Management of acute ischaemic stroke in the elderly: tolerability of thrombolytics

Stroke and its consequences are of global concern. Although stroke can affect individuals of any age, it primarily affects the elderly. It is among the leading causes of severe disability and mortality. In recent years, acute stroke has become a medical emergency requiring urgent evaluation and treatment. Effective management of patients with acute stroke starts with organisation of the entire stroke care chain, from the community and prehospital scene, through the emergency department, to a dedicated stroke unit and then to comprehensive rehabilitation. Intravenous thrombolysis with alteplase (recombinant tissue plasminogen activator; rt-PA) 0.9 mg/kg (maximum dose 90 mg) was shown to significantly improve outcome of acute ischaemic stroke, despite an increased rate of symptomatic intracerebral haemorrhage, if treatment is initiated within 3 hours after the onset of symptoms to patients who meet strict eligibility criteria. Post-marketing studies have demonstrated that intravenous alteplase can be administered appropriately in a wide variety of hospital settings. However, strict adherence to the published protocol is mandatory, as failure to comply may be associated with an increased risk of symptomatic intracerebral haemorrhage. Intra-arterial revascularisation may provide more complete restitution of flow than intravenous thrombolytic therapy and improve the clinical outcome if it can be undertaken in patients with occlusion of the middle cerebral artery, and possibly the basilar artery, within the first hours from stroke onset. However, further data are needed. Although intravenous alteplase is recommended for any age beyond 18 years, elderly patients, in particular patients aged > or = 80 years, were often excluded or under-represented in randomised clinical trials of thrombolysis, so that available data on risk/benefit ratio for the very elderly are limited. Small post-marketing series suggest that despite elderly patients over 80 years having greater pre-stroke disability, the use of intravenous alteplase in this patient group does not significantly differ in effectiveness and complications compared with the same treatment in patients aged under age 80 years. Further studies are necessary and elderly patients with acute stroke should be included in future trials of the merits of thrombolytic therapy.     

Intravenous thrombolysis in acute ischaemic stroke: optimising its use in routine clinical practice

Stroke is a common and important medical problem. Intravenous thrombolysis with alteplase (recombinant tissue plasminogen activator; rtPA) is the only available direct treatment that reduces neurological injury following ischaemic stroke. Strong efficacy data from randomised, controlled trials support the use of intravenous thrombolysis to improve outcomes for patients with acute ischaemic stroke. Numerous studies have provided effectiveness data that demonstrate that intravenous thrombolytic therapy can be given safely outside clinical trial settings. However, effectiveness studies have demonstrated that intravenous thrombolytic therapy is often given despite protocol violations when it is prescribed in routine clinical practice. Protocol violations must be avoided because they are associated with adverse events including higher mortality and increased haemorrhagic complications. Although thrombolytic therapy with alteplase is currently being used in only <10% of patients with acute ischaemic stroke, recent studies demonstrate that quality management efforts can improve both the absolute rate of use as well as the proficiency with which alteplase is administered. Given the complexities inherent in prescribing thrombolysis for patients with acute ischaemic stroke, alteplase should be used by clinicians who are experienced in the diagnosis and management of stroke, working in medical centres that have systems in place to ensure that alteplase is given without protocol violations.     

Cost considerations in the pharmacological prevention and treatment of stroke

Stroke remains the leading cause of neurological disability and the third leading cause of death worldwide, consuming a large share of total healthcare expenditures. In this review, we discuss the cost effectiveness of stroke prevention for various risk factor-modification programmes and pharmacological interventions with aspirin (acetylsalicylic acid), ticlopidine and warfarin. Cost considerations and potential cost savings resulting from acute treatment are discussed for parenterally administered anticoagulants, such as heparin and nadroparin, and for intravenous thrombolysis with alteplase (recombinant tissue plasminogen activator; r-tPA). Patients with multiple risk factors for stroke require more aggressive prevention strategies which are associated with a greater risk of complications. The rates of complications, particularly intracerebral haemorrhage, should be kept low to achieve cost benefits for warfarin and alteplase. Reduced hospital length of stay is the key factor in the implementation of cost-effective stroke therapies. The analysis of future clinical trials of new stroke therapies should also include economic parameters, such as length of hospital stay and intensity of resource usage, to help guide formulary and therapeutic decision.     

Clinical potential of intra-arterial thrombolytic therapy in patients with acute ischaemic stroke

Acute ischaemic stroke is a leading cause of mortality and morbidity around the world. An arterial occlusive lesion is found in the majority of patients with acute ischaemic stroke, and recanalisation has been shown to result in a better clinical outcome. The only widely approved recanalisation strategy is the use of intravenous alteplase (recombinant tissue-type plasminogen activator; tPA) within 3 hours of stroke onset. However, this therapy has limitations, and alternative or supplemental recanalisation strategies need to be considered in a large number of patients with acute ischaemic stroke. One such promising strategy is intra-arterial thrombolysis. This article reviews the pharmacology of the various drugs used for intra-arterial thrombolysis in the setting of acute ischaemic stroke and the results of the clinical trials that have studied their benefit. Three generations of thrombolytic agents have been available for clinical use so far. The first-generation agents such as streptokinase and urokinase were the first to be studied in acute stroke, and a number of positive case reports and series of their intra-arterial use have been reported from around the world. Second-generation products include alteplase and pro-urokinase. The clinical benefits of intra-arterial pro-urokinase were recently proven in a randomised, placebo-controlled study. Third-generation agents, such as reteplase, lanoteplase and tenecteplase, offer superior recanalisation rates with limited systemic adverse effects and might prove to be the agents of choice for intra-arterial acute stroke thrombolysis in the future. The exact administration regimens as well as the identification of patient sub-populations most likely to benefit from intra-arterial thrombolysis are subjects of current investigations, and hopefully firmer guidelines will be established in the next few years, once the results of the clinical trials are available.     

Optimal timing of thrombolytic therapy in acute ischaemic stroke

The clinical benefit of thrombolytic therapy for patients experiencing acute cerebral ischaemia has been demonstrated by both clinical trials and phase IV studies. However, such treatments must be initiated in a rapid manner, with treating physicians adhering to strict protocols designed to minimise delays and maximise safety. The efficacy of intravenous drug administration has been established with alteplase (recombinant tissue plasminogen activator; tPA) and ancrod, but only if these drugs can be administered within 3 hours of symptom onset. The use of alteplase beyond this timeframe, or outside of established protocols, may be hazardous. The use of alternative intravenous thrombolytic agents, such as streptokinase, also appears hazardous. Intra-arterial delivery of thrombolytic drugs such as pro-urokinase may extend clinical benefit to the 6-hour time frame.     

Use of thrombolytic drugs in non-coronary disorders

Clinical experience with thrombolytics in non-coronary disorders is limited to the plasminogen activators streptokinase, urokinase and alteplase; therapeutic trials with anistreplase (APSAC) are almost, and with saruplase completely, limited to acute myocardial infarction. In terms of thrombus clearance, thrombolytic drugs are superior to heparin in patients with recent deep vein thrombosis in the pelvis or lower limbs. In aggregate, thrombi younger than 8 days are lysed in approximately 60% of patients treated with streptokinase, urokinase or alteplase. The results of studies assessing the subsequent development of the postphlebitic syndrome are conflicting, but most suggest that thrombolytic therapy can reduce symptoms of chronic venous insufficiency. Currently, the combination of systemic thrombolytic drugs followed by heparin is recommended for patients with acute major pulmonary embolism who are haemodynamically unstable. Streptokinase, urokinase and alteplase have all been shown to accelerate the lysis of pulmonary emboli and to decrease pulmonary vascular obstruction and pulmonary hypertension. Systemic venous or intrapulmonary infusions of alteplase offers the same benefit in terms of angiographic and haemodynamic improvement. A short infusion of 100 mg alteplase over 2 hours seems to be superior to a 24-hour infusion of urokinase. None of the thrombolytic trials in pulmonary embolism have been large enough to demonstrate a reduction in mortality. It is now generally accepted that, unless contraindicated, thrombolytic therapy is the front-line treatment for patients with massive pulmonary embolism and major haemodynamic disturbance. The local treatment of acute arterial occlusion in limb arteries results in rapid clearing of the artery in 67% of patients treated with streptokinase; the corresponding success rates for urokinase and alteplase are 81% and 88 to 94%, respectively. The main question appears to be the identification of patients in whom local thrombolysis is the treatment of choice, as opposed to established therapeutic modalities. Thrombolytic treatment following a major ischaemic stroke is hazardous, although clinical improvement has been noted in a minority of patients with recanalised cerebral arteries. The safety and efficacy of thrombolytic treatment remains unproven for this indication, and its use must be restricted to experimental protocols. Thrombolytic treatment in retinal artery or vein occlusion has, in practice, been abandoned.     

Pharmacological revascularization of acute ischaemic stroke: focus on challenges and novel strategies

The only currently approved treatment for acute ischaemic stroke (AIS) is alteplase, a thrombolytic agent given intravenously (IV) within 4.5 hours of symptom onset, in an attempt to reopen occluded intracerebral arteries. However, no more than 5% of all AIS patients receive IV alteplase, mainly because of too long symptom-onset-to-hospital intervals. Moreover, this strategy is effective for less than half of the patients treated within the therapeutic window. Early recanalization is the most powerful prognostic factor, and novel drugs or therapeutic strategies are primarily aimed at improving alteplase efficacy to rapidly and safely reopen the occluded arteries. Because IV alteplase-resistant thrombi are those with the largest clot burden, responsible for the most devastating brain-tissue infarctions, development of novel approved AIS therapies is an urgent priority. At present, in the absence of controlled trials, no valid recommendations can be made. However, the most promising emerging strategy is a combination of standard or low-dose IV alteplase with an intra-arterial (IA) procedure, including additional endovascular thrombolytic and/or mechanical clot retrieval. Notably, results of open trials using the IA route had relatively disappointing clinical outcomes, despite remarkable arterial recanalization rates. Controlled trials are urgently needed to evaluate strategies including an IA route. In addition, logistic and cost constraints will likely limit their routine use, even in industrialized countries. Combining of another IV drug and IV alteplase is a far less studied option, although much easier to implement. Add-on IV drugs could be an antiplatelet glycoprotein (GP) IIb/IIIa receptor antagonist, a direct thrombin inhibitor or a second thrombolytic agent, e.g. tenecteplase. However, neuroimaging to measure the clot burden and infarction size will probably be necessary to predict IV alteplase failure and the subsequent use of these eventual additional therapies.     

Should Thrombolytic Therapy Be Used in Patients with Pulmonary Embolism?

More than thirty years have passed since streptokinase was first shown to dissolve pulmonary arterial thrombi and normalize pulmonary artery pressure in patients with acute pulmonary embolism (PE). Following the initial observations, a number of controlled clinical trials confirmed that treatment with streptokinase, urokinase or alteplase recombinant tissue plasminogen activator is superior to heparin alone in improving angiographic and hemodynamic parameters in these patients. At present, there is consensus that patients with massive PE presenting with overt right ventricular failure (clinical instability and cardiogenic shock) should promptly be treated with thrombolytic agents, since they are at a particularly high risk for death or life-threatening complications during the acute phase. At the other end of the clinical spectrum, thrombolysis for PE is not indicated in the absence of right ventricular dysfunction. In fact, the prognosis of patients with small pulmonary emboli (not affecting pulmonary artery pressure and right ventricular afterload), is excellent and, as a result, the bleeding risks of thrombolysis may outweigh the potential benefits of this treatment. Currently, the thrombolysis debate focuses on patients with submassive PE, i. e. those who present with signs of subclinical, impending right heart failure. Recently, a number of clinical studies demonstrated that these patients are also at risk for an adverse clinical outcome. Besides the established prognostic value of echocardiography, evidence is now accumulating that cardiac troponins and, possibly, pro-brain natriuretic peptide levels also may permit an early, reliable risk stratification of patients with PE and particularly help identify submassive PE in the presence of apparent clinical stability. Recently, the Management Strategies and Prognosis of Pulmonary Embolism-3 trial examined the effects of thrombolysis on the prognosis of patients with acute submassive PE. The study patients were randomly assigned to receive alteplase (100mg over 2 hours) or placebo with concomitant heparin anticoagulation. Although in-hospital mortality was low in both the alteplase and the heparin-only group, this study showed for the first time that early treatment with alteplase can improve the clinical course of patients with acute submassive PE, and particularly reduce the need for emergency escalation of treatment. Importantly, no fatal or cerebral bleeding episodes were observed in the alteplase group. This fact indicates that use of thrombolysis in PE can be safe in patients who have no contraindications to this type of treatment. Based on these data, the indications for thrombolysis can be extended to include patients presenting with submassive PE.     

Novel thrombolytic drugs: will they make a difference in the treatment of ischaemic stroke?

Treatment of acute ischaemic stroke aims to recanalize the occluded artery, salvage the at-risk brain tissue and thus minimize neurological sequelae. Efforts a decade ago have led to the only currently approved medical treatment for acute ischaemic stroke, i.e. intravenous alteplase given within 3 hours of stroke onset. Recanalization occurs in only one-half of the patients receiving alteplase, and only approximately 5% of all ischaemic stroke patients in industrialized countries receive this treatment. Studies are currently being carried out to determine whether intravenous alteplase would be safe and effective for up to 4.5 hours after ischaemic stroke onset, and whether it should be followed by an intra-arterial approach. Two novel thrombolytic drugs being studied for acute ischaemic stroke are desmoteplase and tenecteplase. Although the first trials were promising, the most recent evidence suggests that desmoteplase is not superior to placebo, even in carefully selected patients, in the 3- to 9-hour time window after stroke onset. Tenecteplase has only been studied for acute ischaemic stroke in a single noncontrolled, dose-finding trial in the 3-hour time window after stroke onset, which suggested a similar efficacy to that demonstrated in the historical data from the alteplase trials. A trial to compare the safety and efficacy of tenecteplase versus alteplase is ongoing. Safer and more effective thrombolytic drugs for the treatment of ischaemic stroke are thus being sought. Such agents will be welcome, but they are not here yet. While waiting we are likely to see the emergence of additive therapies, including ultrasound insonation, neuroprotective/regenerative agents and invasive intra-arterial techniques. Novel thrombolytic drugs, or other novel therapies, possess great potential to make a difference in the future, but the most urgent priority now is in the organization of stroke treatment in such a way that more patients receive the currently available optimal treatments.     

Thrombolysis in acute ischaemic stroke: a guide to patient selection

Thrombolysis should be a routine treatment for selected patients with acute ischaemic stroke and shows promise in a much larger group of patients. This recommendation is based on data from two completed meta-analyses: the Cochrane Library and the rt-PA Study Group individual patient meta-analysis. In patients with ischaemic stroke, treatment with alteplase (recombinant tissue plasminogen activator; rt-PA) is associated with a non-significant excess of deaths, equivalent to about 19 extra deaths per 1000 treated. Furthermore, thrombolysis, regardless of which drug is used, definitely increases the odds of fatal intracranial haemorrhage by 4-fold. However, despite these risks, thrombolysis with alteplase reduces the odds of death or disability, with the benefit being equivalent to about 55 extra independent survivors per 1000 treated. Unfortunately, there are currently too few data to provide a comprehensive guide to patient selection. The available data suggest that younger patients (<80 years of age) who can be treated with alteplase within 3 hours of stroke onset have the most to gain, equivalent to about 100 more independent survivors per 1000 treated. The role of thrombolysis beyond 3 hours, in those with more extensive CT scan ischaemic change, and patients >80 years of age needs further evaluation. In summary, thrombolysis with alteplase is now an established treatment for acute ischaemic stroke, but clinicians need to cooperate in terms of enrolling more patients in further trials if we are to get the most out of this important treatment.     

急性脑梗死阿替普酶静脉溶栓治疗的临床分析

胃的评价急性脑梗死（Acutecerebralinfarction,ACI）患者应用阿替普酶静脉溶栓治疗的有效性与安全性。方法回顾分析2010年5月罩2013年5月78例AcI溶栓治疗的患者临床资料,并选取同期未予溶栓治疗的ACI患者80例为对照组,应用美国国立卫生研究院卒中量表（NHISS评分）和改良Rankin量表（mRS评分）评价两组的神经功能改善程度和近期预后。结果溶栓组治疗后24hNIHSS评分（7．68±4．62）,mRS评分（3．28±0．41）,治疗后7d的NIHSS评分（5．25±4．43）,mRS评分（1．11±0．62）,两组相比差异具有统计学意义（P〈0．01）。溶栓组患者齿龈出血58例（74％）,7d无症状性出血性转化14例（18％）,症状性颅内血肿3例（4％）,死亡4例（5％）。非溶栓组齿龈出血2例（3％）,7d无症状性出血性转化5例（6％）,症状性颅内血肿2倒（3％）,死亡3例（4％）。结论在ACI治疗时间窗内,阿替普酶静脉溶栓治疗,可以减轻患者的神经功能障碍评分,不增加病死率,有效安全。     

Alteplase: a review of its use in the management of acute ischaemic stroke

Alteplase (Actilyse?, Activase?) is a recombinant tissue-type plasminogen activator that activates plasminogen directly to plasmin. It is the only pharmacological treatment currently approved for patients with acute ischaemic stroke. This article reviews the efficacy and tolerability of alteplase, focusing on data relevant to treatment between 0 and 4.5 hours after onset of stroke, and summarizes its pharmacological properties. Well designed clinical trials showed that alteplase administered within 3 hours (in the NINDS trial) and between 3 and 4.5 hours (in the ECASS III trial) after stroke onset significantly improved clinical outcomes at 90 days relative to placebo. Alteplase was generally well tolerated in these trials, with no significant difference observed between alteplase and placebo recipients in the 90-day mortality rates, despite significantly higher incidences of any and symptomatic intracranial haemorrhages in alteplase recipients. These results were generally supported by those of the SITS-MOST and SITS-ISTR observational studies, which showed that alteplase was effective and generally well tolerated when administered within 4.5 hours of stroke onset in routine clinical practice. However, results from SITS-ISTR indicated that the safety and functional outcomes were generally less favourable when alteplase was administered 3-4.5 hours after stroke onset than within 3 hours of stroke onset. Additionally, results from pooled analyses of randomized clinical trials indicated that the benefit of alteplase therapy over placebo decreased as the time between stroke onset and treatment initiation increased, with no significant benefit observed when treatment was initiated >4.5 hours after stroke onset. Moreover, the odds of mortality increased as the time between stroke onset and treatment initiation increased. Thus, the greatest benefit of alteplase therapy is gained with early treatment. Based on these results, current EU labelling and treatment guidelines recommend that alteplase should be administered as early as possible within 4.5 hours of symptom onset in patients with acute ischaemic stroke. However, recent results from a meta-analysis and IST-3 suggest that some patients may benefit from treatment up to 6 hours after stroke onset. Patients for whom alteplase therapy is contraindicated as per current EU licensing criteria, such as those aged >80 years, may also benefit from therapy. Further randomized trials of alteplase administered >4.5 hours after stroke in selected patients are required to confirm these findings.     

Fibrin binding and the regulation of plasminogen activators during thrombolytic therapy

First generation thrombolytics (streptokinase and urokinase) had no fibrin binding capabilities and caused systemic plasminogen activation with concomitant destruction of haemostatic proteins. A primary driving force behind the development of the second generation plasminogen activator tissue plasminogen activator (tPA or alteplase) was its ability to bind to fibrin and target thrombolysis. Although in vitro assays highlighted advantages of fibrin binding, clinical trials were disappointing, showing only small benefits in mortality with tPA versus streptokinase, but also with some increase in haemorrhagic stroke. Third generation thrombolytic agents (reteplase, tenecteplase and pamiteplase) are variants of tPA engineered to have improved structure/function, such as longer half life and resistance to inhibitors. However, clear therapeutic advantages of third generation thrombolytics in clinical trials have also been difficult to demonstrate. Although fibrin binding is critical in regulating the activity of tPA, it is not clear how important it is for thrombolytic treatment. Advances are needed in our understanding of the relationship between structure/binding and activity of PAs in vivo under normal conditions and when administered in pharmacological doses. Clearly the impact of fibrin structure and the other components in fibrin clots must also be considered. Ultimately these studies may lead to better engineered therapeutics or optimised mixtures of molecules. With a more detailed understanding of the regulation of plasminogen activation and fibrinolysis it might be possible to tailor thrombolytic therapy to different situations such as myocardial or cerebrovascular treatment or to the patient's age and sex and other characteristics.     

阿替普酶静脉溶栓联合氯吡格雷、阿司匹林治疗急性心肌梗死疗效观察

目的：观察阿替普酶静脉溶栓联合氯吡格雷、阿司匹林治疗急性心肌梗死的疗效。方法：36例急性心肌梗死（AMI）患者给予阿替普酶静脉溶栓联合氯吡格雷、阿司匹林治疗,根据发病时间分为6h以内组及6h以上组,对比两组患者治疗前后冠脉再通率及并发症发生率。结果：36例患者静脉溶栓治疗26例,总再通率为72.2%。其中,6h以内组再通16例,再通率为80.0%,出血2例,死亡2例;6h以上至12h以内再通10例,再通率为62.5%,出血3例,死亡3例。结论：阿替普酶静脉溶栓联合氯吡格雷、阿司匹林治疗急性心肌梗死疗效好,在没有开展PCI的基层医院,是一套可行的治疗方法。     

Reteplase

Reteplase (Retavase) is a plasminogen activator, mimicking endogenous tissue plasminogen activator (t-PA), a serine protease, converting plasminogen to plasmin and thereby precipitating thrombolysis. It is a third-generation recombinant form of t-PA that operates in the presence of fibrin (i.e. it is fibrin specific). Reteplase can be administered as a bolus dose (nonweight-based) rather than an infusion, which promotes rapid and safe administration. The ease of administration of this reteplase dosage regimen (two 10U bolus doses, each over 2 minutes, 30 minutes apart) is conducive to prehospital initiation of thrombolytic treatment in patients with ST-segment elevation myocardial infarction (STEMI), which reduces the time to treatment, a critical factor in improving long-term survival. In large randomized clinical trials of patients with STEMI, reteplase was superior to alteplase for coronary artery patency (according to TIMI [thrombolysis in myocardial infarction] flow) at 60 and 90 minutes, but there was no significant difference between agents for mortality rate and incidence of intracranial bleeding. The 35-day mortality rates were equivalent for reteplase and streptokinase recipients; there was reduced incidence of some cardiac events with reteplase versus streptokinase, but a greater incidence of hemorrhagic stroke. Reteplase has also shown thrombolytic efficacy (in nonapproved indications) as a catheter-directed intra-arterial or intravenous infusion for peripheral vessel occlusions, as 5-minute bolus doses (in 1U increments) for acute ischemic stroke, as a low-dose solution for occluded catheters or grafts, and as an intravenous double bolus for massive pulmonary embolism. Across studies in these indications, the incidence of bleeding complications associated with reteplase treatment appeared to be similar to that associated with other thrombolytic agents. With its efficacy, and the ease of administration of the bolus doses potentially minimizing dosage errors when treatment is administered under time pressure, reteplase is a valuable option for pre- or in-hospital thrombolytic treatment in patients with STEMI, and is a useful thrombolytic for the treatment of the other thrombotic occlusive disorders described.     

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.     

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.     

Recent strategies on targeted delivery of thrombolytics

Thrombus formed in blood vessel is a progressive process, which would lead to life-threatening thrombotic diseases such as ischemic stroke. Unlike other diseases, the recognition of thrombus is usually in the late stage where blood vessels are largely blocked. So acute thrombotic diseases have a narrow therapeutic window, and remain leading causes of morbidity and mortality, whereas current thrombolysis therapy has limited therapeutic effects and bleeding complications. Thrombolytic agents in unwanted sites would cause hemorrhage due to the activation of plasminogen. Moreover, untargeted thrombolysis therapy require large amounts of thrombolytic agents, which in return would enhance hemorrhage risk. To improve the efficiency while minimizing the adverse effects of traditional thrombolysis therapy, novel drug delivery systems have been investigated. Various targeting strategies including ultrasound and magnetic field directed targeting, and specific binding, have been designed to deliver thrombolytic drugs to the thrombotic sites. These strategies demonstrate promising results in reducing bleeding risk as well as allowing less dosage of thrombolytic drugs with lowered clot lysis time. In this review, we discuss recent progress on targeted delivery of thrombolytics, and summarize treatment advantages and shortcomings, potentially helping to further promote the development of targeted thrombolysis.     

Can the time window for administration of thrombolytics in stroke be increased?

Level 1 evidence now shows that thrombolysis in cases of acute ischaemic stroke is effective if administered within 3 hours of stroke onset. This benefit has been shown to be time dependent and potentially extends beyond 3 hours, with evidence that potentially viable penumbral tissue may be present in a significant proportion of cases well beyond 3-6 hours and, in isolated cases, perhaps up to 48 hours. This exposes a "stroke recovery gap", the difference observed between the clinical response to thrombolytic therapy in a given population of patients presenting with ischaemic stroke and the potential clinical recovery if all of the penumbra were salvaged under ideal circumstances. The means of bridging this "stroke recovery gap" using thrombolysis must involve extending the therapeutic time window (i.e. the time between stroke onset and administration of thrombolytics). Approaches to do this include the use of: (i) improved patient selection with modern neuroimaging techniques, particularly magnetic resonance imaging using perfusion-weighted image/diffusion-weighted image mismatch; (ii) newer thrombolytic agents; (iii) lower doses of these agents; (iv) varied methods of administration of thrombolytic therapy including combined intravenous and intra-arterial approaches; and (v) adjunctive therapies such as neuroprotectants. Should these means of extending the time window for thrombolysis prove successful, a more widespread use of this form of acute stroke therapy will be possible.     

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.