 .79 .46 .68 .83 .88 .78 .91 .92
156 (54.9) 86 (30.3) 29 (10.2) 0
160 (55.9) 92 (32.2) 31 (10.8) 0
.79 .69 .92
*Statistical significance was based on the Student t test and the chi-squared (c2) test.
Neurologic deterioration within 7 days post-treatment was found in 38 (6.7%) patients. Of the 570 patients, 23 (4%) suffered recurrent ischemic stroke within 30 days of admission to the hospital after the index stroke. Most of these (19 of 23) occurred within the first 7 days, then 2 at 8-14 days, and 1 each at 15-21 days and 22-28 days. Compared with patients who did not suffer neurologic deterioration or recurrent stroke, the platelet aggregation induced by AA or ADP and platelet–leukocyte aggregates at day 1 were higher in patients who did experience these afflictions (P , .001 for each; Table 2). In the combination therapy group, 10 patients suffered from neurologic deterioration within 7 days and 5 patients suffered from recurrent ischemic stroke within 30 days. In the monotherapy group, 28 experienced neurologic deterioration within 7 days and 18 suffered recurrent ischemic stroke within 30 days. The prevalence of neurologic deterioration and recurrent ischemic stroke were lower in patients in the combination therapy group than those in the monotherapy group (3.52% versus 9.78%; RR, .69; 95% CI, 0.57-.83; P , .001% and 1.76% versus 6.29%; RR, .72; 95% CI, .61-.96; P 5 .006, respectively) (Table 3). However, the prevalence of myocardial infarction, deep venous thrombosis, and death from all causes was not significantly different between the 2 groups (P . .05; Table 3). There were no serious hemorrhagic events observed in the 2 treatment groups (Table 3). Data analysis demonstrated no significant differences (P . .05) between the
combination and monotherapy groups in terms of rates of hemorrhagic transformation of the cerebral infarction (3.52% [10 of 284] versus 3.85% [11 of 286], respectively), intracerebral hemorrhage (.4% [1 of 284] versus .4% [1 of 286]), or extracranial hemorrhage (1.8% [5 of 284] versus 1.05% [3 of 286]). Before the administration of therapy, the platelet aggregations and platelet–leukocyte aggregates were not significantly different between the 2 groups (Table 4). Table 2. Platelet aggregation and platelet–leukocyte aggregates at day 1 of patients with (n 5 61) and without (n 5 509) subsequent RS or ND (%)*
Parameter Platelet aggregation AA-induced ADP-induced Platelet–leukocyte aggregates Leukocyte Neutrophil Monocyte Lymphocyte
With RS or ND
Without RS or ND
P value
91.4 6 11.4 85.3 6 11.2 ,.001 90.2 6 13.2 86.1 6 11.6 .021 26.8 6 5.46 24.3 6 6.4 33.2 6 7.1 26.5 6 6.8
22.0 6 4.2 21.1 6 3.8 28.2 6 5.5 23.5 6 4.6
,.001 ,.001 ,.001 ,.001
Abbreviations: AA, arachidonic acid; ADP, adenosine 50 -diphosphate; ND, neurologic deterioration; RS, recurrent ischemic stroke. *Statistical significance based on the Student t test.
A RANDOMIZED TRIAL
5
Table 3. Outcomes of patients in the C 1 ASA (n 5 284) and ASA (n 5 286) groups (n, %)* Outcome Efficacy outcomes Neurologic deterioration Recurrent ischemic stroke Myocardial infarction Deep venous thrombosis Safety outcomes Death, all causes Hemorrhagic transformation Intracerebral hemorrhage Extracranial hemorrhage Serious hemorrhage
C 1 ASA
ASA
RR (95% CI)
P value
10 (3.5) 5 (1.7) 3 (1.0) 10 (3.5)
28 (9.8) 18 (6.3) 3 (1.0) 11 (3.8)
.69 (.57-.83) .72 (.61-.96) 1.01 (.38-2.70) .97 (.40-2.33)
,.001 .006 .99 .97
2 (.7) 10 (3.5) 1 (.4) 5 (1.8) 0
2 (.7) 11 (3.8) 1 (.4) 3 (1.0) 0
.94 (.24-3.79) .73 (.16-3.26) .96 (.34-3.81) .82 (.53-1.26) —
.99 .96 .99 .45 —
Abbreviations: CI, confidence interval; RR, relative risk. *Data are shown as number of patients (in percent).
activity. We therefore conducted a randomized controlled study, which evaluated the effects of combined clopidogrel and aspirin therapy relative to aspirin monotherapy on platelet activation, neurologic deterioration, and stroke recurrence in patients within 30 days of acute large-artery atherosclerosis stroke. In the present study, 38 (6.7%) patients among a total of 570 patients developed neurologic deterioration. These 38 patients comprised 10 patients who were given clopidogrel and aspirin and remaining 28 who received aspirin alone. The results showed that the combined antiplatelet therapy reduced the incidence of neurologic deterioration more efficiently than did the monotherapy. Patients who do not receive thrombolytic treatment after transient ischemic attack or stroke are at a high subsequent risk of death or dependency.23,24 Thus, clinical guidelines recommend antiplatelet therapy for patients with noncardioembolic stroke or transient ischemic
However, at day 30 of treatment, the platelet aggregations and platelet–leukocyte aggregates were lower in patients given combined clopidogrel and aspirin than in patients given aspirin alone (P , .001, each).
Discussion In acute stroke patients, neurologic deterioration and recurrent strokes are very common events and both have severe prognoses.15,16 Because platelet activation has a crucial role in arterial thrombogenesis and in the pathophysiology of ischemic stroke, antiplatelet therapy is considered standard in the prevention of ischemic stroke.17,18 On the basis of the clues from earlier studies, it was hypothesized that clopidogrel and aspirin in combination may be more effective than aspirin alone in reducing the risk of stroke recurrence and neurologic deterioration by more efficiently inhibiting platelet
Table 4. Platelet aggregation and platelet–leukocyte aggregates of patients in the C 1 ASA (n 5 284) and ASA (n 5 286) groups Parameter Platelet aggregation AA-induced ADP-induced Platelet–leukocyte aggregates Leukocyte Neutrophil Monocyte Lymphocyte
Day
C 1 ASA (%)
ASA (%)
P value*
1 30 1 30
88.6 6 10.2 14.6 6 7.5 87.6 6 12.6 47.6 6 10.9
89.5 6 11.7 20.6 6 8.4 89.0 6 13.9 70.0 6 13.6
.63 ,.001 .572 ,.001
1 30 1 30 1 30 1 30
24.3 6 5.2 16.1 6 5.8 22.2 6 5.2 18.1 6 4.2 31.5 6 7.0 22.1 6 5.6 24.7 6 6.4 20.6 6 5.8
23.5 6 4.4 20.0 6 3.8 22.5 6 4.9 22.3 6 4.9 30.5 6 6.5 28.1 6 6.7 25.4 6 5.1 24.4 6 4.9
.063 ,.001 .361 ,.001 .122 ,.001 .172 ,.001
Abbreviations: AA, arachidonic acid; ADP, adenosine 50 -diphosphate. *Statistical significance was based on the Student t test.
X. YI ET AL.
6 25-27
attack. In our study, combined antiplatelet therapy with clopidogrel and aspirin reduced the incidence of recurrent ischemic stroke more effectively than did the aspirin monotherapy. Thrombosis and atherosclerosis are major contributors to the development of ischemic stroke. Platelets have a crucial role in triggering arterial thrombosis28 and in promoting atherogenesis.29 Platelet activation and platelet– leukocyte aggregates have also been described in patients with stroke.30,31 However, whether platelet activation and platelet–leukocyte aggregation are involved in the pathogenesis of neurologic deterioration and recurrent stroke after acute large-artery atherosclerosis stroke is not known. In the present study, we found that AAinduced or ADP-induced platelet aggregation and platelet–leukocyte aggregates on the day of admission were higher in patients who later experienced neurologic deterioration or recurrent stroke than in patients who did not suffer these problems. This suggests that platelet aggregation and platelet–leukocyte aggregates may have a key role in the pathogenesis of neurologic deterioration or recurrent stroke after acute large-artery atherosclerosis stroke. Therefore, intensive antiplatelet therapy such as combined antiplatelet therapy may reduce the incidence of recurrent ischemic stroke or neurologic deterioration. Because aspirin and clopidogrel have different biochemical pathways by which they inhibit platelet adhesiveness, a combination of these 2 drugs might be more effective than either alone in secondary prevention of vascular events. In contrast to our present study, in the MATCH and the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance) trials, treatment with clopidogrel and aspirin failed to show any significant difference from aspirin monotherapy.10,32 However, in the MATCH and CHARISMA study, treatments were not given in the acute setting and the period was rather for 18 and 28 months, respectively. This may be an important factor contributing to the more frequent and serious bleeding observed in those studies. In the present study, the platelet aggregations and platelet–leukocyte aggregates were not significantly different between the 2 groups at day 1 of treatment. However, at day 30 of treatment these indicators were lower in patients given dual therapy than in patients who received monotherapy, which indicates that dual antiplatelet therapy can more efficiently inhibit platelet activity. There were no significant differences between the 2 groups regarding the rates of hemorrhagic transformation of the cerebral infarction, intracerebral hemorrhage, or extracranial hemorrhage. In fact, there were no serious hemorrhagic events in the patients overall. In conclusion, our study shows that among patients with acute large-artery atherosclerosis stroke, treatment with combined clopidogrel and aspirin for 1 month provided significantly greater inhibition of platelet activity
than did aspirin alone, and appears to be safer and more effective in reducing ischemic stroke recurrence and neurologic deterioration. Thus, we recommend the more intensive antiplatelet therapy for reducing the risk of neurologic deterioration or early recurrent stroke in patients with acute large-artery atherosclerotic stroke.
Limitations Before the proposed drug regime is applied in clinical practice, studies of larger scale are required to validate the advantage of dual antiplatelet therapy in acute large-artery ischemic stroke. The results of this 2-center study, with its limited sample size may not represent most accurately disease outcome after dual and monoantiplatelet therapy in China, and they should be further validated in larger, multicenter studies before dual therapy is put into practice. The major aim of this study was to evaluate the effects of combined clopidogrel and aspirin on early neurologic deterioration up to a period of 30 days. Therefore, the groups should be followed for longer-term outcomes. Acknowledgment: The authors thank Medjaden Bioscience for assisting in the preparation of this manuscript. The authors declare that they have no competing interests.
References 1. Barnett HJM, Eliasziw M, Meldrum HE. Drugs and surgery in the prevention of ischemic stroke. N Engl J Med 1995;332:238-248. 2. Algra A, van Gijn J. Aspirin at any dose above 30 mg offers only modest protection after cerebral ischemia. J Neurol Neurosurg Psychiatry 1996;60:197-199. 3. Diener HC, Cunha L, Forbes C, et al. European Stroke Prevention Study 2: dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996;143:1-13. 4. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischemic events. Lancet 1996;348:1329-1339. 5. Schwammenthal Y, Tsabari R, Shenkman B, et al. Aspirin responsiveness in acute brain ischaemia: association with stroke severity and clinical outcome. Cerebrovasc Dis 2008;25:355-361. 6. Grundmann K, Jaschonek K, Kleine B, et al. Aspirin nonresponder status in patients with recurrent cerebral ischemic attacks. J Neurol 2003;250:63-66. 7. Gurbel PA, Bliden KP, Hiatt BL, et al. Clopidogrel for coronary stenting: response variability, drug resistance and the effect of pretreatment platelet reactivity. Circulation 2003;107:2908-2913. 8. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502. 9. Teal PA. Recent clinical trial results with antiplatelet therapy: implications in stroke prevention. Cerebrovasc Dis 2004;17(Suppl 3):6-10. 10. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent
A RANDOMIZED TRIAL
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
ischaemic stroke or transient ischaemic attack in highrisk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004;364:331-337. Wong KS, Chen C, Fu J, et al. Clopidogrel plus aspirin versus aspirin alone for reducing embolisation in patients with acute symptomatic cerebral or carotid artery stenosis (CLAIR study): a randomised, open-label, blindedendpoint trial. Lancet Neurol 2010;9:489-497. Markus HS, Droste DW, Kaps M, et al. Dual antiplatelet therapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using Doppler embolic signal detection: the clopidogrel and aspirin for reduction of emboli in symptomatic carotid stenosis (CARESS) trial. Circulation 2005;111:2233-2240. Kennedy J, Hill MD, Ryckborst KJ, et al. Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomized controlled pilot trial. Lancet Neurol 2007;6:961-969. Esagunde RU, Wong KS, Lee MP, et al. Efficacy of dual antiplatelet therapy in cerebrovascular disease as demonstrated by a decline in microembolic signals. A report of eight cases. Cerebrovasc Dis 2006;21:242-246. Alawneh JA, Moustafa RR, Baron JC. Hemodynamic factors and perfusion abnormalities in early neurological deterioration. Stroke 2009;40:e443-e450. Nolte CH, Albach FN, Heuschmann PU, et al. Silent new DWI lesions within the first week after stroke. Cerebrovasc Dis 2012;33:248-254. Lavallee PC, Labreuche J, Faille D, et al. Circulating markers of endothelial dysfunction and platelet activation in patients with severe symptomatic cerebral small vessel disease. Cerebrovasc Dis 2013;36:131-138. Toghi H, Suzuki H, Tamura K, et al. Platelet volume, aggregation, and adenosine triphosphate release in cerebral thrombosis. Stroke 1991;22:17-22. Han SW, Kim SH, Lee JY, et al. A new subtype classification of ischemic stroke based on treatment and etiologic mechanism. Eur Neurol 2007;57:96-102. Yi X, Zhou Q, Lin J, et al. Platelet response to aspirin in Chinese stroke patients is independent of genetic polymorphisms of COX-1 C50T and COX-2 G765C. J Atheroscler Thromb 2013;20:65-72. Zeller JA, Frahm K, Baron R, et al. Platelet-leukocyte interaction and platelet activation in migraine: a link to
7
22.
23.
24.
25.
26.
27.
28. 29.
30.
31.
32.
ischemic stroke? J Neurol Neurosurg Psychiatry 2004; 75:984-987. Wang Q, Chen C, Chen XY, et al. Low-molecular-weight heparin and early neurologic deterioration in acute stroke caused by large artery occlusive disease. Arch Neurol 2012;69:1454-1460. Hill MD, Barber PA, Demchuk AM, et al. Building a ‘brain attack’ team to administer thrombolytic therapy for acute ischemic stroke. CMAJ 2000;162: 1589-1593. Barber PA, Zhang J, Demchuk AM, et al. Why are stroke patients excluded from TPA therapy? An analysis of patient eligibility. Neurology 2001;56:1015-1020. 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;39:1647-1652. Albers GW, Amarenco P, Easton JD, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest 2008; 133:630S-669S. The European Stroke Association (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. Ruggeri ZM. Platelets in atherothrombosis. Nat Med 2002;8:1227-1234. Fateh-Moghadam S, Li Z, Ersel S, et al. Platelet degranulation is associated with progression of intima-media thickness of the common carotid artery in patients with diabetes mellitus type 2. Arterioscler Thromb Vasc Biol 2005;25:1299-1303. Marquardt L, Ruf A, Mansmann U, et al. Course of platelet activation markers after ischemic stroke. Stroke 2002;33:2570-2574. McCabe DJ, Harrison P, Mackie IJ, et al. Platelet degranulation and monocyte-platelet complex formation are increased in the acute and convalescent phases after ischaemic stroke or transient ischaemic attack. Br J Haematol 2004;125:777-787. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:1706-1717.
Background: Antiplatelet drugs are recommended for patients with acute noncardioembolic stroke. However, few randomized clinical trials have investigated the safety and efficacy of dual antiplatelet therapy for these patients. The aim of this study was to evaluate the effects of treatment with clopidogrel and aspirin (combination therapy) and aspirin alone (monotherapy) on neurologic deterioration, platelet activation, and other short-term outcomes in patients with acute largeartery atherosclerosis stroke. Materials and Methods: Altogether 574 patients with acute (#2 days) large-artery atherosclerosis stroke were randomly assigned to receive either combined clopidogrel and aspirin or aspirin alone. Platelet aggregation and platelet–leukocyte aggregation studies were performed at days 1 and 30. Primary outcomes including recurrent ischemic stroke, neurologic deterioration, periphery vascular events, and myocardial infarction were monitored. Safety endpoints were hemorrhagic episodes and death. Results: The prevalence of neurologic deterioration and recurrent ischemic stroke were lower in patients in the combination therapy group than in those of the monotherapy group (3.52% versus 9.78% and 1.76% versus 6.29%, respectively). At day 30 of treatment, the platelet aggregations and platelet–leukocyte aggregates were lower in patients who were treated with clopidogrel and aspirin than in patients given aspirin alone (P , .001). Conclusions: For patients with acute large-artery atherosclerosis stroke, treatment with clopidogrel and aspirin for 1 month provided significantly greater inhibition of platelet activity than aspirin alone. Thus, dual therapy can be safer and more effective in reducing ischemic stroke recurrence and neurologic deterioration. Key Words: Acute ischemic stroke—stroke recurrence—dual antiplatelet therapy—monoantiplatelet therapy—neurologic degeneration. Ó 2014 by National Stroke Association
Introduction Aspirin (acetylsalicylic acid [ASA]) is the most commonly used antiplatelet drug worldwide for both From the *Department of Neurology, People’s Hospital of Deyang City, Deyang, Sichuan; and †Department of Neurology, Third Affiliated Hospital of Wenzhou Medical College, Wenzhou, Zhejiang, China. Received December 24, 2013; revision received January 28, 2014; accepted January 30, 2014. This study was supported by Scientific Research Foundation of Zhejiang Province Health Department (2007A178). Address correspondence to Jing Lin, Department of Neurology, People’s Hospital of Deyang City, Deyang 618000, Sichuan, China. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.01.022
primary and secondary prevention of cardiovascular disease and stroke. Compared with placebo, aspirin reduces the relative risk (RR) of vascular events by 13% according to 2 meta-analyses,1,2 and stroke risk by 18% in the European Stroke Prevention Study 2.3 In a large trial, it was found that clopidogrel was marginally, although significantly, more effective than aspirin; in reducing the risk of an outcome cluster of stroke, myocardial infarction, and vascular death in patients with atherosclerotic vascular disease, stroke, however, clopidogrel alone was not significant in reducing the risk of stroke.4 However, recent observations have suggested that drug resistance contributes to the failure of therapy in as many as 40% of patients using aspirin or clopidogrel treated for the secondary prevention of cerebrovascular incidents.5-7
Journal of Stroke and Cerebrovascular Diseases, Vol. -, No. - (---), 2014: pp 1-7
1
X. YI ET AL.
2
Aspirin prohibits platelet aggregation by inhibiting cyclooxygenase, whereas clopidogrel reduces platelet activation via adenosine diphosphate (ADP) receptor– dependent pathways. Because aspirin and clopidogrel have different modes of action, it is attractive to hypothesize that their combination may have additive effects on platelet inhibition. Combination antiplatelet treatment with clopidogrel and aspirin has been found to reduce the risk of recurrent cardiac ischemia in acute cardiac ischemic patients.8,9 Many large and influential stroke studies have not differentiated early from long-term secondary prevention. For example, the MATCH (Management of Atherothrombosis with Clopidogrel in High-risk Patients with Recent Transient Ischaemic Attack or Ischaemic Stroke) trial followed patients with stroke through 18 months of treatment to find that the combination of clopidogrel and aspirin was not more effective than clopidogrel alone in preventing recurrent ischemic events.10 Yet, data in the acute setting have suggested that the combination might be more effective than aspirin alone in reducing microembolic signals and for the prevention of early recurrent stroke and transient ischemic attack.11-14 Researchers of the latter studies maintain, however, that more data are required before any firm conclusion can be drawn. Neurologic deterioration and recurrent stroke are very common events in acute stroke patients, and both have severe prognoses.15,16 To prevent these occurrences, it is important to delineate the underlying mechanisms of their pathogenesis. Platelet activation, such as platelet aggregation and platelet–leukocyte aggregation, has a crucial role in arterial thrombogenesis and in the pathophysiology of ischemic stroke,17,18 consequently antiplatelet therapy is considered standard in the prevention of ischemic stroke. However, it is not known conclusively whether platelet activation is involved in neurologic deterioration and recurrent stroke. Our hypothesis is that platelet activation may lead to neurologic deterioration, recurrent stroke, or both. Furthermore, clopidogrel and aspirin in combination may be more effective than aspirin alone in reducing the risk of these terrible events by more efficiently inhibiting platelet activity. Herein, we describe a randomized controlled study, which evaluated the effects of combined clopidogrel and aspirin therapy relative to aspirin monotherapy on platelet activation, neurologic deterioration, and stroke recurrence in patients within 30 days of acute large-artery atherosclerosis stroke.
Materials and Methods Study Populations The Ethics Committee of our hospital reviewed and approved this study. Each patient or a family member gave their informed consent in writing before enrollment. We prospectively enrolled 574 patients (mean age,
69.4 6 10.3 years) who were admitted within 48 hours of their index stroke. The patients were selected from the People’s Hospital of Deyang City and the Third Affiliated Hospital of Wenzhou Medical College. For inclusion in the study, all subjects were aged 18 years or older, with a diagnosis of ischemic stroke by cranial computed tomography and magnetic resonance imaging scanning. Stroke in all cases was because of large-artery atherosclerosis according to the Trial of ORG 10172 in the Acute Stroke Treatment classification system.19 All the patients had no history of carotid endarterectomy or carotid stent therapy, and during the 30 days of treatment none underwent carotid endarterectomy or carotid stent therapy. Patients who presented or had experienced any of the following were excluded from the study: coma or National Institutes of Health Stroke Scale (NIHSS) score of 13 or more11; any clinically relevant arrhythmia on admission including atrial fibrillation; any major concurrent illness including renal failure and malignancies; fever, hypoxia, alterations in consciousness, or any relevant hemodynamic compromise on admission; use of ticlopidine, dipyridamole, other nonsteroidal anti-inflammatory drugs, or other aspirincontaining drugs previously or at the time of the index stroke; administration of heparin or low-molecularweight heparin within 24 hours before their enrollment in the study; any major surgical procedure within 1 week before enrollment; malignant paraproteinemias or a family or personal history of bleeding disorders; platelet count less than 100 3 109/L or greater than 450 3 109/L and hemoglobin less than 8 g/dL; any history of myeloproliferative disorders or of heparin-induced thrombocytopenia; or conditions such as sensitivity to aspirin, asthma, or severe cardiovascular, liver, or renal disease. Neurologic functions of the patients were scored using the NIHSS on admission and on days 3, 7, 14, and 30 after the onset. All enrolled patients were randomly assigned to either of the 2 treatment groups: clopidogrel and aspirin in combination (C 1 ASA group; n 5 286) or aspirin alone (ASA group; n 5 288). Randomization into the trial was done through the randomization office in our hospital by means of sealed envelopes or allocation via the Internet.
Treatment For patients in the ASA group, aspirin (Bayer Healthcare, Beijing, China) was administered daily beginning on the day of admission (200 mg/day for 30 days and 100 mg/ day thereafter). Patients in the C 1 ASA group received 200 mg aspirin and 75 mg clopidogrel (Sanofi, Hangzhou, China) daily from the day of admission and continuing for 30 days, and 75 mg/day clopidogrel thereafter.
Platelet Aggregation Tests Blood samples were collected before the initial dose of aspirin or clopidogrel and at day 30 of therapy.
A RANDOMIZED TRIAL
Platelet-rich plasma (PRP) and platelet-poor plasma (PPP) were obtained from citrated blood samples (.129 mol/L citrate-containing tubes, Vacutainer; Becton Dickinson, Meylon, France) when needed. Functional studies were performed with PRP or whole blood within 2 hours of extraction. Platelet aggregation was measured by optical platelet aggregometry (OPA).20 In brief, whole-blood specimens were centrifuged at 200g for 10 minutes to obtain PRP. PPP was obtained from the remaining specimens by centrifugation at 4000g for 10 minutes. Classical OPA in PRP was performed using a PAP-4D aggregometer (Bio/Data Corporation, Alpha Laboratories Limited, Horsham, PA). Platelet aggregation was recorded as changes in light transmission. The recorder was adjusted to make sure that the difference in light transmission between PRP and PPP was 100%. The results of OPA are presented as the amplitude of light transmittance at 5 minutes after addition of the agonist .5 mM of arachidonic acid (AA) and 10 mM of ADP (Helena Laboratories, Beaumont, TX).
Platelet–leukocyte Aggregates Venous blood was drawn from an antecubital vein before the administration of the initial dose of aspirin or clopidogrel and again at day 30. This was anticoagulated with 3.8% sodium citrate and processed after 10 minutes of resting time without further manipulation. Blood samples were kept at body temperature at all times. Platelet–leukocyte aggregates were measured by flow cytometry,21 we used direct fluorescent markers (all commercially available; Coulter Immunotech, Krefeld, Germany). Whole blood was diluted 1:10 with warmed hydroxyethyl-piperazineethane-sulfonic acid (HEPES) buffer. Two aliquots of 50 mL were incubated with CD61-phycoerythrin (an activation-independent subunit of the glycoprotein IIb/IIIa complex) to immunologically identify all platelets. Simultaneously, in a 1-step procedure, the sample for measuring platelet activation was stained with anti-CD62P. The other sample was double stained with the pan-leukocyte marker CD45 to identify leukocytes. After incubation for 5 minutes, the process was stopped using cold buffer and immediately followed by flow cytometry.
Study Endpoints The primary efficacy outcome was neurologic deterioration. Neurologic deterioration was defined as an increase of 4 or more in the NIHSS score occurring within 7 days after the index stroke, except recurrent stroke or hemorrhagic transformation after acute ischemic stroke.22 The secondary efficacy outcomes included the recurrence of stroke and peripheral vascular event (deep venous thrombosis, periphery arterial embolisms, or myocardial infarction) during the 30 days of treatment. Recurrent stroke was defined as a newly acute neurologic vascular
3
event with focal signs that persisted for more than 24 hours. The safety outcomes included hemorrhagic episodes and deaths occurring during the 30 days of treatment. Hemorrhagic episodes were defined as hemorrhagic transformation of the cerebral infarction, intracerebral hemorrhage not associated with cerebral infarction, or extracranial hemorrhage (eg, gastrointestinal bleeding or hematuria). All deaths and information on the causes of death were recorded, whether myocardial infarction, ischemic cerebrovascular accident, or any other vascular or nonvascular cause. Any symptomatic intracranial hemorrhage or any hemorrhage requiring blood transfusion or prolonged hospitalization was considered as serious hemorrhage. All reported efficacy and safety outcomes were confirmed by our central adjudication committee that was unaware of the study group assignments.
Statistical Analyses We speculated that a sample of 574 patients would provide 90% power to detect a RR reduction of 15% in the percentage of neurologic deterioration in the combination therapy group, with a 2-sided type I error of .05, assuming an event rate of 15% in the monotherapy group. SPSS 16.0 statistical software (SPSS, Chicago, IL) was used to perform statistical analyses. Categorical variables are presented as frequencies and percentages. For the categorical variables, patient demographics between the groups were compared using chi-squared tests or, when expected cell frequencies were small, exact tests were conducted. Continuous variables are presented as the mean 6 standard deviation and were compared with the Student t test. Differences in outcome parameters between the groups were assessed by the RR and their associated 95% confidence intervals (CIs). All analyses were done by an investigator masked to both patient identity and the day the recording was taken.
Results Between August 2009 and December 2011, altogether 574 patients were enrolled of which 286 were randomly assigned to the dual therapy (C 1 ASA group) and 288 to the monotherapy (ASA group). During the 30 days, 1 patient was withdrawn because of a drug eruption and 1 was withdrawn because of a change in physician in both the C 1 ASA and ASA groups. Thus, altogether 570 patients (284 in the C 1 ASA group and 286 in the ASA group) were selected for the study. There were no significant differences in demographic or baseline clinicopathologic features of the C 1 ASA and ASA groups (Table 1). The average times from stroke onset to randomization were 26 6 13 and 24 6 14 hours in the C 1 ASA and the ASA groups, respectively. There was no significant difference between the 2 groups.
X. YI ET AL.
4
Table 1. Demographics and clinicopathologic features of patients in the C 1 ASA (n 5 284) and ASA (n 5 286) groups on admission Characteristic
C 1 ASA
ASA
P value*
Age, y Gender, female, n (%) Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Stroke onset to antiplatelet therapy, d Smoking, n (%) Hypertension, n (%) Diabetes, n (%) Previous myocardial infarction, n (%) Previous angina, n (%) Total cholesterol, mmol/L Triglyceride, mmol/L High-density lipoprotein, mmol/L Low-density lipoprotein, mmol/L Admission NIHSS score Previous or ongoing drug treatments, n (%) Antihypertensive drugs Hypoglycemic drugs Statins Antiplatelet drugs
69.2 6 10.1 128 (45.1) 137.6 6 21.2 80.5 6 12.4 2.1 6 .91 112 (39.4) 204 (71.8) 105 (37.0) 4 (1.41) 6 (2.11) 4.9 6 4.7 1.8 6 .9 1.29 6 .38 3.10 6 .75 11.2 6 2.1
70.1 6 10.4 129 (45.1) 135.9 6 23.2 81.6 6 11.8 2.2 6 .9 116 (40.6) 210 (73.4) 110 (38.5) 3 (1.0) 7 (2.4) 5.0 6 1.05 1.8 6 .8 1.28 6 .3 3.13 6 .81 11.5 6 2.2
.46 .94 .75 .89 .89 .83 .44 .79 .46 .68 .83 .88 .78 .91 .92
156 (54.9) 86 (30.3) 29 (10.2) 0
160 (55.9) 92 (32.2) 31 (10.8) 0
.79 .69 .92
*Statistical significance was based on the Student t test and the chi-squared (c2) test.
Neurologic deterioration within 7 days post-treatment was found in 38 (6.7%) patients. Of the 570 patients, 23 (4%) suffered recurrent ischemic stroke within 30 days of admission to the hospital after the index stroke. Most of these (19 of 23) occurred within the first 7 days, then 2 at 8-14 days, and 1 each at 15-21 days and 22-28 days. Compared with patients who did not suffer neurologic deterioration or recurrent stroke, the platelet aggregation induced by AA or ADP and platelet–leukocyte aggregates at day 1 were higher in patients who did experience these afflictions (P , .001 for each; Table 2). In the combination therapy group, 10 patients suffered from neurologic deterioration within 7 days and 5 patients suffered from recurrent ischemic stroke within 30 days. In the monotherapy group, 28 experienced neurologic deterioration within 7 days and 18 suffered recurrent ischemic stroke within 30 days. The prevalence of neurologic deterioration and recurrent ischemic stroke were lower in patients in the combination therapy group than those in the monotherapy group (3.52% versus 9.78%; RR, .69; 95% CI, 0.57-.83; P , .001% and 1.76% versus 6.29%; RR, .72; 95% CI, .61-.96; P 5 .006, respectively) (Table 3). However, the prevalence of myocardial infarction, deep venous thrombosis, and death from all causes was not significantly different between the 2 groups (P . .05; Table 3). There were no serious hemorrhagic events observed in the 2 treatment groups (Table 3). Data analysis demonstrated no significant differences (P . .05) between the
combination and monotherapy groups in terms of rates of hemorrhagic transformation of the cerebral infarction (3.52% [10 of 284] versus 3.85% [11 of 286], respectively), intracerebral hemorrhage (.4% [1 of 284] versus .4% [1 of 286]), or extracranial hemorrhage (1.8% [5 of 284] versus 1.05% [3 of 286]). Before the administration of therapy, the platelet aggregations and platelet–leukocyte aggregates were not significantly different between the 2 groups (Table 4). Table 2. Platelet aggregation and platelet–leukocyte aggregates at day 1 of patients with (n 5 61) and without (n 5 509) subsequent RS or ND (%)*
Parameter Platelet aggregation AA-induced ADP-induced Platelet–leukocyte aggregates Leukocyte Neutrophil Monocyte Lymphocyte
With RS or ND
Without RS or ND
P value
91.4 6 11.4 85.3 6 11.2 ,.001 90.2 6 13.2 86.1 6 11.6 .021 26.8 6 5.46 24.3 6 6.4 33.2 6 7.1 26.5 6 6.8
22.0 6 4.2 21.1 6 3.8 28.2 6 5.5 23.5 6 4.6
,.001 ,.001 ,.001 ,.001
Abbreviations: AA, arachidonic acid; ADP, adenosine 50 -diphosphate; ND, neurologic deterioration; RS, recurrent ischemic stroke. *Statistical significance based on the Student t test.
A RANDOMIZED TRIAL
5
Table 3. Outcomes of patients in the C 1 ASA (n 5 284) and ASA (n 5 286) groups (n, %)* Outcome Efficacy outcomes Neurologic deterioration Recurrent ischemic stroke Myocardial infarction Deep venous thrombosis Safety outcomes Death, all causes Hemorrhagic transformation Intracerebral hemorrhage Extracranial hemorrhage Serious hemorrhage
C 1 ASA
ASA
RR (95% CI)
P value
10 (3.5) 5 (1.7) 3 (1.0) 10 (3.5)
28 (9.8) 18 (6.3) 3 (1.0) 11 (3.8)
.69 (.57-.83) .72 (.61-.96) 1.01 (.38-2.70) .97 (.40-2.33)
,.001 .006 .99 .97
2 (.7) 10 (3.5) 1 (.4) 5 (1.8) 0
2 (.7) 11 (3.8) 1 (.4) 3 (1.0) 0
.94 (.24-3.79) .73 (.16-3.26) .96 (.34-3.81) .82 (.53-1.26) —
.99 .96 .99 .45 —
Abbreviations: CI, confidence interval; RR, relative risk. *Data are shown as number of patients (in percent).
activity. We therefore conducted a randomized controlled study, which evaluated the effects of combined clopidogrel and aspirin therapy relative to aspirin monotherapy on platelet activation, neurologic deterioration, and stroke recurrence in patients within 30 days of acute large-artery atherosclerosis stroke. In the present study, 38 (6.7%) patients among a total of 570 patients developed neurologic deterioration. These 38 patients comprised 10 patients who were given clopidogrel and aspirin and remaining 28 who received aspirin alone. The results showed that the combined antiplatelet therapy reduced the incidence of neurologic deterioration more efficiently than did the monotherapy. Patients who do not receive thrombolytic treatment after transient ischemic attack or stroke are at a high subsequent risk of death or dependency.23,24 Thus, clinical guidelines recommend antiplatelet therapy for patients with noncardioembolic stroke or transient ischemic
However, at day 30 of treatment, the platelet aggregations and platelet–leukocyte aggregates were lower in patients given combined clopidogrel and aspirin than in patients given aspirin alone (P , .001, each).
Discussion In acute stroke patients, neurologic deterioration and recurrent strokes are very common events and both have severe prognoses.15,16 Because platelet activation has a crucial role in arterial thrombogenesis and in the pathophysiology of ischemic stroke, antiplatelet therapy is considered standard in the prevention of ischemic stroke.17,18 On the basis of the clues from earlier studies, it was hypothesized that clopidogrel and aspirin in combination may be more effective than aspirin alone in reducing the risk of stroke recurrence and neurologic deterioration by more efficiently inhibiting platelet
Table 4. Platelet aggregation and platelet–leukocyte aggregates of patients in the C 1 ASA (n 5 284) and ASA (n 5 286) groups Parameter Platelet aggregation AA-induced ADP-induced Platelet–leukocyte aggregates Leukocyte Neutrophil Monocyte Lymphocyte
Day
C 1 ASA (%)
ASA (%)
P value*
1 30 1 30
88.6 6 10.2 14.6 6 7.5 87.6 6 12.6 47.6 6 10.9
89.5 6 11.7 20.6 6 8.4 89.0 6 13.9 70.0 6 13.6
.63 ,.001 .572 ,.001
1 30 1 30 1 30 1 30
24.3 6 5.2 16.1 6 5.8 22.2 6 5.2 18.1 6 4.2 31.5 6 7.0 22.1 6 5.6 24.7 6 6.4 20.6 6 5.8
23.5 6 4.4 20.0 6 3.8 22.5 6 4.9 22.3 6 4.9 30.5 6 6.5 28.1 6 6.7 25.4 6 5.1 24.4 6 4.9
.063 ,.001 .361 ,.001 .122 ,.001 .172 ,.001
Abbreviations: AA, arachidonic acid; ADP, adenosine 50 -diphosphate. *Statistical significance was based on the Student t test.
X. YI ET AL.
6 25-27
attack. In our study, combined antiplatelet therapy with clopidogrel and aspirin reduced the incidence of recurrent ischemic stroke more effectively than did the aspirin monotherapy. Thrombosis and atherosclerosis are major contributors to the development of ischemic stroke. Platelets have a crucial role in triggering arterial thrombosis28 and in promoting atherogenesis.29 Platelet activation and platelet– leukocyte aggregates have also been described in patients with stroke.30,31 However, whether platelet activation and platelet–leukocyte aggregation are involved in the pathogenesis of neurologic deterioration and recurrent stroke after acute large-artery atherosclerosis stroke is not known. In the present study, we found that AAinduced or ADP-induced platelet aggregation and platelet–leukocyte aggregates on the day of admission were higher in patients who later experienced neurologic deterioration or recurrent stroke than in patients who did not suffer these problems. This suggests that platelet aggregation and platelet–leukocyte aggregates may have a key role in the pathogenesis of neurologic deterioration or recurrent stroke after acute large-artery atherosclerosis stroke. Therefore, intensive antiplatelet therapy such as combined antiplatelet therapy may reduce the incidence of recurrent ischemic stroke or neurologic deterioration. Because aspirin and clopidogrel have different biochemical pathways by which they inhibit platelet adhesiveness, a combination of these 2 drugs might be more effective than either alone in secondary prevention of vascular events. In contrast to our present study, in the MATCH and the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance) trials, treatment with clopidogrel and aspirin failed to show any significant difference from aspirin monotherapy.10,32 However, in the MATCH and CHARISMA study, treatments were not given in the acute setting and the period was rather for 18 and 28 months, respectively. This may be an important factor contributing to the more frequent and serious bleeding observed in those studies. In the present study, the platelet aggregations and platelet–leukocyte aggregates were not significantly different between the 2 groups at day 1 of treatment. However, at day 30 of treatment these indicators were lower in patients given dual therapy than in patients who received monotherapy, which indicates that dual antiplatelet therapy can more efficiently inhibit platelet activity. There were no significant differences between the 2 groups regarding the rates of hemorrhagic transformation of the cerebral infarction, intracerebral hemorrhage, or extracranial hemorrhage. In fact, there were no serious hemorrhagic events in the patients overall. In conclusion, our study shows that among patients with acute large-artery atherosclerosis stroke, treatment with combined clopidogrel and aspirin for 1 month provided significantly greater inhibition of platelet activity
than did aspirin alone, and appears to be safer and more effective in reducing ischemic stroke recurrence and neurologic deterioration. Thus, we recommend the more intensive antiplatelet therapy for reducing the risk of neurologic deterioration or early recurrent stroke in patients with acute large-artery atherosclerotic stroke.
Limitations Before the proposed drug regime is applied in clinical practice, studies of larger scale are required to validate the advantage of dual antiplatelet therapy in acute large-artery ischemic stroke. The results of this 2-center study, with its limited sample size may not represent most accurately disease outcome after dual and monoantiplatelet therapy in China, and they should be further validated in larger, multicenter studies before dual therapy is put into practice. The major aim of this study was to evaluate the effects of combined clopidogrel and aspirin on early neurologic deterioration up to a period of 30 days. Therefore, the groups should be followed for longer-term outcomes. Acknowledgment: The authors thank Medjaden Bioscience for assisting in the preparation of this manuscript. The authors declare that they have no competing interests.
References 1. Barnett HJM, Eliasziw M, Meldrum HE. Drugs and surgery in the prevention of ischemic stroke. N Engl J Med 1995;332:238-248. 2. Algra A, van Gijn J. Aspirin at any dose above 30 mg offers only modest protection after cerebral ischemia. J Neurol Neurosurg Psychiatry 1996;60:197-199. 3. Diener HC, Cunha L, Forbes C, et al. European Stroke Prevention Study 2: dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996;143:1-13. 4. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischemic events. Lancet 1996;348:1329-1339. 5. Schwammenthal Y, Tsabari R, Shenkman B, et al. Aspirin responsiveness in acute brain ischaemia: association with stroke severity and clinical outcome. Cerebrovasc Dis 2008;25:355-361. 6. Grundmann K, Jaschonek K, Kleine B, et al. Aspirin nonresponder status in patients with recurrent cerebral ischemic attacks. J Neurol 2003;250:63-66. 7. Gurbel PA, Bliden KP, Hiatt BL, et al. Clopidogrel for coronary stenting: response variability, drug resistance and the effect of pretreatment platelet reactivity. Circulation 2003;107:2908-2913. 8. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502. 9. Teal PA. Recent clinical trial results with antiplatelet therapy: implications in stroke prevention. Cerebrovasc Dis 2004;17(Suppl 3):6-10. 10. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent
A RANDOMIZED TRIAL
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
ischaemic stroke or transient ischaemic attack in highrisk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004;364:331-337. Wong KS, Chen C, Fu J, et al. Clopidogrel plus aspirin versus aspirin alone for reducing embolisation in patients with acute symptomatic cerebral or carotid artery stenosis (CLAIR study): a randomised, open-label, blindedendpoint trial. Lancet Neurol 2010;9:489-497. Markus HS, Droste DW, Kaps M, et al. Dual antiplatelet therapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using Doppler embolic signal detection: the clopidogrel and aspirin for reduction of emboli in symptomatic carotid stenosis (CARESS) trial. Circulation 2005;111:2233-2240. Kennedy J, Hill MD, Ryckborst KJ, et al. Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomized controlled pilot trial. Lancet Neurol 2007;6:961-969. Esagunde RU, Wong KS, Lee MP, et al. Efficacy of dual antiplatelet therapy in cerebrovascular disease as demonstrated by a decline in microembolic signals. A report of eight cases. Cerebrovasc Dis 2006;21:242-246. Alawneh JA, Moustafa RR, Baron JC. Hemodynamic factors and perfusion abnormalities in early neurological deterioration. Stroke 2009;40:e443-e450. Nolte CH, Albach FN, Heuschmann PU, et al. Silent new DWI lesions within the first week after stroke. Cerebrovasc Dis 2012;33:248-254. Lavallee PC, Labreuche J, Faille D, et al. Circulating markers of endothelial dysfunction and platelet activation in patients with severe symptomatic cerebral small vessel disease. Cerebrovasc Dis 2013;36:131-138. Toghi H, Suzuki H, Tamura K, et al. Platelet volume, aggregation, and adenosine triphosphate release in cerebral thrombosis. Stroke 1991;22:17-22. Han SW, Kim SH, Lee JY, et al. A new subtype classification of ischemic stroke based on treatment and etiologic mechanism. Eur Neurol 2007;57:96-102. Yi X, Zhou Q, Lin J, et al. Platelet response to aspirin in Chinese stroke patients is independent of genetic polymorphisms of COX-1 C50T and COX-2 G765C. J Atheroscler Thromb 2013;20:65-72. Zeller JA, Frahm K, Baron R, et al. Platelet-leukocyte interaction and platelet activation in migraine: a link to
7
22.
23.
24.
25.
26.
27.
28. 29.
30.
31.
32.
ischemic stroke? J Neurol Neurosurg Psychiatry 2004; 75:984-987. Wang Q, Chen C, Chen XY, et al. Low-molecular-weight heparin and early neurologic deterioration in acute stroke caused by large artery occlusive disease. Arch Neurol 2012;69:1454-1460. Hill MD, Barber PA, Demchuk AM, et al. Building a ‘brain attack’ team to administer thrombolytic therapy for acute ischemic stroke. CMAJ 2000;162: 1589-1593. Barber PA, Zhang J, Demchuk AM, et al. Why are stroke patients excluded from TPA therapy? An analysis of patient eligibility. Neurology 2001;56:1015-1020. 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;39:1647-1652. Albers GW, Amarenco P, Easton JD, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest 2008; 133:630S-669S. The European Stroke Association (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. Ruggeri ZM. Platelets in atherothrombosis. Nat Med 2002;8:1227-1234. Fateh-Moghadam S, Li Z, Ersel S, et al. Platelet degranulation is associated with progression of intima-media thickness of the common carotid artery in patients with diabetes mellitus type 2. Arterioscler Thromb Vasc Biol 2005;25:1299-1303. Marquardt L, Ruf A, Mansmann U, et al. Course of platelet activation markers after ischemic stroke. Stroke 2002;33:2570-2574. McCabe DJ, Harrison P, Mackie IJ, et al. Platelet degranulation and monocyte-platelet complex formation are increased in the acute and convalescent phases after ischaemic stroke or transient ischaemic attack. Br J Haematol 2004;125:777-787. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:1706-1717.
