Low-molecular-weight Heparins for the Treatment of Venous Thromboembolism

Recent studies have indicated that certain low-molecular-weight heparins given subcutaneously may replace continuous intravenous unfractionated heparin for the treatment of venous thromboembolism. Low-molecular-weight heparins have a predictably high absorption rate when given subcutaneously and they do not require laboratory monitoring. These characteristics of low-molecular-weight heparin therapy raise the possibility of treating uncomplicated patients with deep venous thrombosis or pulmonary embolism in the outpatient setting. The advantages to the patient of avoiding in-hospital care and its associated hazards are obvious. Outpatient lowmolecular-weight heparin will likely prove to be highly cost-effective. At the present time, the findings associated with an individual low-molecular-weight heparin preparation cannot be extrapolated to different low-molecular-weight heparins and each must be evaluated in separate clinical trials. Recent randomized clinical trials indicate that low-molecular-weight heparin may be safer and more effective than continuous intravenous unfractionated heparin in the treatment of proximal venous thrombosis. A decreased mortality rate, which was particularly striking in patients with metastatic carcinoma, was unexpected and requires confirmation in further prospective randomized trials.     

缺血性卒中的抗凝治疗

几个大规模、多中心、随机试验发现,天然肝素(UFH)或低分子肝素(LMWH)并不能改善急性缺血性卒中患者的总体预后。紧急抗凝可预防长期卧床急性缺血性卒中患者深静脉血栓的形成。伴房颤及附加危险因素,如附壁血栓和(或)新发心肌梗死的心源性栓塞性卒中患者具有较高复发性卒中危险,若无显著出血可紧急抗凝。华法令抗凝可作为伴心房纤颤卒中患者的初级和二级预防。颅内静脉窦栓塞形成、颈动脉夹层和抗磷脂抗体综合征患者可常规抗凝,而非心源性栓塞性卒中或症状性颅内动脉狭窄综合征患者长期抗凝治疗证据不足。     

急性脑梗死患者病因分型特点及其预后研究

目的 了解急性脑梗死(ACI)患者急性卒中治疗低分子肝素试验(TOAST)分型的构成特点及其与预后的相关性.方法 对164例ACI患者进行美国国立卫生研究所卒中量表(NIHSS)评分,并按照TOAST标准分为5大亚型,分析不同亚型与NIHSS评分的关系.结果 本组TOAST各亚型构成比:小动脉闭塞型42.68%、大动脉粥样硬化型17.07%、心源性栓塞型10.37%、其他病因型3.66%和不明原因型26.22%;TOAST五个亚型中,心源性栓塞型NIHSS评分最高,其次为大动脉粥样硬化型,而小动脉闭塞型最低;与小动脉闭塞型比较,心源性栓塞型、大动脉粥样硬化型NIHSS评分差异有统计学意义(P<0.01).结论 ACI患者NIHSS评分水平随TOAST亚型的不同而变化.     

Are serum lipids measured on stroke admission prognostic?

BACKGROUND: It has been hypothesized that serum lipids measured in the early period of stroke are predictive of stroke severity and outcome. The optimal time for lipid measurement is not established. We explored whether lipid profile assessed within the first 24 h after stroke onset: (i) differs from that in stroke-free individuals; (ii) differs between stroke subtypes; and (iii) is predictive of stroke severity and outcome. METHODS: We prospectively enrolled 70 acute ischemic stroke patients who presented to the Stroke Unit within 24 h of the onset of stroke symptoms, and 68 stroke-free control subjects. RESULTS: Triglycerides (p<0.001) and high-density lipoprotein (HDL) cholesterol (p<0.001) were significantly lower in patients than in controls. HDL cholesterol was different across stroke subtypes classified according to the Trial of ORG 10172 in Acute Stroke Treatment scale (p=0.035). Patients with more severe stroke had higher serum triglycerides (odds ratio 2.755; p=0.030). CONCLUSIONS: Serum triglycerides might serve as a prognostic marker in acute stroke patients.     

Endovascular Therapy for Acute Ischemic Stroke: A Systematic Review and Meta-analysis

ObjectiveTo consolidate the evidence from randomized trials for the use of endovascular therapy (ET) in patients with acute ischemic stroke.MethodsWe searched major databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus) from their inception to February 12, 2013, for randomized trials evaluating the efficacy of ET compared with standard of care for acute ischemic stroke. Pooled absolute and relative risk estimates were synthesized by using a random-effects model. Heterogeneity was assessed by using Q statistic and I² statistic. Subset analysis was performed for patients with severe stroke (National Institutes of Health Stroke Scale score ≥20). The study was conducted from January 15, 2013 to April 30, 2013.ResultsOf the 1252 retrieved articles, 5 randomized trials enrolling 1197 patients with acute ischemic stroke were included. Seven hundred eleven patients received ET, and 486 received intravenous (IV) tissue plasminogen activator. There was no significant improvement in any of the outcomes in patients receiving ET compared with those receiving IV thrombolysis. On subgroup analysis, ET was found to have better outcomes in patients with severe stroke (National Institutes of Health Stroke Scale score ≥20), showing a dose-response gradient and improving excellent, good, and fair outcomes by an additional 4%, 7%, and 13%, respectively, compared with IV thrombolysis.ConclusionOverall, ET is not superior to IV thrombolysis for acute ischemic strokes (level B recommendation). However, ET showed promise and improved outcomes in patients with severe strokes, but the evidence is limited due to sample size. There is a need for further trials evaluating the role of ET in this high-risk group.     

Venous thromboembolism prophylaxis and treatment in patients with acute stroke and traumatic brain injury

PURPOSE OF REVIEW: Patients with acute stroke and traumatic brain injury are at risk to develop venous thromboembolism. This review analyzes the available literature to propose guidelines for the prevention and treatment of venous thromboembolism in these groups of patients. RECENT FINDINGS: In acute ischemic stroke, low-dose low-molecular-weight heparin has the best benefit-risk ratio to prevent venous thromboembolism. Patients with primary intracerebral hemorrhage and traumatic brain injury should receive intermittent pneumatic compression, followed by low-dose low-molecular-weight heparin or unfractioned heparin 3-4 days after stroke onset or 24 h after injury or surgery, respectively, and after cessation of bleeding. Concerning treatment, in patients with deep-vein thrombosis lower doses of heparin are indicated to prevent pulmonary embolism, and a vena cava filter should be considered. In patients with pulmonary embolism, treatment could be more aggressive, because of a high mortality risk. SUMMARY: Adequate prevention of venous thromboembolism with intermittent pneumatic compression or pharmacological prophylaxis is important. The best treatment of venous thromboembolism remains unclear. In case of pulmonary embolism, more aggressive treatment is warranted.     

Prevention of venous thromboembolism after acute ischemic stroke

Venous thromboembolism (VTE) is a common complication after acute ischemic stroke. When screened by 125I fibrinogen scanning or venography, the incidence of deep-vein thrombosis (DVT) in stroke patients is comparable with that seen in patients undergoing hip or knee replacement. Most stroke patients have multiple risk factors for VTE, like advanced age, low Barthel Index severity score or hemiplegia. As pulmonary embolism is a major cause of death after acute stroke, the prevention of this complication is of crucial importance. Prospective trials have shown that both unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are effective in reducing DVT and pulmonary embolism in stroke patients. Current guidelines recommend the use of these agents in stroke patients with risk factors for VTE. Some clinicians are concerned that the rate of intracranial bleeding associated with thromboprophylaxis may outweigh the benefit of prevention of VTE. Low-dose LMWH and UFH seem, however, safe in stroke patients. Higher doses clearly increase the risk of cerebral bleeding and should be avoided for prophylactic use. Both aspirin and mechanical prophylaxis are suboptimal to prevent VTE. Graduated compression stockings should be reserved to patients with a clear contraindication to antithrombotic agents.     

C-反应蛋白与脑梗死TOAST亚型梗死灶大小神经功能损害程度的关系

目的 观察急性脑梗死（ACI）患者发病早期血清C-反应蛋白（CRP）的水平变化及其与TOAST亚型、梗死灶大小、神经功能损害程度的关系。方法 采用免疫比浊法对136例ACI患者发病72h内的血清CRP水平进行测定，按照TOAST标准对患者进行病因分型，记录梗死灶大小，采用NIHSS评分及Barthel指数记分法进行临床神经功能损害程度评价，并与对照组比较分析。结果 ACI患者血清CRP水平与对照组比较显著升高（P〈0．01）。心源性栓塞脑梗死CRP水平最高，其余依次为大动脉粥样硬化脑梗死、其他明确病因性脑梗死、不明原因性脑梗死，而小动脉闭塞脑梗死最低。血清CRP水平升高程度与梗死灶大小及神经功能损害程度密切相关。CRP与NIHSS评分呈正相关（rs=0．53，P〈0．01），与Barthel指数呈负相关（rs=-0．41，P〈0．01）。结论 血清CRP水平在TOAST各型中的不同，说明不同的ACI亚型在病因及病理生理学机制方面存在着一定的差异。CRP测定对ACI病因学分型有一定的参考价值，CRP可作为ACI患者病情评估的重要指标。     

Cerebral infarction

Diabetes mellitus is the second major risk factor for ischemic stroke. Recent increase in atherothrombotic stroke appears to be related with recent increasing of diabetes. Diabetes is, however, a risk factor not only for atherothrombotic stroke but also for lacunar stroke because there is no difference in prevalence of diabetes between atherothrombotic and lacunar strokes. Diabetes can be a risk factor for cardioembolic stroke as well because the major cause of cardioembolic stroke is atrial fibrillation, and diabetes is a risk factor for stroke in patients with atrial fibrillation. Acute ischemic stroke should be classified into above three subtypes according to the brain and artery imaging as well as cardiac sources of embolism. In hyper-acute patients within 3 hours of onset and without early ischemic signs on CT or ischemic lesions less than one third of the hemisphere on magnetic resonance diffusion-weighted imaging, thrombolytic therapy with alteplase is indicated. In acute stroke patients later than 3 hours of onset, argatroban, heparin, and ozagrel are indicated for atherothrombotic, cardioembolic, and lacunar stroke, respectively. For stroke prevention, total management is required by simultaneous treatments for all risk factors existed. In secondary prevention for stroke, in addition to the more strict control of risk factors antithrombotic therapy is required, that is, antiplatelet therapy is indicated for non-cardioembolic stroke, and anticoagulant therapy is indicated for cardioembolic stroke.     

Cyclin-dependent kinase inhibition with roscovitine: neuroprotection in acute ischemic stroke

Stroke is the third most common cause of mortality and the leading cause of disability in industrialized country. According to population based-studies, ischemic stroke accounts for 67-80% of all strokes. Thrombolysis is used during the acute phase in only 2-5% of ischemic patients. Clinical trials of candidate neuroprotective agents have failed to identify viable therapies for ischemic stroke in humans. There is therefore a great need for new therapeutic strategies, considering that not all brain cells die immediately after ischemic stroke.     

Efficacy and safety of bivalirudin versus heparins in reduction of cardiac outcomes in acute coronary syndrome and percutaneous coronary interventions

Recent data suggest that bivalirudin, a reversible direct thrombin inhibitor, may be noninferior to heparins (unfractionated heparin/low molecular weight heparin) in providing protection against cardiovascular events, with significantly fewer bleeding complications. Whether this advantage is consistent has not been fully defined. We evaluated cardiac outcomes with bivalirudin vs the heparins in management of acute coronary syndromes (ACS), including patients undergoing percutaneous coronary interventions (PCI). Formal computer-aided searches of electronic databases (MEDLINE, PubMed, Cochrane Controlled Trials Registry) were performed by scrutiny of the reference lists of trials and review articles, abstracts, meeting proceedings, and the manufacturers of direct thrombin inhibitors. Five randomized controlled trials (BAT, 1995; CACHET, 2002; REPLACE-2, 2003; REPLACE-1, 2004; and ACUITY, 2006) comparing bivalirudin to the heparins in patients with ACS, including patients undergoing PCI, were identified. The meta-analysis consisted of 25 457 patients (bivalirudin, 15 077; heparins, 10 380). The primary safety end point was major bleeding, defined as intracranial, intraocular, or retroperitoneal hemorrhage; clinically overt blood loss leading to a hemoglobin drop exceeding 3 g/dL (or 10% of hematocrit) and transfusion of 2 or more units of whole blood or packed red blood cells. The combined relative risks (RR) across all of the studies and the 95% confidence intervals of death, myocardial infarction (MI), and revascularization (bivalirudin vs heparins) were computed using the Mantel-Haenszel fixed-effect model, whereas the random-effect model was used for major bleeding. A 2-sided alpha error < .05 was considered to be significant. There were no significant differences in patient characteristics between the 2 groups. Compared to the heparins, the risk of death, MI, revascularization, and composite ischemic end points were similar with bivalirudin monotherapy. However, the risk of major bleeding was significantly lower with bivalirudin use (RR = 0.553; 95% CI = 0.402-0.761; P = .001). The present meta-analysis suggests that bivalirudin may be noninferior to the heparins in reducing the composite of ischemic end points. Additionally, compared to the heparins, bivalirudin monotherapy may lower the rate of major bleeding.     

急性缺血性卒中血管内治疗技术研究进展

急性缺血性卒中已经成为我国第一大致残、致死性疾病。随着以荷兰血管内治疗急性缺血性卒中多中心随机临床试验为代表的五大试验结果公布,机械取栓已经成为治疗颅内大血管闭塞引起的急性缺血性脑卒中的主要手段,迎来了急性脑梗死机械取栓治疗的新时代。目前机械取栓的主要装置有Merci取栓装置、Penumbra吸栓装置、Solitaire™FR支架、Revive SE支架、Trevo支架和Aperio®支架等,针对血管栓塞部位及血管条件要选择不同类型的取栓装置,同时采用不同的取栓技术,比如ADAPT技术、Solumbra技术、Advance技术、SAVE技术、SWIM技术等,才能提高血管再通率,降低并发症。     

Prevalence of carotid artery stenosis in Taiwanese patients with one ischemic stroke

PURPOSE: Ethnic differences in the distribution of atherosclerosis in the brain-supplying vessels are well described. However, only scarce data exist on the prevalence of extracranial carotid artery stenosis in Taiwanese patients who have had a single ischemic stroke. METHODS: Color-coded duplex sonography was used to evaluate the carotid arteries in a hospital-based study on 276 consecutive first-time Taiwanese stroke patients. Significant atherosclerotic lesions of the internal carotid arteries (ICA) were defined as a stenosis of more than 50% or an occlusion. RESULTS: The prevalence of significant carotid lesions was 6% (35/552) in the entire cohort and 8% (17/224) in patients with hemispheric strokes. Among patients with large-artery atheroscleroses, according to criteria of the Trial of Org 10172 in Acute Stroke Treatment, only 27% had significant extracranial ICA disease whereas 69% had intracranial vessel stenoses. Older patients tended to have more severe ICA lesions, while other risk factors were not correlated with carotid stenosis. CONCLUSION: The prevalence of more than 50% ICA stenosis was low in Taiwanese patients with first hemispheric ischemic strokes, indicating that it is not a major cause of ischemic stroke in this population.     

血清白蛋白浓度与缺血性卒中TOAST亚型预后的关系

目的：在TOAST分型的基础上,研究血清白蛋白浓度与缺血性脑卒中及其亚型预后之间的关系。方法连续性登记394例在神经内科住院治疗的急性缺血性卒中患者,依据TOAST分型标准确定每个患者所属病因学亚型,患者入院24 h内行血清白蛋白浓度测定,并随访3个月,确定卒中预后,通过t检验分析,研究血清白蛋白浓度与各TOAST亚型预后之间的关系。结果卒中预后较差（Rankin量表评分＞3分）的患者入院时血清白蛋白浓度低于预后较好（Rankin量表评分≤3分）的患者,差异有统计学意义。血清白蛋白浓度与各TOAST亚型预后皆有相关性。结论提高血清白蛋白浓度可以改善缺血性卒中预后。     

Preventable stroke and stroke prevention

Stroke is a major cause of death and disability in the world. The main causes of stroke are atherothromboembolism and cardiogenic embolism. The main causal and treatable risk factors for atherothromboembolic ischemic stroke are increasing blood pressure (BP), increasing cholesterol, cigarette smoking and diabetes; and the main risk factors for cardiogenic ischemic stroke are atrial fibrillation (AF) and ischemic heart disease. Strategies to reduce the incidence of stroke include prevention of first-ever and recurrent stroke, and treatment of patients with acute stroke to reduce death and disability. The two main strategies of stroke prevention are the 'population' (or 'mass') approach and the 'high risk' approach. The 'population' approach aims to reduce stroke by lowering the prevalence and mean level of causal risk factors in the community, by means of public education and government legislation. The 'high risk' approach aims to reduce stroke by identifying individuals at high risk of stroke, and lowering their risk by means of optimal medical therapies. Level 1 evidence from randomized controlled trials indicates that effective treatments for high risk patients include control of causal risk factors (lowering BP, lowering blood cholesterol), antithrombotic therapy (antiplatelet therapy with aspirin, clopidogrel, or the combination of aspirin and dipyridamole for patients in sinus rhythm, and anticoagulation with warfarin or ximelagatran for patients in AF) and, where appropriate, carotid revascularization for patients with severe carotid stenosis.     

Desmoteplase

The high fibrin specificity of Desmodus rotundus salivary plasminogen activator α1 (desmoteplase) renders it a promising candidate for the treatment of acute ischemic stroke. In the DIAS (Desmoteplase in Acute Ischemic Stroke) and DEDAS (Dose Escalation study of Desmoteplase in Acute ischemic Stroke) Phase II studies, doses of 90 μg/kg and 125 μg/kg desmoteplase were reported to have acceptable safety profiles, leading to potentially superior reperfusion compared with placebo, with possible clinical efficacy for up to 9 h after the onset of symptoms in patients with a significant ischemic penumbra selected from magnetic resonance perfusion-diffusion weighted mismatches imaging. However, a Phase III clinical trial (DIAS-2) was unable to detect any benefit from desmoteplase when given 3 – 9 h after stroke onset. In this study with a modest sample size, certain methodological factors may have reduced its potential to detect a desmoteplase effect, as only 30% of these patients had a visible occlusion at presentation, with only small core and mismatched lesion volumes. Indeed, it is surprising that a study testing an occluded vessel ‘reopener’ was conducted in a cohort of stroke patients, the majority of whom was known not to have a detected vessel occlusion. It has also been claimed that the DIAS-2 patients selection using core/penumbra mismatch calculation may not have followed an appropriate mismatch threshold. However, the corrective value of changing the mismatch threshold remains unclear, because the relative mismatch volumes were in fact higher in the ‘negative’ DIAS-2 than in the ‘positive’ DIAS and DEDAS. Two Phase II randomized trials with tPA, Diffusion-weighted imaging Evaluation For Understanding Stroke Evolution (DEFUSE) and Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) provided strong biological support for the relation between infarct growth, reperfusion and clinical outcome in the 3 – 6 h time window after onset of stroke using penumbral imaging. In this frame, why exactly desmoteplase should have specific advantages over tPA, is not clear. Taken together, these findings may also lead to the disappointing conclusion that vessel recanalization after 4.5 – 5 h from stroke onset may generally be inefficacious for tissue salvage. Nevertheless, other randomized Phase III clinical trials (DIAS-3 and DIAS-4) are currently under way with a planned sample size of 320 patients having vessel occlusion or high-grade stenosis on MRI or CT-angiography in the proximal cerebral arteries.     

急性脑梗死早期预后的影响因素

目的观察影响急性脑梗死早期预后的因素,分析糖代谢情况、腹围、基线美国国立卫生院卒中量表(NIHSS)评分、低分子肝素试验(TOAST)分型是否为急性脑梗死早期预后的独立影响因素。方法采用前瞻性研究设计,连续纳入急性脑梗死病例76例,测量腹围,确定糖代谢情况及TOAST分型,入院及发病2周或出院时进行美国国立卫生研究院卒中量表(NIHSS)评分,将评分的差值作为结局变量。比较预后良好(NIHSS差值≥4)及预后不良(NIHSS差值<4)两组患者的糖代谢情况、腹围、基线NIHSS评分及TOAST分型的差异。结果糖代谢正常的急性脑梗死患者早期预后良好比例为29/37,而糖代谢异常者为14/39,差异有统计学意义(P=0.000)。基线NIHSS高者预后相对较差(P=0.011);腹围数值对早期预后无影响(P=0.770),不同TOAST分型的急性脑梗死患者的早期预后差异无统计学意义(P=0.462)。结论糖代谢情况、基线NIHSS与急性脑梗死的早期预后明确相关,而腹围、TOAST分型对早期预后无影响。     

Plasma levels of von Willebrand factor in the etiologic subtypes of ischemic stroke

Summary. Background: Compared with coronary artery disease, there are few studies on von Willebrand factor (VWF) in ischemic stroke (IS). Moreover, there is little information on VWF in the etiologic subtypes of IS. Objectives: The aim of the present study was to investigate VWF in IS and in the etiologic subtypes of IS. Patients/methods: The Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS) is a case–control study comprising 600 patients and 600 matched controls. Etiologic IS subtype was defined according to the TOAST criteria. Blood sampling was performed in the acute phase and after 3 months. Results: The levels of VWF were increased in overall IS, at both time‐points. The 3‐month VWF levels were increased in the subtypes of large‐vessel disease (LVD), cardioembolic (CE) stroke and cryptogenic stroke, but not in the subtype of small‐vessel disease (SVD), as compared with the controls. The acute phase VWF levels were significantly increased in all four subtypes. In the multivariate regression analysis, with vascular risk factors as covariates, the 3‐month VWF levels were associated with CE stroke and cryptogenic stroke, and the acute phase VWF levels with all subtypes. There were significant subtype‐specific differences in VWF, with the highest levels in LVD and CE stroke. Conclusions: The present results show that VWF levels are increased in patients with IS. Furthermore, the VWF levels differ between etiologic IS subtypes and thus, it is important to consider etiologic subtypes in future studies of VWF in patients with IS.     

Intravenous Tissue Plasminogen Activator for Stroke: A Review of the ECASS III Results in Relation to Prior Clinical Trials

Background: Intravenous tissue plasminogen activator (IV tPA) is currently approved by the Food and Drug Administration for use in acute ischemic stroke patients up to 3 h from symptom onset, based primarily on the National Institute of Neurological Disorders and Stroke tPA trials published in 1995. The most recent trial published with IV tPA in stroke (European Cooperative Acute Stroke Study [ECASS] III) studied patients between 3 and 4.5 h from symptom onset and found a benefit to treatment in the rate of favorable outcome when compared to placebo, with no difference in mortality. Objectives: To examine the patient selection criteria and primary outcomes in ECASS III as compared to prior clinical trials and the current practice in the United States to determine how these new data could be applied to clinical practice. Discussion: With the exception of the longer time from symptom onset to treatment, ECASS III used more restrictive patient selection criteria than is the current practice in the United States to determine patient eligibility for IV tPA. Conclusions: Based on the combined data from all trials, the benefits of thrombolysis with IV tPA for acute ischemic stroke outweigh the risks of treatment for selected patients up to 4.5 h from symptom onset. It is already known that thrombolysis is not beneficial for all stroke patients and strict criteria should be applied before treatment. As time from symptom onset increases, the need for careful patient selection likely also increases.     

Deep vein thrombosis after ischemic stroke: rationale for a therapeutic trial

Deep venous thrombosis (DVT) in the legs occurs in 23% to 75% of patients with acute ischemic stroke, and pulmonary embolism accounts for about 5% of deaths. New heparinoid substances, lacking the hazards of more established anticoagulants, raise the question of DVT prophylaxis for these patients. Two hundred fifty consecutive acute ischemic stroke patients were evaluated for the presence of DVT of the legs in a feasibility study for a trial of low-molecular-weight heparin prophylaxis. Forty-nine patients were found suitable for the study, of whom 11 (22.5%) developed DVT. All patients underwent clinical examination, I-125 fibrinogen leg scanning, and impedance plethysmography. Five patients were sufficiently alert and without serious neurologic deficits to justify DVT prophylaxis. Recent advances in noninvasive diagnostic techniques to detect DVT early and the development of relatively safe heparinoid compounds increase the need for a prophylactic study in patients with ischemic stroke.