Stroke Treatment Using Intravenous and Intra-Arterial Tissue Plasminogen Activator

OPINION STATEMENT: Acute ischemic stroke is the most common cause of adult disability in the world and the third most common cause of death. Early restoration of perfusion to ischemic brain has been a highly successful strategy to decrease the disability associated with acute ischemic stroke. For acute stroke, intravenous (IV) tissue plasminogen activator (t-PA) is the only proven acute treatment that results in improved clinical outcomes. IV t-PA is indicated for ischemic stroke when administered within 4.5?h or less of symptom onset. This 4.5-hour treatment window represents a significant expansion from the previous 3-hour treatment window for therapy. Despite a longer time window, patients have the greatest chance for an improved outcome when treatment occurs as soon as possible from the time of symptom onset. The Emergency Department goal for treatment is a door to t-PA administration time of 60?min. In order to facilitate rapid evaluation and treatment, systems of care that streamline treatment should be developed at every institution that cares for acute ischemic stroke patients. For those with contraindications to t-PA and those outside the treatment window, catheter-directed intra-arterial (IA) t-PA administration or mechanical clot extraction is a potential means of restoring brain perfusion. These therapies should not preclude the use of IV t-PA when feasible and are frequently only available at tertiary care centers. Technological advances in IA devices for mechanical clot extraction make this a promising and growing area for advancing stroke therapy but remain under ongoing investigation to establish improved clinical outcomes.     

Neuroendovascular Rescue: Interventional Treatment of Acute Ischemic Stroke

Opinion statement Stroke continues to be a major health problem for our society. Despite the proven effectiveness of intravenous tissue plasminogen activator (t-PA) for the treatment of acute ischemic stroke, only a minority of patients qualify for this type of therapy. Furthermore, the existing literature has demonstrated that t-PA is not as effective in the treatment of occlusion of large cerebral arteries. The benefit-to-risk assessment of this subpopulation of stroke patients makes them the best candidates for neuroendovascular rescue. This term refers to the intra-arterial application of techniques designed to promote arterial recanalization, and includes intra-arterial thrombolysis and antithrombotic agents, direct mechanical disruption, angioplasty, stenting, embolectomy, and vasoactive pharmacologic intervention. The timing and choice of these procedures, as well as the care of the patient prior to, during, and after the intervention, requires a highly focused and expert approach.     

Melatonin attenuates the postischemic increase in blood-brain barrier permeability and decreases hemorrhagic transformation of tissue-plasminogen activator therapy following ischemic stroke in mice

Melatonin protects against transient middle cerebral artery (MCA) occlusion and may be suited as an add-on therapy of tissue plasminogen activator (t-PA) thrombolysis. Herein, we examined whether melatonin would reduce postischemic increase in the blood-brain barrier (BBB) permeability and, therefore, attenuate the risk of hemorrhagic transformation after t-PA therapy in experimental stroke. Twelve mice were subjected to transient occlusion of the MCA for 1 hr, followed by 24 hr of reperfusion. Melatonin (5 mg/kg, i.p.) or vehicle was given at the beginning of reperfusion. BBB permeability was evaluated by quantitation of Evans Blue leakage. An additional 32 mice underwent photothrombotic occlusion of the distal MCA, and were administered vehicle or t-PA (10 mg/kg, i.v.), alone or in combination with melatonin (5 mg/kg, i.p.), at 6 hr postinsult. The animals were then killed after 24 hr for the determination of infarct and hemorrhage volumes. Relative to controls, melatonin-treated animals had significantly reduced BBB permeability (by 52%; P < 0.001). Additionally, we found that at 6 hr after photo-irradiation, either t-PA or melatonin, or a combined administration of t-PA plus melatonin, did not significantly affect brain infarction (P > 0.05), compared with controls. Mice treated with t-PA alone, however, had significantly increased hemorrhagic formation (P < 0.05), and the event was effectively reversed by co-treatment with melatonin (P < 0.05). Thus, melatonin improved postischemic preservation of the BBB permeability and a decreased risk of adverse hemorrhagic transformation after t-PA therapy for ischemic stroke. The findings further highlight melatonin's potential role in the field of thrombolytic treatment for ischemic stroke patients.     

Thrombolytic therapy in acute ischemic stroke

Opinion statement The use of intravenous thrombolytic therapy for the treatment of patients with acute ischemic stroke is now approved in the United States, Canada, Germany, and the European Union. Guidelines published in 1996 from the American Heart Association and American Academy of Neurology committees recommended intravenous administration of recombinant tissue-plasminogen activator (rt-PA) (0.9 mg/kg; maximum of 90 mg) given in a 10% bolus, followed by an infusion lasting 60 minutes, to patients within 3 hours of onset of ischemic stroke. The recommendations stipulate that a computed tomography scan before the infusion should not show major infarction, mass effect, edema, or hemorrhage. Yet, only a small fraction of eligible patients (< 5%) have received rt-PA during the 7 years since its approval in the United States. Although effective, thrombolysis carries an important risk (5% to 10%) of brain hemorrhage and edema that can prove fatal. Many physicians and medical centers are not presently equipped or willing to give thrombolytic drugs for stroke treatment.     

Acute [corrected] stroke thrombolysis: an update [corrected

Acute stroke therapy took a major step forward in 1996 after the approval of Intravenous (IV) tissue plasminogen activator (t-PA) by the US Food and Drug Administration for patients presenting within 3 hours of the onset of stroke symptoms. Since that time, there have been considerable advances in imaging techniques as well as the advent of devices to help in the management of acute stroke patients. As a result, the arsenal to treat acute stroke has grown, and the field of stroke as a subspecialty of neurology has emerged. Despite these advances, only 3% to 8% of eligible patients with acute stroke in the United States are administered thrombolytics.(1) We herein review the use of thrombolytics in stroke and provide an overview of the imaging advances, new devices, and recent trials that are shaping modern stroke therapy. Finally, we provide a practical approach to the management of acute stroke, specifically for the practicing cardiologist, who may encounter stroke during cardiac catheterization, post myocardial infarction (MI), and in a variety of other settings.     

Ischemic stroke. Clinical strategies based on mechanisms and risk factors

Ischemic stroke is a common disorder associated with significant morbidity and mortality. Results of several pivotal clinical trials completed within the last decade have helped refine stroke prevention and treatment strategies. Endarterectomy for symptomatic carotid artery stenosis, anticoagulation in atrial fibrillation, and IV t-PA treatment of hyperacute ischemic stroke may reduce the burden of stroke. Ongoing studies are addressing newly recognized risk factors, such as aortic arch and intracranial atherosclerosis, as well as neuroprotective agents and locally delivered thrombolytics. Successful patient management requires a targeted clinical approach based on vascular localization and risk factor assessment.     

Thrombolyse mit Alteplase 3 bis 4.5 Stunden nach akutem isch?mischen Schlaganfall

Intravenous thrombolysis with alteplase is the only approved treatment for acute ischemic stroke. It is approved to be administered within 3 hours after the onset of stroke. In 1995, the National Institute of Neurological Disorders and Stroke (NINDS) study group reported that patients with acute ischemic stroke who received alteplase within 3 hours after the onset of symptoms were at least 30% more likely to have minimal or no disability at 3 months than those who received placebo. In a subsequent analysis of the NINDS study and the combined analysis of data from six randomized trials, which investigated thrombolysis treatment for ischemic stroke in a total of 2775 patients, a favorable outcome was observed even if treatment was given between 3 and 4.5 hours. International guidelines recommend alteplase as a first-line treatment when administered within 3 hours after the onset of stroke. Despite this recommendation, it is estimated that fewer than 2% of patients receive this treatment in most countries, primarily because of delayed admission to a stroke center. The European Cooperative Acute Stroke Study (ECASS) III, a randomized, double-blind, placebo-controlled phase 3 trial was designed to test the hypothesis that the efficacy of alteplase administered in patients with acute ischemic stroke can be safely extended to a time window of 3 to 4.5 hours after the onset of stroke symptoms. A total of 821 patients with acute ischemic stroke were assigned to a study group 3 to 4.5 hours after onset of stroke symptoms. 418 patients were randomized assigned to receive alteplase and 403 patients were assigned to receive placebo. The primary end point was disability at day 90 after stroke, dichotomized as a favorable outcome (a score of 0 or 1 on the modified Rankin scale, which has a range of 0 to 6, with 0 indicating no symptoms at all and 6 indicating death) or an unfavorable outcome (a score of 2 to 6 on the modified Rankin scale). As compared with placebo, intravenous alteplase administered 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcome in patients with acute ischemic stroke. The incidence of intracranial hemorrhage was higher with alteplase than with placebo. Mortality did not differ significantly. Still the effect size of thrombolysis is time-dependant. Early treatment shows higher efficacy and remains essential. Until now there is no approval for the treatment with alteplase in the extended time window and therefore it can only be applied as a individual therapeutic option.     

脑微出血危险因素、可能发生机制及其并缺血性脑卒中的治疗进展

脑微出血(CMBs)是脑小血管病的重要影像学表现,常在缺血性脑卒中、颅内出血、痴呆等患者经颅MRI检查时被检出。近年来,随着医学影像学技术的进步,CMBs的检出率呈逐渐上升趋势。有研究发现,CMBs的存在会增加脑卒中发生率及恶化风险,对缺血性脑卒中的发生及病情进展具有一定的预测价值。因此,本文详细阐述了CMBs的流行病学、危险因素、可能发生机制、临床表现,并进一步总结CMBs与缺血性脑卒中的相关性及其并缺血性脑卒中的治疗方案,旨在为科研工作者更深入地研究CMBs提供思路,最终将研究成果运用于临床,进而指导CMBs并缺血性脑卒中患者的个体化防治。     

Management of Acute Ischemic Stroke

The treatment of acute ischemic stroke includes both intravenous (IV) thrombolysis and mechanical thrombectomy. Important advances regarding both treatment modalities have occurred recently that all physicians who see patients at risk for or who have had a stroke should be aware of. This review will focus on recent clinical trials of IV thrombolysis both positive and negative. Additionally, the results of a large number of early and late time window thrombectomy trials will be presented that demonstrate the remarkable efficacy of this treatment for appropriately selected patients.     

Impaired capacity for stimulated fibrinolysis in primary hypertension is restored by antihypertensive therapy

The increased risk for myocardial infarction and ischemic stroke in primary hypertension suggests that the condition is associated with prothrombotic mechanisms. We have shown that patients with hypertension have an impaired capacity for acute endothelial tissue-type plasminogen activator (t-PA) release, an important local protective response to prevent formation of intravascular thrombi. The aim of the present study was to investigate whether this impairment could be restored by the lowering of blood pressure. The capacity for acute t-PA release in response to intraarterial infusion of substance P at 8 pmol/min was investigated in a perfused-forearm study in 20 hypertensive patients (12 men and 8 women). Studies were performed when patients were untreated and after 8 weeks of randomized treatment with lisinopril or felodipine that lowered blood pressure by 26/10 and 24/12 mm Hg, respectively. The t-PA release response increased significantly with treatment (ANOVA, P=0.0001), with a similar effect in the 2 treatment groups. The peak release of t-PA increased from 257 (58) to 445 (77) ng/min x L/tissue(-1) (t test, P=0.02). Also, treatment shortened the average time to peak secretion from 6.7 (1.4) to 2.7 (0.3) min (t test, P=0.01). In 6 patients with a delayed secretory peak (9 minutes or later), treatment normalized the response (chi2 test, P=0.008). Antihypertensive therapy restores the capacity for acute t-PA release and improves the rapidity of the response in patients with primary hypertension. Similar responses with the 2 regimens suggest that the improvement is related to the blood pressure reduction as such. This effect may contribute to the thromboprotective effect of antihypertensive treatment.     

Thrombolytic therapy for acute ischaemic stroke: successful implementation in an Australian tertiary hospital

The use of tissue-type plasminogen activator (t-PA) in ischaemic stroke outside of experienced stroke centres remains controversial. The aim of this study was to present the initial experience with t-PA in patients with ischaemic stroke at an institution with no prior experience in i.v. stroke thrombolysis and to compare results to published reports. Prospective audit of 888 patients with consecutive stroke and transient ischaemic attack admitted to a 426-bed tertiary referral hospital from March 2003 to October 2005. Main outcome measures were treatment rate, exclusion criteria, protocol violations, intracerebral haemorrhage, disability (modified Rankin scale) and mortality at 3 months. Over the study period, 72 patients received t-PA (11% of ischaemic strokes). The main reason for exclusion was presentation beyond 3 h of onset (44%); if all eligible patients had arrived within 3 h, treatment rate was estimated at 32.5%. Protocol violations occurred in 15 (21%) patients. There were seven (10%) asymptomatic intracerebral haemorrhage and one (1%) non-fatal symptomatic intracerebral haemorrhage. At 3 months, 37% had achieved excellent recovery (modified Rankin scale 0-1) and seven (10%) had died. The delivery and outcomes associated with the use of t-PA were comparable to the results of the National Institute of Neurological Disorders and Stroke trial and meta-analysis of open-labelled studies. With appropriate infrastructure and protocols, previously inexperienced tertiary referral centres can replicate the experience and outcome measures reported by clinical trials of t-PA in patients with stroke.     

Patent foramen ovale and stroke

Opinion statement Observational data from prospective and retrospective trials indicate that a patent foramen ovale (PFO) is associated with the risk of ischemic stroke. The mechanism involved is presumed to be paradoxical embolism from a venous thrombus that travels via the PFO to the systemic circulation causing an ischemic stroke. Primary stroke prevention data for patients with a PFO are nonexistent. Given the substantial prevalence of PFO in the total population (≈25% to 30%), a primary prevention study may not be feasible. However, whether targeted primary prevention for patients with PFOs of certain morphologic characteristics (eg, larger size, greater degree of shunt) would be possible remains undefined. Given the large number of asymptomatic subjects, no therapy is currently recommended. The best treatment modality to prevent recurrent stroke in patients with PFO has not been defined. There are four major treatment choices: surgical closure, percutaneous device closure, medical therapy with anticoagulants, and medical therapy with antiplatelet agents. Regarding medical therapy, the Patent Foramen Ovale in Cryptogenic Stroke Study has demonstrated that antiplatelet and anticoagulant therapies are of equal benefit in preventing recurrent adverse events. Although closure of the PFO, either surgical or percutaneous, may further reduce the event rates, this remains to be demonstrated because no randomized trial to date has compared PFO closure with medical therapy.     

Schlaganfallsekund?rpr?vention bei Diabetespatienten

Patients with diabetes mellitus who have suffered a transient ischemic attack or ischemic stroke are at higher risk for a recurrent stroke. Thus, early initiation of non-medical and medical secondary prevention treatment is of major importance in this patient group. The basic principles of stroke prevention are the same in patients with diabetes as in those without. We review the evidence for antithrombotic treatment based on the pathophysiology of ischemic stroke, treatment with antihypertensive and lipid-lowering agents, as well as the significance of intensive blood glucose control in secondary stroke prevention in diabetics.     

Stroke intervention: catheter-based therapy for acute ischemic stroke

The majority (>80%) of the three-quarters of a million strokes that will occur in the United States this year are ischemic in nature. The treatment of acute ischemic stroke is very similar to acute myocardial infarction, which requires timely reperfusion therapy for optimal results. The majority of patients with acute ischemic stroke do not receive any form of reperfusion therapy, unlike patients with acute myocardial infarction. Improving outcomes for acute stroke will require patient education to encourage early presentation, an aggressive expansion of qualified hospitals, and willing providers and early imaging strategies to match patients with their best options for reperfusion therapy to minimize complications.     

Emergency Management of Acute Ischemic Stroke

With the advent of new therapeutic options for acute ischemic stroke, expeditious evaluation of patients with suspected stroke has become imperative. Goals of the initial evaluation are to determine the time of symptom onset, severity of the neurologic deficit, and to exclude intracranial hemorrhage and other mimics of acute ischemic stroke. CT and MRI perfusion studies may demonstrate the presence of an ischemic penumbra and aid in identification of patients who may benefit from thrombolysis. Intravenous recombinant tissue plasminogen activator (IV rtPA) remains the gold standard for acute ischemic stroke treatment, and the therapeutic time window recently has been extended to 4.5 h in certain patients. Catheter-based intra-arterial thrombolysis is being used increasingly as “rescue therapy” after IV rtPA and as primary therapy in select patients who are ineligible for intravenous therapy. Trials investigating the efficacy and safety of intra-arterial therapy are ongoing.     

缺血性卒中患者抗栓药依从性研究

目的：评估缺血性卒中患者起病1年后使用抗栓药的依从性及其影响因素。方法：由住院病历中获取连续出院的缺血性卒中患者的一般资料、是否应用抗栓药及其种类，对其中应用抗栓药的患者在出院后1年进行电话随访，调查卒中后1年时抗栓治疗的依从性，同时对影响抗栓药依从性的相关因素进行了分析。结果：连续出院的缺血性卒中患者225例，应用抗栓药患者201例（其中95．0％使用阿司匹林）。完成出院1年时随访176例，其中67．0％继续抗栓治疗。Logistic回归分析显示，应用阿司匹林（OR7．028，95％CI1．241～39．784）、卒中门诊随访（OR2．257，95％CI1．050～4．764）、功能预后好（MRS评分〈2分）（ORl．337，95％C10．997～1．793）为依从性良好的独立预测因素。结论：在缺血性卒中二级预防中，抗栓治疗的依从性尚不能令人满意，应用阿司匹林、卒中门诊随访、功能预后较好有助于提高长期抗栓治疗的依从性。     

Percutaneous devices for left atrial appendage occlusion: A contemporary review

Patient with atrial fibrillation(AF) are at risk of developing stroke with the left atrial appendage(LAA) being the most common site for thrombus formation. If left untreated, AF is associated with 4 to 5 folds increase in the risk of ischemic stroke in all age groups. About 5% to 15% of AF patients have atrial thrombi on transesophageal echocardiography, and 91% of those thrombi are located in the LAA in patient with nonrheumatic AF. Although oral anticoagulants are the gold-standard treatment for stroke prevention in patients with non-valvular AF,some patients are at high risk of bleeding and deemed not candidates for anticoagulation. Therefore, LAA occlusion(LAAO) has emerged as alternative approach for stroke prevention in those patients. Surgical LAAO is associated with high rate of unsuccessful closure and recommended only in patients with AF and undergoing cardiac surgery. Percutaneous LAAO uses transvenous access with trans-septal puncture and was first tested using the PLAATO device.Watchman is the most common and only Food and Drug Administration(FDA)approved device for LAAO. LAAO using Watchman device is non-inferior to warfarin therapy in preventing ischemic stroke/systemic thromboembolism.However, it is associated with lower rates of hemorrhagic stroke, bleeding and death. Amplatzer is another successful LAAO device that has CE mark and is waiting for FDA approval. Optimal antithrombotic therapy post LAAO is still under debate and highly patient-specific. The aim of this paper is to systematically review the current literature to evaluate the efficacy and safety of different LAAO devices.     

Modern Medical Management of Acute Ischemic Stroke

The modern management of patients with ischemic stroke begins by having a system in place that organizes the provision of preventive, acute treatment, and rehabilitative services. In the acute setting, initial evaluation is aimed at rapidly establishing a diagnosis by excluding stroke mimics, distinguishing between ischemic and hemorrhagic strokes, and determining if the patient is a candidate for treatment with intravenous tissue plasminogen activator (IV-tPA, alteplase). In some centers, select patients who do not qualify for administration of IV-tPA may be considered for endovascular intervention. General measures include the use of platelet antiaggregants, treatment of fever, blood pressure management, and continuation of statins if the patient has already been taking them. Post-acute evaluation and management is aimed at secondary prevention and optimizing recovery, including recognition and treatment of post-stroke depression.     

Cancer‐associated ischemic stroke is associated with elevated d‐dimer and fibrin degradation product levels in acute ischemic stroke with advanced cancer

Aim: Although several studies have reported various causes of ischemic stroke in patients with cancer, only a few have evaluated the clinical relevance of ischemic stroke pathogenesis to cancer. The aim of the present study was to elucidate the clinical characteristics of cancer‐associated ischemic stroke. Methods: We evaluated 154 ischemic stroke patients without cancer and 57 ischemic stroke patients with cancer who had either received continuous treatment for cancer within 5 years before to the onset of ischemic stroke, or who had been diagnosed with cancer within 1 year after the onset of ischemic stroke. Cancer patients were grouped into “cancer‐associated ischemic stroke,” the “conventional ischemic stroke,” or “other.” Results: A total of 15 patients (26%) were classified into the cancer‐associated ischemic stroke in cancer patients. In univariate analysis of the cancer‐associated ischemic stroke and the others, there were significant differences in the prevalence of hypertension, hyperlipidemia and advanced cancer (clinical stage IV), and the levels of d ‐dimer, fibrin degradation product and hemoglobin. With multivariate regression analysis of those factors, the prevalence of hypertension, hyperlipidemia and advanced cancer (clinical stage IV), and the levels of d ‐dimer and fibrin degradation product remained as statistically independent factors, which were associated with cancer‐associated ischemic stroke (n = 111, χ² = 67.21, P < 0.0001). Conclusion: In acute ischemic stroke, the cancer‐associated ischemic stroke is associated with elevated d ‐dimer and fibrin degradation products, even after controlling hypertension, hyperlipidemia and advanced cancer (clinical stage IV). Geriatr Gerontol Int 2012; 12: 468–474.     

Antihypertensive Drug Treatment and Fibrinolytic Function

Thromboembolic complications such as ischemic stroke and myocardial infarction are significantly more frequent in patients with arterial hypertension. From the available intervention studies, it appears that pharmacologic treatment of hypertension—at least with diuretics and β-blockers—may more effectively protect against cerebrovascular as compared to coronary thromboembolic events. Whether other antihypertensive substances provide a more effective protection with respect to cardiac morbidity and mortality is the subject of numerous studies presently underway. These studies will help to answer the question of whether the extent of protection from coronary events during antihypertensive treatment depends on factors beyond blood pressure control. The fibrinolytic system is crucially involved in the pathogenesis of thromboembolic events. One determinant of this system is the balance between plasminogen activators (tissue-type plasminogen activator [t-PA]) and inhibitors (plasminogen activator inhibitor 1 [PAI-1]). Experimental and clinical evidence suggests that at least some of the drugs used in the treatment of hypertension may alter the activity of the fibrinolytic system. Scarce and controversial data with respect to such an interaction exist with respect to diuretics, β-blockers, and calcium antagonists. In addition, experimental evidence demonstrates that PAI-1 is stimulated by angiotensin II (A II), whereas t-PA is activated by bradykinin. Thus, antihypertensive drugs acting within the renin angiotensin system should exert effects also within the fibrinolytic system. However, results from clinical studies with angiotensin converting enzyme (ACE) inhibitors and A II receptor antagonists do not unequivocally support such a concept. The discrepancy in the results may, at least in part, be explained by studies performed in healthy volunteer subjects showing that ACE inhibition profoundly affected fibrinolysis only during stimulation of the renin angiotensin system by NaCL restriction.