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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intracerebral hemorrhage is the least treatable form of stroke and is associated with 30% to 50% mortality rate. Early hematoma growth occurs in 18% to 38% of patients scanned within 3 hours of intracerebral hemorrhage onset, and hematoma volume is an important predictor of poor outcome. Recombinant activated factor VII, a potent initiator of hemostasis, is currently approved for the treatment of bleeding in hemophilia patients with inhibitors and has also been shown to promote hemostasis in patients with normal coagulation. A recent phase IIB randomized, double-blind, placebo-controlled, dose-ranging "proof-of-concept" trial enrolled 399 intracerebral hemorrhage patients to determine whether recombinant activated factor VII can limit ongoing bleeding and improve outcome. An approximate 50% relative reduction in hematoma growth was evident with all 3 doses that were tested (40, 80, and 160 microg/kg), which translated into an average reduction in absolute intracerebral hemorrhage volume growth of approximately 5 milliliters. More importantly, recombinant activated factor VII was associated with a 38% relative reduction in mortality and significantly improved functional outcome among survivors, despite a 5% frequency of arterial thromboembolic events (primarily ischemic stroke and myocardial infarction). A large phase III trial (the FAST trial [Factor Seven for Acute Hemorrhagic Stroke Treatment]) is now in progress to confirm these findings.
Stroke 2007 Feb
PMID:Recombinant activated factor VII for acute intracerebral hemorrhage. 1751 Apr 50

Stroke is a major public health problem in the United States and the development of novel therapeutic strategies is an important research priority. Advances in this field are proceeding on several fronts, including the use of next-generation plasminogen activators and glycoprotein IIb/ IIIa inhibitors, refined patient selection with advanced magnetic resonance imaging sequences, endovascular approaches to thrombolysis and thrombectomy, and adjuvant use of ultrasound. There remains no proven therapy for intracerebral hemorrhage, but early results with recombinant activated factor VII look very promising. It is hoped that in the near future, physicians managing patients with acute neurological events will have a robust armamentarium of therapies to bring to bear on both ischemic and hemorrhagic vascular disease.
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PMID:Emerging therapies for acute ischemic stroke. 1751 6

Intracerebral haemorrhage (ICH) is the deadliest form of stroke, carrying a mortality rate between 30% and 55%, increasing to 67% in patients on oral anticoagulant therapy (OAT). Despite its relevant incidence, the treatment of ICH has been until recently a largely neglected item, addressed by only a few trials. Early treatment of ICH in non-anticoagulated patients with recombinant activated factor VII (rFVII) has been demonstrated to be able to limit the growth of the haematoma, but such a promising result requires further confirmations. In ICH patients receiving OAT a prompt reversal of the anticoagulant effect should be warranted in order to reduce the consequences of this dreadful adverse event. In clinical practice, however, just a small proportion of anticoagulated patients receive this treatment, probably because of the fear of thromboembolic complications. It is now time to check our way of thinking about ICH, regarding and treating it as a compelling medical emergency.
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PMID:Intracerebral haemorrhage: an often neglected medical emergency. 1791 91

Intracerebral hemorrhage (ICH) comprises 15% of all strokes, and carries the highest risk of mortality and poor long-term outcome. ICH has long been recognized as the least treatable form of stroke, and hematoma volume as the strongest single predictor of mortality and outcome. CT-based studies have found that early substantial hematoma expansion occurs in 18-38% of patients initially scanned within 3 h of symptom onset. This finding is associated with early neurological deterioration and an increased risk of poor outcome. Ultra-early hemostatic therapy might be beneficial in preventing hematoma growth, resulting in improved mortality and neurological function. Recombinant activated factor VII (rFVIIa) promotes local hemostasis in the presence or absence of coagulopathy at sites of vascular injury, and is a promising treatment for arresting active bleeding in ICH. The safety and feasibility of this approach was confirmed in a phase IIb randomized, double-blind, placebo-controlled, dose-ranging trial of 399 patients with non-coagulopathic ICH. Administration of rFVIIa within 4 h of ICH onset resulted in a significant reduction of hematoma expansion at 24 h, and reduced mortality and improved functional outcome at 90 days. A confirmatory phase III trial (The FAST Trial) to confirm these results will complete enrollment in the end of 2006.
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PMID:Reducing the risk of ICH enlargement. 1763 8

Treatments for spontaneous intracerebral, thrombolytic-induced and intraventricular hemorrhages (IVH) are still at the preclinical or early clinical investigational stages. There has been some renewed interest in the use of surgical evacuation surgery or thrombolytics to remove hematomas, but these techniques can be used only for specific types of brain bleeding. The STICH (Surgical Trial in Intracerebral Haemorrhage) clinical trials should provide some insight into the potential for such techniques to counteract hematoma-induced damage and subsequently, morbidity and mortality. More recently, clinical trials (ATACH [Antihypertensive Treatment in Acute Cerebral Hemorrhage] and INTERACT [Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial]) have begun testing whether or not regulating blood pressure affects the well-being of hemorrhage patients, but the findings thus far have not conclusively demonstrated a positive result. More promising trials, such as the early stage CHANT (Cerebral Hemorrhagic And NXY-059 Treatment) and the late stage FAST (Factor VIIa for Acute Hemorrhagic Stroke Treatment), have addressed whether or not manipulating oxidative stress and components of the blood coagulation cascade can achieve an improved prognosis following spontaneous hemorrhages. However, CHANT was halted prematurely because although it showed that the spin trap agent NXY-059 was safe, it also demonstrated that the drug was ineffective in treating acute ischemic stroke. In addition, the recombinant activated factor VII FAST trial recently concluded with only modestly positive results. Despite a beneficial effect on the primary end point of reducing hemorrhage volume, controlling the coagulation cascade with recombinant factor VIIa did not decrease the mortality rate. Consequently, Novo Nordisk has abandoned further development of the drug for the treatment of intracerebral hemorrhaging. Even though progress in hemorrhage therapy that successfully reduces the escalating morbidity and mortality rate associated with brain bleeding is slow, perseverance and applied translational drug development will eventually be productive. The urgent need for such therapy becomes more evident in light of concerns related to uncontrolled high blood pressure in the general population, increased use of blood thinners by the elderly (e.g., warfarin) and thrombolytics by acute ischemic stroke patients, respectively. The future of drug development for hemorrhage may require a multifaceted approach, such as combining drugs with diverse mechanisms of action. Because of the substantial benefit of factor VIIa in reducing hemorrhage volume, it should be considered as a prime drug candidate included in combination therapy as an off-label use if the FAST trial proves that the risk of thromboembolic events is not increased with drug administration. Other promising drugs that may be considered in combination include uncompetitive NMDA receptor antagonists (such as memantine), antioxidants, metalloprotease inhibitors, statins and erythropoietin analogs, all of which have been shown to reduce hemorrhage and behavioral deficits in one or more animal models.
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PMID:Advances in hemorrhagic stroke therapy: conventional and novel approaches. 1787 68

This article covers three major topics of acute stroke therapy: extension of the time window for thrombolysis with desmoteplase, decompressive surgery after malignant middle cerebral artery infarction, and the effect of hemostatic therapy with recombinant activated factor VII (rFVIIa) in patients with spontaneous primary intracerebral hemorrhage. Thrombolytic therapy with recombinant tissue or tissue-type plasminogen activator is still the only approved acute stroke therapy within a 3-h time window. Imaging-based patient selection seems to help extending this time window. After promising results of two phase II trials with the thrombolytic agent desmoteplase in an extended time window after acute ischemic stroke, the DIAS-II study was reconducted in Europe, North America, and Australia as a phase III trial. First results of the included 186 patients are shown. Surprisingly, patients treated with desmoteplase had no better outcome than placebo-treated patients, and there was increased mortality in the high-dose group. Among all stroke subtypes, space-occupying malignant middle cerebral artery is one with the poorest prognosis. Most patients die within a few days due to the development of massive brain edema, despite maximum intensive care. Decompressive hemicraniectomy represents a much more effective therapy for the treatment of local brain swelling. However, until recently this method was highly controversial. Here we present the results of the randomized trials published in 2007 and discuss their relevance for acute therapy. Hematoma growth occurs within 4 h in one third of patients who suffer from intracerebral hemorrhage. Prospective, placebo-controlled, multicenter trials have shown that intravenous application of rFVIIa reduces volume increase. We present preliminary results of the latest phase III trial (FAST: recombinant factor VIIa in acute hemorrhagic stroke), which tried to find whether the hemostatic effect will translate into clinical effect.
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PMID:[Acute stroke therapy. Current developments]. 1787 77

Intracerebral haemorrhage accounts for 10-15% of strokes and is associated with high mortality and severe disability in survivors. Despite its seriousness, the treatment options for intracerebral haemorrhage are limited. Measures aimed at decreasing elevated intracranial pressure are of limited effectiveness. This has stimulated an interest in attempting to improve the prognosis of intracerebral haemorrhage by addressing the haematoma directly, either removing it by surgical means or limiting its early spontaneous growth. The international Surgical Trial in Intracerebral Haemorrhage (STICH), which randomized subjects with intracerebral haemorrhage within 72 h of symptom onset to medical management vs. surgery, failed to document the superiority of one treatment over the other, when compared with regard to mortality and functional outcome at 90 days. The subgroup of patients with lobar haematomas located at a depth of 1 cm or less from the cortical surface fared better with surgery than with medical management. A similar comparison trial is planned for this subgroup of patients. The neutral results of The international Surgical Trial in Intracerebral Haemorrhage (STICH) prompted the assessment of haemostatic therapies, based on the observation that haematomas often enlarge substantially in the hours that follow the onset of symptoms. Recombinant activated factor VII has been shown in a phase IIb, dose-finding trial to result in a significant reduction of haematoma growth, and both mortality and functional scales trended in favour of recombinant activated factor VIIa. The main complication of this therapy was arterial thromboembolic events (myocardial infarction and ischaemic stroke). A phase III randomized trial has recently been completed.
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PMID:Advances in intracerebral haemorrhage management. 1828 12

Primary intracerebral hemorrhage is the least treatable form of stroke and is associated with high mortality rates. In the thrombolytic era, the attention has bee driven on the first hours of onset, when the hematoma is still growing. Intervention with ultra-early hemostatic therapy might arrest ongoing bleeding. Even if recombinant activated factor VII administered within 4 h of symptom onset did not improve outcome in a recent phase 3 trial, it reduced hematoma growth. Therefore, the rational for ultra-early hemostatic therapy it is still valid and another trial on hemostatic treatment is warranted.
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PMID:Epidemiological, clinical, and therapeutic aspects of primary intracerebral hemorrhage. 1869 May 10

Protein Z (PZ) is a vitamin K-dependent factor identified in human plasma in 1984 characterized by an homology with other vitamin K-dependent factors (factor VII, IX, X, protein C). In contrast to these factors, PZ does not possess any enzymatic activity but is involved as a cofactor in the down-regulation of coagulation by forming a complex with the protein Z-dependent protease inhibitor (ZPI). ZPI inhibits the activated factor X (FXa) on phospholipid surface. In mice, the disruption of PZ gene is asymptomatic, but the association with the factor V Leiden mutation leads to a quasi complete mortality during the neonatal period with microvascular thrombosis. In humans, PZ is characterized by an unusual wide distribution in plasma, and a major decrease induced by warfarin. Isolated PZ deficiency does not seem to constitute a risk for venous thrombosis, but a severe PZ deficiency could increase the risk of well recognized venous thrombotic risk factors such as factor V Leiden, G20210A mutation or hyperhomocysteinemia. Unexpectedly, a relationship between PZ deficiency and ischemic arterial diseases such as stroke, acute coronary syndromes or peripheral arterial disease was described but not confirmed by all studies. PZ deficiency could be also a risk factor for early fetal losses, and increases the arterial risk in antiphospholipid syndrome. This review analyzes the different studies so far published and discusses the various results obtained in order to understand whether or not protein Z deficiency could be considered as an arterial ischemic risk factor.
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PMID:Protein Z, a protein seeking a pathology. 1884 Dec 75

Hematoma growth is common in intracerebral hemorrhage (ICH) and is associated with a poor outcome for patients. To evaluate the efficacy and safety of recombinant activated factor VII (rFVIIa) used as a hemostatic agent in patients with ICH without hemophilia, we searched Medline, Scopus, the Cochrane Library, Clinicaltrials.gov and the Stroke Trials Directory. Five randomized controlled trials were selected for analysis. Although rFVIIa can reduce the change in ICH volume, there was no significant difference in mortality, modified Rankin Scale (mRS) score or extended Glasgow Outcome Scale (GOS-E) score in patients treated with rFVIIa or placebo. There was a significant increase in arterial thromboembolic adverse events (TAE) in patients treated with rFVIIa. There was an increase in deep vein thrombosis in patients with spontaneous ICH and traumatic ICH. In conclusion, the use of rFVIIa reduces the growth of the hematoma but does not improve patient survival or functional outcome after ICH; in addition, rFVIIa increases the incidence of arterial TAE.
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PMID:A meta-analysis of the efficacy and safety of recombinant activated factor VII for patients with acute intracerebral hemorrhage without hemophilia. 2039 68


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