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

Atrial fibrillation is a common rhythm disturbance; its most significant adverse events are ischemic stroke and systemic arterial occlusion. Oral anticoagulation with warfarin is an effective therapy for stroke prevention but remains underused due to numerous complications and barriers. Ximelagatran, an oral direct thrombin inhibitor, may become an alternative strategy for clinicians. This agent was developed to overcome many of the limitations associated with warfarin. Its consistent antithrombotic effect and wide therapeutic index allow fixed dosing without the need for routine coagulation monitoring, and without concerns related to drug, food, and disease state interactions. Ximelagatran has been investigated in patients with atrial fibrillation and has been as effective as warfarin for stroke prevention.
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PMID:The role of oral direct thrombin inhibitors in atrial fibrillation. 1562 39

Atrial fibrillation (AF) causes 50,000 to 100,000 ischemic strokes annually in the U.S., most of which could be prevented by oral anticoagulant treatment of the highest-risk patients. The greatest barrier to such treatment is the narrow therapeutic index of the vitamin K antagonists ([VKAs]: warfarin and related coumarin derivatives), the only oral anticoagulant agents currently available. Safe and effective treatment with the VKAs requires careful monitoring, because they interact with many other drugs and foods, and their anticoagulant action is unpredictable. Besides vitamin K, candidate targets for anticoagulant therapy include thrombin, a key prothrombotic mediator. Ximelagatran, the oral direct thrombin inhibitor at the most advanced stage of clinical development, is rapidly absorbed and bioconverted to its active moiety, melagatran-a potent, competitive inhibitor of both free and clot-bound thrombin. Two large clinical trials have demonstrated that fixed-dose oral ximelagatran, 36 mg twice daily, administered without coagulation monitoring, prevents stroke and systemic embolic events in patients with nonvalvular AF as effectively as well-controlled, adjusted-dose warfarin (international normalized ratio 2.0 to 3.0). The overall risk of bleeding was lower with ximelagatran than warfarin, although differences in rates of major hemorrhage were not statistically significant. Elevation of serum alanine aminotransferase levels above 3x the upper limit of normal occurred in approximately 6% of ximelagatran-treated patients but typically returned toward pretreatment levels without associated symptoms. In terms of preventing thromboembolism without hemorrhage, ximelagatran may have a more favorable benefit:risk profile than warfarin for patients with AF.
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PMID:Ximelagatran: oral direct thrombin inhibition as anticoagulant therapy in atrial fibrillation. 1562 64

Recent advances in neuro-imaging technology assist early clinical diagnosis for ischemic stroke subtype. The precise early diagnosis for stroke subtype plays an important role for the management in patients with acute cerebral infarction. The differential diagnosis is made according to the algorithm in the modified the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification, with reference to the results of diffusion-weighted MRI and MRA. Artery-to-artery embolism and branch atheromatus disease are diagnosed as atherothrombotic infarction according to this algorithm. Thrombolytic therapy is recommended in cardioembolic stroke within 3 hours after onset. The anticoagulant therapy with heparin is often used to prevent the recurrence for thrombosis in acute cardioemboic infarction. The selective thrombin inhibitor has recently been used in the treatment of acute atherothrombotic infarction. The antiplatelet therapy with aspirin is recommended in acute atherothrombotic infarction and lacunar infarction. The sodium ozagrel is recommended in the treatment of acute lacunar infarction. The treatment of acute ischemic stroke should be managed according to Japanese Guidelines for the management of stroke (2004).
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PMID:[Differential diagnosis of acute ischemic stroke and management on the basis of acute ischemic stroke subtype]. 1565 30

By understanding barriers, providing education, and advocating appropriate treatment, case managers play an essential role in the prevention and treatment of thromboembolic disorders. Yet, thromboembolic events such as stroke and deep-vein thrombosis still result in substantial morbidity and mortality despite the availability of effective prophylactic anticoagulation therapy. Although oral warfarin, because of its established efficacy, remains the mainstay in the prevention and treatment of thromboembolic disorders associated with atrial fibrillation, a common antecedent, it is fraught with enduring impediments that hinder effectiveness, safety, and use. With a narrow therapeutic widow, optimal treatment relies on maintaining a tight international normalized ratio (INR) range, usually between 2.0 and 3.0. Lacking intensive anticoagulation clinic monitoring, patients are often outside the therapeutic range, compromising efficacy or safety. Furthermore, the need for frequent and demanding INR monitoring, a slow onset of action, and an elevated risk for drug-drug and food-drug interactions conspire to undermine the use of warfarin, especially in high-risk groups, such as the elderly. Unquestionably, well-tolerated, convenient, and effective alternatives to oral warfarin are needed to improve the management of patients in need of anticoagulation therapy. Several new oral anticoagulants are in development, but only one, ximelagatran, has completed Phase-III development and awaits Food and Drug Administration (FDA) approval. An oral direct thrombin inhibitor, ximelagatran, appears to offer a profile quite different from warfarin: a wide therapeutic window that obviates routine drug-level monitoring and twice-daily oral administration with minimal drug interactions; however, transient liver enzyme elevations remain an unresolved issue. As case managers typically work with those who present with clinical or psychosocial challenges, or both, this treatment approach may provide an alternative that would enhance patient outcomes.
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PMID:Oral anticoagulation: challenges in the case-management setting. 1568 10

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

Argatroban, a direct thrombin inhibitor, effectively inhibits free and clot-bound thrombin without the need of a cofactor and exerts dose-dependent anticoagulant effects that are rapidly active and rapidly reversible (elimination half-life: 39-51 min). Argatroban provides predictable parenteral anticoagulation and is well tolerated with an acceptably low bleeding risk in a variety of clinical settings, including heparin-induced thrombocytopenia, acute ischemic stroke, percutaneous coronary intervention and hemodialysis. This review will discuss the clinical pharmacology and utility of argatroban; in particular, clinical trial experiences will be discussed in patients with, or at risk of, heparin-induced thrombocytopenia (where heparins must be avoided) including those requiring hemodialysis or percutaneous coronary intervention, and in patients with acute ischemic stroke (where heparins are not generally recommended).
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PMID:Alternative parenteral anticoagulation with argatroban, a direct thrombin inhibitor. 1572 73

Ximelagatran is an oral direct thrombin inhibitor (DTI), the active form of which is melagatran. Approximately 20% of an oral ximelagatran dose becomes bioavailable as melagatran, which binds noncovalently and reversibly to both fibrin-bound and freely circulating thrombin. Oral ximelagatran dosing not only inhibits thrombin activity rapidly, competitively, and potently, but also delays and suppresses thrombin generation. In humans, oral ximelagatran exhibits anticoagulant, antiplatelet, and profibrinolytic effects, with only minor prolongation of the capillary bleeding time. Oral ximelagatran exhibits a stable and predictable pharmacokinetic profile during repeated dosing, with low intra- and inter-individual variation, and a low potential for interaction with other medications. It is excreted primarily as melagatran via the kidney, without unexpected bioaccumulation. Dosing requirements do not vary with age, gender, ethnicity, obesity, or food or alcohol intake. Clinical trials (total n>30,000) have evaluated oral ximelagatran in four indications: the prevention of venous thromboembolism (VTE, comprising deep venous thrombosis with or without and pulmonary embolism) after elective hip- or knee-replacement surgery (with approval granted by France, as the Reference Member State for the European Union); treatment and long-term secondary prevention of VTE; the prevention of stroke and other systemic embolic events associated with nonvalvular atrial fibrillation; and the prevention of cardiovascular events after an acute myocardial infarction. The results of these trials suggest that the benefit-risk profile of oral ximelagatran therapy, administered at a fixed-dose without coagulation monitoring, compares favorably with that of currently approved standard therapy.
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PMID:Ximelagatran--a promising new drug in thromboembolic disorders. 1572 69

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

During the past years increasingly stricter criteria have been applied to the primary prevention of ischemic stroke. This applies especially to the treatment of asymptomatic carotid stenosis. An operation is indicated for a blockage of 60% and higher, including symptom-free patients under 75 years of age. At the moment, a final conclusion on the preferred operative procedure--thromboendarterectomy or stent implantation--cannot be made. For the secondary prevention of apoplexy, the highest relative risk reduction for vascular accidents using thrombocyte aggregation inhibitors was achieved with the combination ASA plus dipyridamole. Diuretics, calcium antagonists, ACE inhibitors and angiotensin receptor blockers (ARB) are equally suitable for the reduction of blood pressure after apoplectic insult. Moreover, the latter appear to have advantages for the prevention of a renewed apoplexy. The benefit of statins in the secondary prevention of apoplexy has been substantiated by the Heart Protection Study. Simvastatin has the best evidence for its effectiveness in patients without CHD; in contrast, atorvastatin has possibly more benefits for patients with clinically evident CHD. The direct thrombin inhibitor, ximelagatran, will be available as an alternative to the oral anticoagulant marcumar in the foreseeable future.
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PMID:[Apoplexy--current status of diagnostics and therapy]. 1596 73

Atrial fibrillation (AF) increases the risk of ischemic stroke due to the formation of a thrombus within left atrium. Thus, adjusted-dose (optimal INR: 2-3) anticoagulant therapy such as warfarin dramaticaly decreases this risk of embolic events both in primary and secondary prevention but slightly increases the risk of bleeding, particularly in the elderly. This explains that, although the benefit has been clearly demonstrated, the anticoagulant therapy remains underused. The efficacy of low doses of aspirin is less clear but it may be appropriate in younger patients with lone AF because of a low risk of embolic events. The combination of low doses of warfarin and aspirin should not be given. In case of contraindication to warfarin and aspirin, some others drugs such as indobufen or dipyridamole may be given but the most promising drug is ximelagatran, a direct thrombin inhibitor, which appears to be as effective than warfarin with a lower incidence of bleedings. For patients in AF who require urgent cardioversion, intravenous unfractionated heparin remains the anticoagulant of choice but an approach combining low-molecular-weight heparin and transesophageal echocardiography has been proposed. For each patient the decision of treatment must be tightly correlated to the benefit-risk ratio.
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PMID:Atrial fibrillation and anticoagulation. 1600 78


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