UMLS:C0038454 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The oral direct thrombin inhibitor ximelagatran (Exanta, AstraZeneca) is rapidly absorbed, is efficiently bioconverted to the active form, melagatran (AstraZeneca) and has shown efficacy and relative safety as an anticoagulant for prophylaxis and therapy of thromboembolism. Two Phase III trials, Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation (SPORTIF V), have tested the hypothesis that oral ximelagatran, administered 36 mg twice daily without coagulation monitoring or dose adjustment, prevents stroke and systemic embolism at least as effectively as adjusted-dose warfarin (international normalized ratio, 2.0-3.0) in patients with nonvalvular atrial fibrillation. Both were randomized, multicenter trials (n > 3000 per trial) with blinded end-point assessment. The open-label SPORTIF III trial confirmed the noninferiority of ximelagatran versus warfarin. Publication of the full results from SPORTIF V is pending.
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PMID:Antithrombotic therapy in atrial fibrillation: ximelagatran, an oral direct thrombin inhibitor. 1515 65

Protease-activated receptors (PARs) belong to the superfamily of seven transmembrane domain G protein-coupled receptors. Four PAR subtypes are known, PAR-1 to -4. PARs are highly homologous between the species and are expressed in a wide variety of tissues and cell types. Of particular interest is the role which these receptors play in the brain, with regard to neuroprotection or degeneration under pathological conditions. The main agonist of PARs is thrombin, a multifunctional serine protease, known to be present not only in blood plasma but also in the brain. PARs possess an irreversible activation mechanism. Binding of agonist and subsequent cleavage of the extracellular N-terminus of the receptor results in exposure of a so-called tethered ligand domain, which then binds to extracellular loop 2 of the receptor leading to receptor activation. PARs exhibit an extensive expression pattern in both the central and the peripheral nervous system. PARs participate in several mechanisms important for normal cellular functioning and during critical situations involving cellular survival and death. In the last few years, research on Alzheimer's disease and stroke has linked PARs to the pathophysiology of these neurodegenerative disorders. Actions of thrombin are concentration-dependent, and therefore, depending on cellular function and environment, serve as a double-edged sword. Thrombin can be neuroprotective during stress conditions, whereas under normal conditions high concentrations of thrombin are toxic to cells.
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PMID:Protease-activated receptors in neuronal development, neurodegeneration, and neuroprotection: thrombin as signaling molecule in the brain. 1553 36

Warfarin therapy achieving an International Normalized Ratio between 2 and 3 has been shown to be effective in preventing stroke. However, warfarin administration is problematic because of its variable dose, interaction with numerous foods and drugs, narrow therapeutic range, need for chronic anticoagulation monitoring, and long onset and offset of action, which all contribute to the significant underuse of warfarin in patients with atrial fibrillation at risk for stroke despite clear indication for its use. This has led to new approaches. Studies with idraparinux (AMADEUS), a factor 10a inhibitor, and with aspirin and clopidogrel (ACTIVE), both platelet inhibitors, are on-going. Studies with ximelagatran (Stroke Prevention by Oral Thrombin Inhibition in Atrial Fibrillation [SPORTIF] trials III and V), an oral direct thrombin inhibitor, have been completed. They compared ximelagatran with warfarin in patients with nonvalvular atrial fibrillation at risk for stroke. The studies demonstrated that ximelagatran is not inferior to warfarin. Moreover, ximelagatran has rapid onset and offset of action, fixed oral dosing without the need for anticoagulation monitoring, low potential for food and drug interactions, and a therapeutic margin wider than that of warfarin. We anticipate further studies to demonstrate definitively that the small percentage of patients (0.5%) with elevation of both alanine aminotransferase (ALT) and bilirubin levels can be managed safely, thereby making ximelagatran a promising option for preventing thromboembolism in patients with atrial fibrillation at risk for stroke.
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PMID:New possibilities in anticoagulant management of atrial fibrillation. 1561 13

Coronary heart disease is the number one cause of death in the world and acute coronary syndromes (ACS) continue to be associated with high rates of morbidity. ACS refers to the spectrum of acute myocardial ischemia, including unstable angina, ST segment elevation myocardial infarction (STEMI), and acute MI without ST segment elevation (NSTEMI). Current guidelines indicate both aspirin and glycoprotein IIb/IIIa receptor antagonists (if catheterization/revascularization are planned) as class IA recommendations in ACS. Anticoagulant therapy, in the form of heparin, is a class IA recommendation for the acute hospital phase of ACS. The risk of recurrent thrombotic events following ACS remains high in the post-hospital phase, creating a rationale for the use of oral direct thrombin inhibitors such as ximelagatran, in both the acute and long-term settings. The Efficacy and Safety of the Oral Direct Thrombin Inhibitor Ximelagatran in Patients with Recent and Myocardial Damage (ESTEEM) trial, a placebo-controlled, double-blind study of post-MI patients, evaluated 4 dosing regimens of ximelagatran versus placebo in the initial months following an ACS and found an encouraging reduction in the end points of death, MI, and stroke with the use of an oral direct thrombin inhibitor.
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PMID:Reducing cardiac events after acute coronary syndromes. 1561 14

Thrombin activable fibrinolysis inhibitor antigen levels (TAFI Ag ) exhibit a great inter-individual variability in healthy populations. Our aim is to determine whether variability is due to physiologic variations depending on genetic control or due to validation of the method,in order to allow a better interpretation of the results inpatients with vascular diseases. With this purpose, we performed a strategy validation of specific ELISA method, Zymutest TAFI Ag Hyphen Biomed, base don a commercial monoclonal antibody. After methodology validation we have recently determined plasma TAFI Ag levels in several groups of diseases such as septic patients, menopause and cerebrovascular diseases. TAFI was finally determined in acute ischemic stroke to know its relationship with stroke evolution and response to thrombolytic treatments.
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PMID:Plasma thrombin-activatable fibrinolytic inhibitor (TAFI) among healthy subjects and patients with vascular diseases: a validation study. 1569 48

This article will review 2 clinical trials that recently compared the safety and efficacy of the oral direct thrombin inhibitor ximelagatran (fixed dose, 36 mg twice daily) with warfarin (adjusted dose, target international normalized ratio [INR] 2.0-3.0) in patients with nonvalvular atrial fibrillation and at least 1 risk factor for stroke. These noninferiority trials involved 7329 patients and a mean exposure to study drug of 18.5 months. The Stroke Prevention Using Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) III (open-label, N = 3407) and V trials (double-blind, N = 3922) were designed for pooled analysis, and the data showed the efficacy of ximelagatran therapy was comparable (noninferior) with extremely well-controlled warfarin therapy in preventing stroke and systemic embolic events; the primary event rates were 1.65% per year and 1.62% per year in the warfarin and ximelagatran groups, respectively (P = .941). In patients with a history of stroke or transient ischemic attack (about 20% of the SPORTIF population), the event rates were 3.27% per year and 2.83% per year in the warfarin and ximelagatran groups, respectively (P = .625). The distribution of stroke subtypes was similar in the 2 treatment groups. Intracranial hemorrhage occurred at a rate of 0.20% per year with warfarin and 0.11% per year with ximelagatran. Combined rates of minor and major bleeding were significantly lower with ximelagatran than with warfarin (32% per year vs 39% per year; P < .0001). The myocardial infarction rates were the same in the pooled database (no difference between agents). The aspirin data will be the subject of two substudy papers. Oral ximelagatran administered without coagulation monitoring or dose adjustment was as effective as well-controlled, adjusted-dose warfarin for prevention of stroke and systemic embolic events and was associated with significantly less total bleeding. This oral direct thrombin inhibitor is a potentially promising treatment option for the prevention of thromboembolism.
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PMID:Stroke prevention in atrial fibrillation: pooled analysis of SPORTIF III and V trials. 1569 10

Atrial fibrillation (AF) is the most common cardiac risk factor for stroke. Oral anticoagulants such as the vitamin K antagonist warfarin have been proven effective in reducing the risk of stroke in AF. Warfarin, however, has many disadvantages including the need for coagulation monitoring, a narrow therapeutic index, inter-/intra-patient variability and food-drug interactions. As a result, warfarin is underused in clinical practice and a viable alternative is needed. Ximelagatran, the first oral direct thrombin inhibitor, is given as a fixed dose, does not have a narrow therapeutic index, has low potential for drug interactions, has no significant food interactions and does not require coagulation monitoring. Ximelagatran has been evaluated in the Stroke Prevention using an ORal direct Thrombin Inhibitor in atrial Fibrillation (SPORTIF) trial programme, the largest clinical trials of antithrombotic therapy for stroke prevention in AF to date. The phase III trials, SPORTIF III and V, compared ximelagatran (36 mg twice daily) with well-controlled warfarin (international normalized ratio 2.0-3.0) in a combined population of more than 7,000 moderate- to high-risk AF patients. Data from SPORTIF III show an absolute reduction in stroke and systemic embolic events with ximelagatran compared with warfarin at 21 months (1.6 vs. 2.3% per year, respectively; p = 0.10). Preliminary data from SPORTIF V appear to further support non-inferiority between the two agents. On-treatment analysis of the rate of major bleeding events shows an absolute, nonsignificant reduction in the event rate per year with ximelagatran versus warfarin in both studies. The results of SPORTIF III and V demonstrate that a fixed oral dose of ximelagatran, without coagulation monitoring, is comparable to dose-adjusted warfarin in preventing stroke and other thromboembolic complications among moderate- to high-risk AF patients and has a lower rate of both major and minor bleeding. With its positive benefit-risk ratio, ximelagatran may increase the population of eligible patients for anticoagulation with AF and maximize the potential of anticoagulation in the prevention of stroke.
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PMID:Preventing stroke in atrial fibrillation: the SPORTIF programme. 1581 1

Atrial fibrillation is the most common sustained cardiac arrhythmia and the most frequently encountered cause of embolic stroke. Vitamin K antagonists (such as warfarin) have represented the cornerstone of anticoagulation practice for the last 60 years. Although highly effective in preventing thromboembolic events among patients with atrial fibrillation, warfarin therapy is limited by a multitude of potential problems. Hence, warfarin is significantly underused in clinical practice, with only half of warfarin-treated patients actually achieving therapeutic anticoagulation in routine clinical practice. Consequently, there is an overwhelming need for an alternative oral anticoagulant for patients with atrial fibrillation that is safer, more practical and effective. Ximelagatran (Exanta, AstraZeneca) is a novel oral direct thrombin inhibitor that is rapidly converted to the active compound melagatran after oral absorption. It has a low potential for drug interactions, anticoagulation monitoring is not required, and it is administered at a fixed twice-daily dose. The Stroke Prevention using the ORal Thrombin Inhibitor in patients with nonvalvular atrial Fibrillation (SPORTIF) III and V trials have together demonstrated the noninferiority of ximelagatran relative to warfarin for the prevention of stroke and embolic events in atrial fibrillation. Unfortunately, initial optimism has been tempered by serious concerns over its safety data in view of its propensity to cause elevation in liver enzymes.
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PMID:Ximelagatran for stroke prevention in atrial fibrillation. 1607 67

Nonvalvular atrial fibrillation (AF) is an independent risk factor for stroke that becomes increasingly prevalent as populations age. More than half a dozen clinical trials have demonstrated that anticoagulation with the vitamin K antagonist warfarin is the most effective therapy for stroke prophylaxis in AF. The narrow therapeutic index of warfarin requires that the intensity of anticoagulation be maintained within the international normalized ratio (INR) range of 2.0 to 3.0 to optimize efficacy while minimizing bleeding risk. The pharmacokinetics of warfarin are subject to variability due to interactions with multiple drugs and foods, making maintenance of the INR within this range difficult to achieve in clinical practice without close coagulation monitoring and frequent dose adjustments. Current guidelines recommend oral anticoagulation for high-risk individuals with AF but these inherent limitations lead to substantial underprescribing, particularly in elderly patients at greatest risk. This has stimulated the development of new agents with improved benefit-risk profiles, such as ximelagatran, the first of the oral direct thrombin inhibitors, which has a wider therapeutic margin and low potential for drug interactions, allowing fixed dosing without anticoagulation monitoring. Ximelagatran has been evaluated for stroke prevention in AF in the Stroke Prevention using an Oral Direct Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) program, the largest clinical trials of antithrombotic therapy for stroke prevention in AF to date. The phase III trials of ximelagatran in AF, SPORTIF III and V, found a fixed oral dose of ximelagatran (36 mg twice daily) comparable to dose-adjusted warfarin (INR 2.0 to 3.0) in preventing stroke and systemic thromboembolic complications among high-risk patients with AF. Results from the population of over 7000 patients in SPORTIF III and V demonstrate noninferiority of ximelagatran compared with warfarin. Data from SPORTIF III show an absolute reduction in stroke and systemic embolic events with ximelagatran compared with warfarin of 1.6% per year versus 2.3% per year, respectively ( P = 0.10). SPORTIF V further supports noninferiority between the two agents with an absolute risk reduction of 0.45%, well within the predefined noninferiority margin (95% confidence interval -0.13, 1.03; P = 0.13). Although event rates for major bleeding did not differ significantly with ximelagatran versus warfarin in either study, combined rates for major and minor bleeding were significantly reduced with ximelagatran. The overall net clinical benefit, taking into account effects on stroke or systemic embolic events, major bleeding, and death, was also greater with ximelagatran compared with warfarin in both studies. Elevated serum transaminase enzymes were observed in approximately 6% of patients given ximelagatran in these trials. These typically occurred 1 to 6 months after initiating treatment and usually abated without clinical sequelae whether or not treatment was continued. Given the consistency of response, the favorable overall benefit-risk ratio and the convenience of fixed oral dosing, ximelagatran may increase the number of patients with AF eligible for anticoagulation and amplify the potential for prophylaxis against stroke.
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PMID:Prevention of stroke in patients with atrial fibrillation. 1612 16

Recently, ximelagatran and warfarin have been compared for stroke prevention in the Stroke Prevention using an Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) V trial in patients with non-valvular atrial fibrillation, and for the treatment of deep vein thrombosis in the Thrombin Inhibitor in Venous Thromboembolism (THRIVE) trial. In a mean follow-up of 20 months in SPORTIF V, the primary end point of stroke or systemic embolic events occurred in 37 patients in the warfarin group (of 1962) and 51 in the ximelagatran group (1960 patients). There was no difference between the groups in major bleeding. The rates of elevated alanine aminotransferase were much higher in the ximelagatran group (6%) than in the warfarin group (0.8%). In THRIVE, the primary efficacy end point of recurrent venous thromboembolism occurred in 26/1240 ximelagatran patients and 24/1249 patients in the enoxaparin/warfarin group. The incidence of alanine aminotransferase levels greater than three times the upper limit of normal was much higher with ximelagatran than with enoxaparin/warfarin (9.6 and 2.0%, respectively). In conclusion, although the trials comparing ximelagatran with warfarin as prophylaxis for stroke in atrial fibrillation and in the treatment of venous thromboembolism show noninferiority, concerns about the hepatic safety of ximelagatran remain.
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PMID:Ximelagatran--recent comparisons with warfarin. 1614 13

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