Negative interaction of aspirin and streptokinase in acute ischemic stroke: further analysis of the Multicenter Acute Stroke Trial-Italy

BACKGROUND: Thrombolytic therapy improves the functional outcome in acute ischemic stroke, but the risk of death and cerebral hemorrhage remains high. Aspirin given together with a thrombolytic agent may worsen the risk-to-benefit ratio. We performed a further Multicenter Acute Stroke Trial-Italy (MAST-I) which is the only randomized, controlled trial that has tested the effect of this combination to evaluate the risk of aspirin use plus streptokinase. Patients and METHODS: We made a post hoc analysis of the MAST-I results comparing streptokinase plus aspirin (156 patients) with streptokinase alone (157 patients). We evaluated the risk of death and cerebral hemorrhage. RESULTS: The combined regimen significantly increased early case fatality from day 3-10 (53 vs. 30; OR 2.1; CI 1.2-3.6). The death excess was solely due to treatments and was not explained by the main prognostic predictors (multifactorial analysis). The cause of death in the combination group was mainly cerebral (42 vs. 24; OR 2.0; CI 1.3-3.7) and associated with hemorrhagic transformation (22 vs. 11; OR 2.2; CI 1.0-5.0). The rate of stroke reoccurrence was not increased in patients treated with streptokinase alone (15 vs. 11; OR 1.4; CI 0.6-3.4). CONCLUSIONS: Stroke patients treated with streptokinase plus aspirin have an increased risk of early death, probably due to cerebral hemorrhagic complications. Whenever thrombolytics are chosen for acute stroke treatment, aspirin and other antiplatelet agents should be avoided.     

Antiplatelet Agents for Stroke Prevention

Stroke is one of the leading causes of disability and death. Ischemic stroke is a syndrome with heterogeneous mechanisms and multiple etiologies, rather than a singularly defined disease. Approximately one third of ischemic strokes are preceded by another cerebrovascular ischemic event. Stroke survivors are at high risk of vascular events (i.e., cerebrovascular and cardiovascular events), particularly during the first several months after the ischemic event. The use of antiplatelet agents remains the fundamental component of secondary stroke prevention. Based on the available data, antiplatelet agents should be used for patients with noncardioembolic stroke. The use of combination therapy (aspirin plus clopidogrel) has not been proven to be effective or safe to use for prevention of early stroke recurrence or in long-term treatment. There is no convincing evidence that any of the available antiplatelet agents are superior for a given stroke subtype. Currently, the uses of aspirin, clopidogrel, or aspirin combined with extended release dipyridamole are all valid alternatives after an ischemic stroke or transient ischemic attack. However, to maximize the effects of these agents, the treatment should be initiated as early as possible and be continued on a lifelong basis.     

Antiplatelet therapy in ischemic stroke

Stroke is the third leading cause of death and the leading cause of disability in the developed world. Atherothrombosis is the underlying condition that results in events leading to ischemic stroke and vascular death. Antiplatelet therapy is commonly used for both acute stroke and in secondary prevention. Numerous trials and meta-analyses have left little doubt that antiplatelet therapy effectively reduces stroke risk in patients with prior stroke or transient ischemic attack. Current antiplatelet agents include acetylsalicylic acid, clopidogrel, ticlopidine and extended release dipyridamole with low doses of acetylsalicyclic acid (aspirin). The optimum doses of antiplatelet drugs depend upon several variables, such as genetic and environmental factors, so that clinical and laboratory response for dosage varies for each patient. Recently, the correlation between the laboratory-measurable effect of antiplatelet agents and the clinical effectiveness on the mortality of ischemic stroke and cardiovascular patients has been documented. Due to the side effect of bleeding with different antithrombotic drugs, their future employment will be determined in combination with low dosages of each component. Laboratory-controlled, tailored drug therapy will be needed for long-lasting secondary prevention of ischemic stroke.     

New modalities and aspects of antiplatelet therapy for stroke prevention

Antiplatelet therapy is indicated for secondary prevention of ischaemic stroke. The first-line antiplatelet agent is aspirin. The effect of aspirin is, however, very limited, and this limited effect of aspirin is argued with termed 'aspirin resistance'. Strategies against aspirin resistance may include alternative use of other antiplatelet agents, combination of aspirin with other antiplatelet agents and investigation into molecular targets to develop novel antiplatelet agents. Progress in antiplatelet therapy should be directed at further reducing the risk of ischaemic events including ischaemic stroke without increasing the risk of haemorrhagic events including haemorrhagic stroke.     

Antithrombotics for secondary prevention of noncardioembolic ischaemic stroke

Antiplatelet therapy is more effective than anticoagulation for the prevention of noncardioembolic ischaemic stroke. The choice of antiplatelet regimen, however, remains contentious. Recent controversies regarding aspirin resistance and the optimal dosing of aspirin, as well as recognition of the variable bioactivation of clopidogrel, have added further confusion to the debate. The American Heart Association (AHA) and American Stroke Association (ASA) recently released their third joint guideline in the past 5 years on secondary stroke prevention. The European Stroke Organisation has published three guidelines on this issue since 2000. These frequent updates have been necessary because of rapidly accumulating data from clinical trials. Careful consideration of the sometimes confusing trial results reveals that the 2011 AHA-ASA guidelines are correct in no longer specifying a 'preferred' antiplatelet regimen from among the choices recently studied. This recommendation does not, however, mean that all antiplatelet regimens should be considered equal. This Review discusses the various antiplatelet regimens, and the trials that led to the rapid evolution of the guidelines for secondary prevention of ischaemic stroke.     

Choices in medical management for prevention of acute ischemic stroke

Stroke is a leading cause of death and disability. Although advances are being made in the treatment of acute ischemic stroke, its prevention is equally as important. Identification and management of risk factors are essential. Medical therapy is also helpful in the secondary prevention of ischemic stroke. There are currently four plateletantiaggregating agents used to prevent ischemic stroke: aspirin, aspirin plus dipyridamole, clopidogrel, and ticlopidine. The relevant studies proving their efficacy are noted, as are some of their similarities and differences. The use of warfarin is also discussed.     

The experiences of an acute stroke unit--implications for multicentre acute stroke trials.

The suitability of 200 consecutive patients admitted to a newly established acute stroke unit was assessed for participation in two multicentre trials currently in their pilot phase: the International Stroke Trial of aspirin and heparin, and the Multicentre Acute Stroke Trial of streptokinase versus placebo. Of the 200 patients (74 men, 126 women, mean age 71 years), 96% had cerebral CT, and 94% had a final diagnosis of cerebrovascular disease. Overall, 50% of patients presented within 6 hours and 70% within 12 hours of the onset of ictus. A total of 113 patients (56.5%) were potentially eligible for trial treatment with aspirin/heparin. Only 9 patients (4.5%) were eligible for streptokinase treatment: 50% were excluded because they presented after 6 hours; 23% had a previous stroke with clinical sequelae and 23% had severe systemic illness. Forty eight per cent of patients had more than one exclusion criterion. The potentially high enrollment rates in trials of antithrombotic agents contrast with the restricted recruitment for trials of streptokinase, emphasising the need for multiple centres to achieve useful study enrollment.     

Streptokinase in acute ischemic stroke: an individual patient data meta-analysis : The Thrombolysis in Acute Stroke Pooling Project

BACKGROUND AND PURPOSE: Three major randomized controlled trials of streptokinase in acute ischemic stroke were curtailed because of safety concerns. The prospective Thrombolysis in Acute Stroke Pooling Project (TAS-PP) was established to examine the aggregate data to identify factors influencing the effect of streptokinase. METHODS: Individual patient data from the Australian Streptokinase Trial (ASK), Multicentre Acute Stroke Trial-Europe (MAST-E), Multicentre Acute Stroke Trial-Italy (MAST-I), and Glasgow Trial (Glasgow) were pooled. Multivariate modeling determined the interaction between treatment effect and delay from symptom onset to treatment, predicted baseline risk, age, concomitant aspirin or heparin use, and the presence of early CT signs on the outcomes of 10-day death, death and disability, or death alone at 3 or 6 months. RESULTS: Patients' records were pooled (total 1292 patients; streptokinase, n=653, no streptokinase n=639). The subgroup analysis of treatment effect according to delay from symptoms to inclusion shows only a trend toward a better treatment effect with shorter delay, which is not statistically significant for any outcome. Heavier patients in MAST-E may have had a lower (non significant) risk from the fixed dose of 1.5 million units of streptokinase. Concomitant aspirin increased the excess mortality rates in streptokinase-treated patients (17% without aspirin versus 91% with aspirin, P=0.005). The presence of early CT scan signs did not increase the detrimental effect of streptokinase. CONCLUSIONS: Few factors influenced the response to streptokinase. However, earlier administration, lower doses of streptokinase, and avoidance of concomitant aspirin should be considered if further streptokinase trials in acute stroke are planned.     

Future perspectives for optimizing oral antiplatelet therapy

Secondary prevention of stroke and other manifestations of atherothrombosis is essential if the burden of disease associated with these events is to be reduced. Therefore, it is important to identify patients most likely to benefit from antiplatelet therapy. There is a good rationale for combining antiplatelet agents with different modes of action, since different signalling pathways contribute to platelet activation. Based on the promising results obtained with an adenosine diphosphate receptor antagonist-aspirin combination in coronary stenting, several additional trials with clopidogrel plus aspirin are ongoing. They include CURE (Clopidogrel in Unstable angina to prevent Recurrent Events, in unstable angina and non-Q-wave myocardial infarction) and COMMIT (in acute myocardial infarction), which compare clopidogrel with placebo in patients receiving aspirin, and CREDO (Clopidogrel for Reduction of Events During extended Observation), a 1-year treatment follow-up to the clopidogrel arms of the CLASSICS trial (Clopidogrel Aspirin Stent International Cooperative Study). Planned trials with clopidogrel in neurology include SPS3 (Secondary Prevention of Small Subcortical Strokes, in patients with symptomatic lacunar stroke), and MATCH (Management of Atherothrombosis with Clopidogrel in High-risk patients, in patients with stroke or transient ischaemic attack plus one additional risk factor), which will compare the efficacy of clopidogrel plus aspirin versus clopidogrel in reducing important ischaemic events. Combination therapy with an oral glycoprotein (GP) IIb/IIIa receptor antagonist plus aspirin has so far been less promising. Trials of three compounds--orbofiban, xemilofiban and sibrafiban--in combination with aspirin for secondary prevention in cardiac patients have reported increased mortality compared with aspirin alone. A similar effect was seen when sibrafiban monotherapy was compared directly with aspirin alone. Trials of newer oral GP IIb/IIIa inhibitors are under way or are planned. The combination of dipyridamole plus aspirin appears to be superior to aspirin alone for the prevention of stroke in patients with stroke or transient ischaemic attack; the effectiveness of this combination is being further investigated in ESPRIT (European/Australian Stroke Prevention in Reversible Ischaemia Trial).     

强化抗血小板治疗在缺血性脑卒中复发高危患者二级预防中的临床研究

目的观察强化抗血小板药物氯吡格雷在缺血性脑卒中复发高危患者二级预防中的长期疗效及安全性。方法采用艾森卒中风险评分（ESRS）量表筛选住院的急性非心源性缺血性脑卒中复发高危患者100例,随机分为氯吡格雷组和阿司匹林组,每组50例。两组均给予脑卒中常规治疗,氯吡格雷组予氯吡格雷75mg及阿司匹林100mg口服,1周后仅予氯吡格雷75mg,口服。阿司匹林组予阿司匹林200mg,口服,1周后改为100mg,口服。随访3个月和1年,观察两组缺血性脑卒中复发率及药物不良反应发生率。结果随访3个月时,脑卒中复发率：阿司匹林组为6．3％,氯吡格雷组为2．0％,差异无统计学意义（P〉0．05）;药物不良反应发生率：阿司匹林组为14％,氯吡格雷组为2％,差异有统计学意义（P〈0．05）。随访1年时,脑卒中复发率：阿司匹林组为13％,氯吡格雷组为2％,差异有统计学意义（P〈0．05）;药物不良反应发生率：阿司匹林组为38％,氯吡格雷组为6％,差异有统计学意义（P〈0．01）。结论缺血性脑卒中复发高危患者二级预防中强化抗血小板治疗可降低脑卒中复发风险,长期应用获益较高,安全性好。     

Ischemic stroke prevention: an update on antiplatelet therapy

Stroke is the third leading cause of mortality in the United States. As the leading cause of neurological deficits worldwide, stroke is associated with tremendous costs both to society and to the individuals and families stroke impacts. Antiplatelet agents have demonstrated efficacy in preventing recurrent atherothrombotic strokes and are the principal pharmacologic modality employed. With the recent development of the thienopyridines and the resurgence of dipyridamole, recommendations for antiplatelet therapy have undergone several iterations over the past decade. The focus of this review is to provide an update on the individual antiplatelet agents and recapitulate the current guidelines for antiplatelet selection and use in either transient ischemic attack or noncardiogenic ischemic stroke patients. Mechanisms of action, demonstrated efficacy, adverse effect profiles, and current consensus recommendations are reviewed for four conventional antiplatelet strategies, aspirin, ticlopidine, clopidogrel, and the combination of aspirin and extended-release dipyridamole.     

Current Status of Antiplatelet Agents to Prevent Stroke

Stroke is one of the leading causes of disability; most are due to atherothrombotic mechanisms. About one third of ischemic strokes are preceded by other stroke or transient ischemic attacks. Stroke survivors are at high risk for vascular events (i.e., cerebrovascular and cardiovascular). Prevention of recurrent stroke and other major vascular events can be accomplished by control of risk factors. Nonetheless, the use of antiplatelet agents remains the fundamental component of secondary stroke prevention strategy in patients with noncardioembolic disease. Currently, the uses of aspirin, clopidogrel, or aspirin plus extended-release dipyridamole are valid alternatives for stroke or transient ischemic attack patients. To maximize the beneficial effects of these agents, the treatment should be initiated as early as possible and continue on a lifelong basis.     

Prior therapy with antiplatelet agents is not associated with outcome in patients with acute ischemic stroke/TIA

BACKGROUND AND PURPOSE: It is unclear whether prior therapy with antiplatelet agents (APA) is associated with a better outcome in patients with acute ischemic cerebrovascular events. METHODS: Within a multi-center cross-sectional study, nested in a cohort we analyzed the relation between prior therapy with APA and stroke severity in 1643 patients with acute ischemic stroke or TIA. Clinical severity of the vascular event was evaluated by the National Institutes of Health Stroke Scale on admission (NIHSS1) and after 1 week (NIHSS2). By means of analysis of variance we analyzed a possible association of APA with stroke severity and interactions regarding stroke severity between APA and other clinical measures. RESULTS: 475 patients (29 %) received aspirin prior to the cerebrovascular event, 51 patients (3 %) ticlopidine or clopidogrel and 26 patients (1.6%) aspirin combined with extended release dipyridamole. 66% (1091) of patients did not take any antiplatelet medication. Neither the NIHSS1 nor the NIHSS2 nor the change of stroke severity between these time points (NIHSS1- NIHSS2) was associated with prior APA medication. We did not find significant interactions between APA use and clinical measures regarding stroke severity. CONCLUSIONS: Our results do not indicate that prior therapy with APA is associated with a better outcome in acute ischemic cerebrovascular events. There were no interactions found with other features that were associated with stroke severity.     

Antithrombotic therapy in cerebral infarction]

Antithrombotic therapy for the acute stage of cerebral infarction consists of thrombolysis, anticoagulant therapy and antiplatelet therapy, and their indications depend on the clinicopathological type of lesion, time after onset, and severity of illness. Tissue plasminogen activator has been approved in the United States for use in cerebral infarction within 3 hours after onset. The usefulness of heparin as anticoagulant therapy at the acute stage of cerebral infarction was not proved by the International Stroke Trial due to hemorrhagic complication. A selective thrombin inhibitor (argatroban) is used in Japan for atherothrombotic cerebral infarction within 48 hours after onset. A selective thromboxane A2 synthetase inhibitor (sodium ozagrel) had been approved for cerebral thrombosis within 5 days after onset. Aspirin (160-300 mg/day) is effective, but slightly, in the acute stage of cerebral infarction by the International Stroke Trial and Chinese Acute Stroke Trial. To prevent recurrence of stroke in the chronic stage of cerebral infarction, antiplatelet therapy (with aspirin or ticlopidine) is used for atherothrombotic cerebral infarction, and anticoagulant therapy with warfarin for cardioembolic cerebral infarction.     

Progress in clinical neurosciences: pharmacotherapies for the secondary prevention of stroke

Stroke is a leading cause of mortality and long-term disability worldwide. Survivors of a previous stroke or transient ischemic attack are vulnerable to further cerebrovascular events, as well as myocardial infarction, peripheral vascular disease, congestive heart failure and vascular death. Traditional approaches to the secondary prevention of stroke have included aspirin after ischemic stroke, warfarin for stroke associated with cardioembolic sources, and carotid endarterectomy for eligible candidates with significant carotid artery stenosis. In recent years, much evidence has emerged to support a broader array of pharmacotherapies, including newer antiplatelet agents, lipid lowering drugs, and several classes of blood pressure lowering therapies. Also under study are B vitamins for patients with cerebrovascular disease and hyper-homocysteinemia, and oral direct thrombin inhibitors for high-risk patients with atrial fibrillation. We review the literature to determine the clinical significance of these therapies, and provide recommendations regarding their use in the prevention of recurrent stroke.     

Prevention of stroke recurrence

Stroke recurrence can be reduced substantially by intervention with the appropriate stroke preventive(s). Control of blood pressure, use of one of the antiplatelet agents aspirin, aspirin plus extended (modified)-release dipyridamole, or clopidogrel, administration of warfarin for patients with atrial fibrillation and high-risk profiles for stroke, and use of carotid endarterectomy in patients with high grades of symptomatic carotid artery stenosis are all proven therapies for prevention of stroke recurrence. Newer therapies to reduce the risk of infection and inflammation promise to further reduce the risk of first and recurrent stroke and are undergoing testing. In this article we review standard and more novel means to prevent stroke recurrence.     

Ischemic stroke prevention: An update on antiplatelet therapy

Abstract

Stroke is the third leading cause of mortality in the United States. As the leading cause of neurological deficits worldwide, stroke is associated with tremendous costs both to society and to the individuals and families stroke impacts. Antiplatelet agents have demonstrated efficacy in preventing recurrent atherothrombotic strokes and are the principal pharmacologic modality employed. With the recent development of the thienopyridines and the resurgence of dipyridamole, recommendations for antiplatelet therapy have undergone several iterations over the past decade. The focus of this review is to provide an update on the individual antiplatelet agents and recapitulate the current guidelines for antiplatelet selection and use in either transient ischemic attack or noncardiogenic ischemic stroke patients. Mechanisms of action, demonstrated efficacy, adverse effect profiles, and current consensus recommendations are reviewed for four conventional antiplatelet strategies, aspirin, ticlopidine, clopidogrel, and the combination of aspirin and extended-release dipyridamole. [Neurol Res 2002; 24: 381-388]     

Follow-up Imaging After Thrombolysis: FIAT,A Randomized Trial

Trial DesignCurrent protocols for treatment of acute ischemic stroke with intravenous thrombolytics, such as alteplase (tPA) and tenecteplase (tNK), recommend the completion of a routine non-contrast head CT at 24 hours post treatment to evaluate for hemorrhage prior to the initiation of antiplatelet therapy for secondary stroke prevention. This guideline was instituted because it had been part of the protocol in the NINDS multicenter randomized placebo-controlled trial that showed the benefit of IV thrombolytics within 3 hours of stroke onset. Recent observational studies indicate that the repeat (stability) head CT rarely alters clinical management, in the absence of neurological worsening or evidence of clinical signs of hemorrhagic conversion, such as seizures, severe headache, or novel acute deficits. A solitary CT carries with it a non-negligible dose of radiation with additive cost to the medical system at large.MethodsWe aimed to identify, with a randomized, blinded outcome assessment trial, if a routine head CT at 24 hours, in the absence of clinical indication, negatively influences clinical outcomes. We enrolled 58 patients, and evaluated differences between groups with t-tests. We also evaluated differences between outcomes (90 day modified Rankin Scale, mRS and change in National Institutes of Health Stroke Scale, NIHSS) from pretreatment to discharge using multivariable logistic regression, including age, baseline NIHSS, and group as independent variables.ResultsWe found no added benefit of routine CT on either outcome measure.ConclusionIt is likely safe to forgo follow up imaging after thrombolysis in the absence of clinical decompensation.     

Use of antiplatelet agents to prevent stroke: What is the role for combinations of medications?

Antiplatelet agents are the medications of choice for preventing non-cardioembolic strokes. The diverse pathways involved in platelet function suggest the possibility of synergistic effects by combining various agents. In heart disease and in the setting of coronary artery stents, antiplatelet therapy with clopidogrel and aspirin has established benefits. Although it is tempting to extrapolate the benefits of this combination for stroke prevention, recent clinical trials have not borne this out. Unacceptable bleeding risks without additional efficacy weigh against the routine use of clopidogrel with aspirin for stroke prophylaxis. The combination of aspirin and extended-release dipyridamole has demonstrated superiority over aspirin in two large secondary stroke prevention trials.