Combining antiplatelet and thrombolytic therapies for stroke

Pharmacological therapy for acute nonhaemorrhagic stroke has become a reality over the last 5 years. Mechanistically, both thrombolytic (tissue plasminogen activator and urokinase) and antiplatelet (aspirin) monotherapy have demonstrated efficacy. However, unintended actions limit the extent of clinical improvement in each circumstance. For example, in addition to excess bleeding, tissue plasminogen activator therapy has been associated with complement activation, neuronal toxicity and laminin degradation, while aspirin may reduce nitric oxide synthase activity and cerebral blood flow. Attention is now directed toward improving the therapeutic index for each class of agents. Generally, while thrombolytic therapy is focused on developing agents with greater fibrin specificity and safety (that is, a reduction in intracranial haemorrhage rate), the development of antiplatelet agents is primarily focused on achieving greater potency. The latter is being investigated by combining agents with different mechanisms (aspirin and dipyridamole, aspirin and clopidogrel) as well as agents designed to block the glycoprotein IIb/IIIa receptor, the final common pathway for platelet aggregation. Thus, combination therapy using both thrombolytic and antiplatelet agents will further attempt to improve the therapeutic index by increasing potency and improving the safety profile. Anecdotal case studies support the merits of this approach and are consistent with the data reported for myocardial ischaemia and interventional strategies. It is anticipated that drug therapy directed at both thrombolytic and antiplatelet targets will ultimately result in a widened therapeutic window that will allow acute stroke therapy to be administrated to a much greater number of patients than is currently possible.     

溶栓药物治疗缺血性卒中的进展

自16年前首次被证明静脉溶栓可有效治疗急性缺血性卒中以来,溶栓率一直不高。尽管很多试验证明了许多溶栓药物的疗效,但静脉注射用组织型纤溶酶原激活剂(rt-PA,0.9 mg.kg-1)几乎成为惟一用于溶栓治疗的溶栓剂。针对这种情况,研究者正在多方面对研究工作进行改进,包括使用新的溶栓药物。另外,研究者正在尝试用新的溶栓剂、低剂量的rt-PA、神经保护剂等减少症状性脑出血的危险。     

Novel situations of endothelial injury in stroke--mechanisms of stroke and strategy of drug development: protective effects of antiplatelet agents against stroke

Stroke is the second cause of mortality worldwide, and intravenous administration of tissue plasminogen activator (t-PA) within 3 h of symptom onset is the only treatment proven effective for re-establishment of cerebral blood flow following acute ischemic stroke. However, its widespread application remains limited by its narrow therapeutic time window and the related risks of intracranial hemorrhage. On the other hand, in patients with atherothrombotic risk, antiplatelet agents are widely used to decrease the risk of occlusive arterial events. All of these drugs are used during coronary interventions and in the medical management of acute coronary syndromes. In contrast, only aspirin, cilostazol, and thienopyridine derivatives (ticlopidine and clopidogrel) are used in the long-term prevention of cerebrovascular events in patients with risk of recurrence. In this paper, we introduce recent clinical findings on antiplatelet therapies for secondary prevention after ischemic stroke and describe basic research that has focused on cerebrovascular protection by cilostazol, which has a unique pharmacological profile.     

Stroke: antithrombin versus antiplatelet therapy

The success of thrombolytic therapy for acute stroke has demonstrated that neurologic outcome can be improved with timely treatment. However, the severely restricted use of thrombolytics has reinforced the need to develop alternative and complementary therapies. Antithrombin and antiplatelet agents represent promising therapeutic approaches for stroke management. Antiplatelet therapy has modestly improved outcome in both acute stroke (aspirin) and in secondary stroke prevention (aspirin with or without dipyridamole; adenosine receptor antagonists), although bleeding and other adverse events associated with antithrombin therapy have largely negated their potential benefit. These findings have prompted innovative solutions to the pharmacokinetic and pharmacodynamic challenges that are crucial to advancing these strategies for acute, primary and secondary stroke therapy. Currently, inhibitors of the platelet surface glycoprotein IIb/IIIa (GP IIb/IIIa, fibrinogen) receptor are being examined in clinical trials while antithrombin therapies focus on thrombin antagonists and inhibitors as well as inhibitors of Factor Xa. Further advances in stroke treatment will include combination therapies. Additionally, the successful design of future drug therapies will result from a more complete understanding of the activity of these agents not only on platelet function and the coagulation cascade, but also for their effects on the endothelium and within the brain parenchyma. The sum of these activities will allow for the maintenance of cerebral blood flow, blood-brain barrier integrity and neuronal function.     

Stroke: antithrombin versus antiplatelet therapy

The success of thrombolytic therapy for acute stroke has demonstrated that neurologic outcome can be improved with timely treatment. However, the severely restricted use of thrombolytics has reinforced the need to develop alternative and complementary therapies. Antithrombin and antiplatelet agents represent promising therapeutic approaches for stroke management. Antiplatelet therapy has modestly improved outcome in both acute stroke (aspirin) and in secondary stroke prevention (aspirin with or without dipyridamole; adenosine receptor antagonists), although bleeding and other adverse events associated with antithrombin therapy have largely negated their potential benefit. These findings have prompted innovative solutions to the pharmacokinetic and pharmacodynamic challenges that are crucial to advancing these strategies for acute, primary and secondary stroke therapy. Currently, inhibitors of the platelet surface glycoprotein IIb/IIIa (GP IIb/IIIa, fibrinogen) receptor are being examined in clinical trials while antithrombin therapies focus on thrombin antagonists and inhibitors as well as inhibitors of Factor Xa. Further advances in stroke treatment will include combination therapies. Additionally, the successful design of future drug therapies will result from a more complete understanding of the activity of these agents not only on platelet function and the coagulation cascade, but also for their effects on the endothelium and within the brain parenchyma. The sum of these activites will allow for the maintenance of cerebral blood flow, blood-brain barrier integrity and neuronal function.     

Fibrinolytic treatment for acute ischaemic stroke

Ischaemic stroke is a leading cause of death and disability in the US. At present, intravenous administration of tissue plasminogen activator within 3 h of symptom onset is the only proven effective treatment for patients with acute ischaemic stroke. Unfortunately, most treated patients do not make a functional recovery and very few patients presenting with acute stroke qualify for intravenous tissue plasminogen activator therapy. The focus of current research is to extend the therapeutic window for intervention beyond 3 h, and to improve the outcome of treated patients. The purpose of the present paper is to describe the current state of affairs for intravenous plasminogen activators, and to review recently published research. Agents and strategies under investigation include the intra-arterial delivery of plasminogen activators or antiplatelet agents, as well as combined intravenous/intra-arterial protocols.     

Fibrinolytic treatment for acute ischaemic stroke

Ischaemic stroke is a leading cause of death and disability in the US. At present, intravenous administration of tissue plasminogen activator within 3 h of symptom onset is the only proven effective treatment for patients with acute ischaemic stroke. Unfortunately, most treated patients do not make a functional recovery and very few patients presenting with acute stroke qualify for intravenous tissue plasminogen activator therapy. The focus of current research is to extend the therapeutic window for intervention beyond 3 h, and to improve the outcome of treated patients. The purpose of the present paper is to describe the current state of affairs for intravenous plasminogen activators, and to review recently published research. Agents and strategies under investigation include the intra-arterial delivery of plasminogen activators or antiplatelet agents, as well as combined intravenous/intra-arterial protocols.     

Thrombolytics: drug interactions of clinical significance.

Thrombolytic agents activate plasminogen and induce a systemic fibrinolytic and anticoagulant state. Interaction of fibrinolysis with coagulation and platelet aggregation might be important for synergistic interactions with other antiplatelet or anticoagulant drugs. Thrombolytic agents are most often used in patients with coexisting cardiovascular medication, including various antihypertensives, beta-blocking agents, nitrates and aspirin (acetylsalicylic acid). In acute coronary syndromes, anticoagulants and antiplatelet compounds such as clopidogrel or glycoprotein IIb/IIIa receptor antagonists might be given. Inducers or inhibitors of the cytochrome P450 system are not reported to affect the pharmacokinetics of any thrombolytic agent. Since the elimination of the recombinant plasminogen activators saruplase and alteplase is dependent on liver blood flow, drugs affecting hepatic blood flow could theoretically affect the hepatic clearance of these agents. In fact, a reduction in thrombolytic activity has only been demonstrated for alteplase with nitroglycerin (glyceryl trinitrate). Pharmacodynamic interactions occur more often. The additive and beneficial effect of aspirin as concomitant therapy to thrombolysis has been demonstrated without excessive bleeding rates. No data are available on the interaction between ticlopidine or clopidogrel and thrombolytic agents in humans. Anticoagulation by heparin concomitantly with thrombolysis improves the patency rate of the occluded coronary vessel, but bleeding complications are seen more frequently. Although there has been no controlled study on the interaction between oral anticoagulants and thrombolytic agents, patients with myocardial infarction who were taking an oral anticoagulant before admission seem to be at higher risk for intracranial haemorrhage during thrombolytic therapy. Currently, no recommendations can be given for possible dose adjustment of thrombolytic therapy in patients receiving antiplatelet comedication. For comedication with heparin, it has been advised to monitor activated partial thromboplastin time frequently and to avoid values >2.5-fold normal. Patients receiving thrombolytic treatment should be monitored frequently for bleeding and the physician should be aware of any comedication exerting antiplatelet (e.g. aspirin, clopidogrel and ticlopidine) or anticoagulant (e.g. warfarin) effects.     

Pharmacoeconomic aspects of treatment of acute myocardial infarction with thrombolytic agents

Thrombolytic therapy reduces early mortality, preserves left ventricular function and improves long term prognosis of acute myocardial infarction. However it is relatively expensive and increasing use will have considerable financial consequences. With competing demand for health resources, information on economic evaluation of this revolutionary therapeutic modality is much needed. Economic evaluation of thrombolytic therapy of acute myocardial infarction entails the assessment of all resources consumed (costs) directly and indirectly in relation to the administration of thrombolytic drugs, versus the beneficial effects (outcome) on health preservation of the patients. To save 1 year of life, the costs of thrombolytic therapy using intravenous streptokinase, alteplase (recombinant tissue plasminogen activator; rt-PA) or anistreplase (anisoylated plasminogen streptokinase activator complex) under standard restricted indication criteria, vary from 1000 pounds British sterling to 1700 pounds British sterling in the UK, SEK3090 to 9660 in Scandinavia and $US35 000 to 800 000 in the US, depending on time delay in starting treatment after pain onset, size of infarct, thrombolytic agents used, study methodology, lists of clinical events considered in cost counting and the discount rate. Cost-utility analyses revealed that the costs of thrombolytic treatment are similar to those of many other treatments for cardiac or other diseases, but methods for evaluating quality of life and utility require further refinement and validation. Economic assessments confirm that thrombolytic treatment of the elderly ( greater than 70 years) is as cost-effective as treatment of younger patients and that both early and late thrombolytic therapy (given 6 to 12 hours after infarction) are beneficial and cost-effective. There are major logistical problems with prehospital thrombolysis, which despite great initial enthusiasm, is unlikely to be cost-effective in saving lives unless savings in time are greater than 1 hour. Cost-effectiveness/utility value of one drug determined from one study cannot be directly compared with that found in other studies using different drugs. More direct prospective comparative trials will be needed in respect of relative benefits and costs with different agents and adjunctive therapies.     

Antiplatelet therapy in cerebrovascular disorders

Antiplatelet treatment is a mainstay in acute and long-term secondary stroke prevention. Aspirin is still most widely used worldwide, however, there is increasing evidence from small randomised trials that dual antiplatelet therapy combining aspirin with dipyridamole or clopidogrel might be more effective in the acute and early chronic post-ischemic phase (i.e. first 90 days). Both clopidogrel and the combination of aspirin and extended-release dipyridamole are recommended by current guidelines in long-term secondary stroke prevention in patients who are at high risk for a recurrent ischemic stroke, since they are more effective compared with aspirin monotherapy.Antiplatelet agents are the therapy of choice in patients with ischemic stroke due to intracranial stenosis and patent foramen ovale. In contrast, oral anticoagulation is clearly superior to single or double antiplatelet therapy in patients with cardioembolic stroke, mainly caused by atrial fibrillation.Concerning newer antiplatelet agents, only cilostazol appears to be a promising therapeutic option in patients with ischemic stroke in the near future, but so far, only studies in Asian stroke patients have been performed.     

Antithrombotic trials in acute ischaemic stroke: a selective review

Stroke is a common cause of morbidity and mortality throughout the US and the world. Given the highly disabling nature of this disease, it is important to provide acute therapy when indicated to improve individual outcomes. Recombinant tissue plasminogen activator (rt-PA) is, at present, the only approved drug for the treatment of acute strokes due to cerebral ischaemia. It can be given intravenously within a 3-h window of the onset of neurological deficits. Intra-arterial administration of rt-PA within a 6-h window is performed at several academic centres in patients with middle cerebral and other intracranial artery occlusions based on results of a randomised clinical trial. Other thrombolytic agents are being studied in randomised trials. Although acute therapy of ischaemic stroke has received much attention since the approval of rt-PA, only a small percentage of individuals actually receive rt-PA. This article will review the main thrombolytic agents and the trials performed thus far, as well as examine some important ongoing trials. How administration of acute thrombolytic therapy may evolve in the future will also be addressed.     

Advances in thrombolytic therapy for acute myocardial infarction

There has been rapid proliferation of understanding and experience with thrombolytic therapy for acute myocardial infarction. Over the last few years, selective intracoronary infusion of lytic therapy has been replaced by intravenous administration because of the fundamental importance of time to reperfusion. Newer thrombolytic agents, such as tissue plasminogen activator (t-PA) and acylated streptokinase (APSAC), with properties distinct from streptokinase (SK) and urokinase, have been developed and have undergone extensive clinical trial evaluation. This review will focus primarily on the recent advances in thrombolytic therapy, with particular attention to efficacy, safety, and comparative aspects of the various agents currently or soon to be available.     

Locally delivered plasmin: why should it be superior to plasminogen activators for direct thrombolysis?

With advances in the field of thrombolytic therapy, whereby clots are routinely treated locally via a catheter, traditional systemic thrombolytics such as plasminogen activators might not be the best drugs for this task. Plasmin represents a new class of thrombolytic agents that exhibit direct fibrinolytic activity, without the need for either plasminogen or a plasminogen activator. In contrast to plasminogen activators, this independence from plasminogen allows plasmin to efficiently dissolve long, retracted blood clots that are inherently deficient in plasminogen. Preclinical safety studies in rabbits demonstrate that plasmin, in contrast to tissue-type plasminogen activator, does not cause re-bleeding from preformed hemostatic plugs. These results predict that plasmin will prove to be both superior to, and safer than, plasminogen activators in the dissolution of long, retracted blood clots in humans.     

The development of new drugs for acute stroke

Stroke represents the third common cause of death and hospitalization. However, there are yet no drugs that have reliable effects on acute stroke in Japan. Therefore, the development of new drugs that can support patients is required. There are various candidate drugs for acute stroke such as antithrombotic agents, anticoagulants, thrombolytic agents, neuroprotectants, and so on. Recently clinical trials suggest that aspirin may improve outcome, although these studies demonstrated a modest benefit of aspirin. Abciximab (ReoPro) is a human/mouse monoclonal antibody directed against the platelet receptor glycoprotein IIb/IIIa. It appears to be safe and might improve functional outcome. The large randomized trails were started to test the hypothesis that thrombolysis by an intravenous administration of a recombinant tissue type plasminogen activator (rtPA) could restore cerebral blood flow and improve patient outcome in acute ischemic stroke. These results can support the use of intravenous rtPA for stroke treatment within 3 h after onset, but not beyond 3 h. Development of an effective neuroprotective agent for the treatment of acute stroke remains problematic. Antioxidants, MCI-186 and ebselen, have finished phase III of clinical trials in Japan and were effective. We hope that efficacious drugs for acute stroke can be used for patients.     

Vascular protection to increase the safety of tissue plasminogen activator for stroke

Thrombolytic therapy with tissue plasminogen activator (tPA) remains the most effective treatment for acute ischemic stroke, but can cause vascular damage leading to edema formation and hemorrhagic transformation (HT). In this review, we discuss how tPA contributes to the pathogenesis of vascular damage and highlight evidence to support combination therapy of tPA with pharmacological agents that are vascular protective. There is an unmet need to develop therapeutic interventions which target the underlying mechanisms of vascular damage after acute ischemic stroke in order to prevent HT and improve the safety and impact of tPA.     

Plasminogen activation-based thrombolysis for ischaemic stroke: the diversity of targets may demand new approaches

The plasminogen activating enzyme system has been exploited and harnessed for therapeutic, mainly thrombolytic benefit for many years. While plasminogen activator-based thrombolysis turned out to be a resounding success, it has become apparent that the "plasminogen activating system" per se is not only designed to simply remove fibrin and some other matrix proteins. Indeed, the plasminogen activators and the plasminogen activator inhibitors have important effects on cell signalling through both proteolytic and non-proteolytic means and can promote unwanted side effects, particularly in the brain. Tissue type plasminogen activator (t-PA) was heralded as a fibrin-selective plasminogen activator and subjected to clinical development in the early 1980's initially for the treatment of patients with myocardial infarction. t-PA was given FDA approval in the mid 1990's for use in ischaemic stroke patients, but it could only be administered within a short 3h window post- stroke as later use was associated with an increased risk of intracerebral haemorrhage. Hence only a small percentage of these patients were eligible for thrombolysis to restore blood flow to the brain. Since t-PA-mediated plasmin generation is not only impacting on the cerebral blood clot, extending the therapeutic time window for thrombolysis is not a simple task. The ultimate success will depend on how well the future generation of thrombolytic agents promote efficacious removal of a fibrin clot without promoting collateral damage particularly in the brain.     

溶血栓药物在急性脑梗死中的应用进展

脑梗死是导致人类致残和死亡的主要疾病之一,在发生脑梗死的超急性期,积极给予溶栓治疗,开通闭塞的血管,恢复缺血区的再灌注是治疗的关键。目前只有重组组织型纤溶酶原激活剂(rt-PA)被FDA批准应用于急性脑梗死的溶栓治疗,其他的许多药物如瑞替普酶,替奈普酶,去氨普酶、安克洛酶等在脑梗死治疗应用方面正在探索中。本文将针对上述几种主要的溶血栓药物及其已经开展的相关临床研究进行论述。     

Advances in ischemic stroke treatment: neuroprotective and combination therapies

Thrombolysis with intravenous alteplase (recombinant tissue-type plasminogen activator) continues to be the sole recourse for acute ischemic stroke therapy, provided that patients seek treatment preferably within 3 h of stroke onset. The narrow window of efficacy, coupled with the significant risk of hemorrhage and the high mortality rate, preclude the use of alteplase beyond this time frame. Moreover, in part because of safety concerns, only a small percentage (6-15%) of eligible patients is treated with alteplase. Clearly, safer and more effective treatments that focus on improving the shortcomings of the present thrombolysis for stroke need to be identified. Therefore, newer thrombolytics are being developed with the goal of minimizing side effects, while also shortening the time of cerebral reperfusion and extending the therapeutic window of efficacy. Besides thrombolytics, new and potentially useful drugs and devices are also being studied either as monotherapeutic agents or for use in conjunction with alteplase. In animal models of stroke, neuroprotective agents that affect various components of the ischemic injury cascade that results in neurodegeneration have shown promise for the latter. Examples of such agents include spin traps that block oxidative stress, metalloprotease inhibitors that prevent vascular damage, anti-inflammatory drugs that suppress inflammation and transcranial infrared laser irradiation, which promotes recovery of function. Ideally, a successful combination of neuroprotectant (drug or device) and thrombolytic therapy for stroke would minimize the side effects of thrombolysis followed by supplementary neuroprotection thereafter.     

卒中单元联合重组组织型纤溶酶原激活剂静脉溶栓治疗脑梗死效果观察

目的探讨卒中单元联合重组组织型纤溶酶原激活剂（rt—PA）静脉溶栓治疗急性脑梗死的效果。方法2012年1—10月采用卒中单元联合rt—PA静脉溶栓治疗发病4．5h内急性脑梗死15例,观察治疗后神经功能缺损量表（NIHSS）评分改善情况、临床疗效和不良反应发生情况。结果治疗后各时点NIHSS评分较治疗前均降低,差异有统计学意义（P〈0．05）;治疗21d总有效率为86．67％,治疗期间未见明显不良反应。结论急性脑梗死发病4．5h内给予卒中单元联合rt—PA静脉溶栓治疗疗效显著,且安全可行。     

Advances in ischemic stroke treatment: neuroprotective and combination therapies

Thrombolysis with intravenous alteplase (recombinant tissue-type plasminogen activator) continues to be the sole recourse for acute ischemic stroke therapy, provided that patients seek treatment preferably within 3 h of stroke onset. The narrow window of efficacy, coupled with the significant risk of hemorrhage and the high mortality rate, preclude the use of alteplase beyond this time frame. Moreover, in part because of safety concerns, only a small percentage (6 – 15%) of eligible patients is treated with alteplase. Clearly, safer and more effective treatments that focus on improving the shortcomings of the present thrombolysis for stroke need to be identified. Therefore, newer thrombolytics are being developed with the goal of minimizing side effects, while also shortening the time of cerebral reperfusion and extending the therapeutic window of efficacy. Besides thrombolytics, new and potentially useful drugs and devices are also being studied either as monotherapeutic agents or for use in conjunction with alteplase. In animal models of stroke, neuroprotective agents that affect various components of the ischemic injury cascade that results in neurodegeneration have shown promise for the latter. Examples of such agents include spin traps that block oxidative stress, metalloprotease inhibitors that prevent vascular damage, anti-inflammatory drugs that suppress inflammation and transcranial infrared laser irradiation, which promotes recovery of function. Ideally, a successful combination of neuroprotectant (drug or device) and thrombolytic therapy for stroke would minimize the side effects of thrombolysis followed by supplementary neuroprotection thereafter.