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

The active control trials, SPORTIF III and SPORTIF V, compared the direct thrombin inhibitor ximelagatran to warfarin, where each was given as a treatment to prevent systemic embolism and stroke in patients with atrial fibrillation. Because warfarin has previously been compared to placebo in similar patients and ximelagatran has now been compared to warfarin, an indirect comparison between ximelagatran and placebo is possible (imputed placebo analysis). In this analysis, ximelagatran reduces the risk of stroke and systemic embolism by 66% (hazard ratio 0.338; 95% confidence interval [CI] 0.204-0.560). Ximelagatran preserves 102% (95% CI 72-132%) of the benefit of warfarin. Based on these data, ximelagatran may be an effective alternative to warfarin for the prevention of stroke and systemic embolism in high-risk patients with atrial fibrillation.
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PMID:Ximelagatran compared with warfarin for the prevention of systemic embolism and stroke. An imputed placebo analysis. 1602 34

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

Ximelagatran is a direct thrombin inhibitor that offers numerous potential advantages compared with traditional anticoagulants. It is given orally, has a rapid onset of action, does not require laboratory monitoring, and is not associated with immune-mediated thrombocytopenia. Numerous phase III trials with ximelagatran focusing on deep vein thrombosis prophylaxis and treatment, stroke prevention in patients with atrial fibrillation, and secondary prevention after acute myocardial infarction have been conducted. Results of these trials indicate that ximelagatran has similar efficacy and risk of bleeding compared with currently used anticoagulants. Accordingly, the potential of this agent to replace warfarin therapy for a variety of indications has been widely touted. Ximelagatran has already been approved in Europe for prophylaxis of venous thromboembolism in patients undergoing hip or knee surgery. However, an adverse effect of ximelagatran is liver enzyme elevation, which has been observed in 5% to 10% of patients with chronic administration of the drug. Although initially felt to be transient in nature, subsequent data presented to the Federal Drug Administration suggest a small but real risk of significant hepatotoxicity. These data led the advisory committee to the Federal Drug Administration to recommend against immediate approval of ximelagatran pending further information. The consistent results of completed trials with ximelagatran suggest that it has the potential to be used in many conditions that currently require treatment with warfarin and heparin products. The potential benefit that may be achieved by the replacement of these historically problematic narrow therapeutic index agents must be weighed against as yet undetermined long-term risks of hepatotoxicity.
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PMID:A review of the oral direct thrombin inhibitor ximelagatran: not yet the end of the warfarin era... 1608 46

A 73-year-old woman developed mental confusion and finger pain after treatment with enoxaparin following arthroplasty. A platelet count was 163,000/microL. Because digital embolism was suspected, she was emergently treated with heparin and recombinant tissue plasminogen activator (rTPA). During rTPA infusion, she reported sudden hemifield loss, so the infusion was aborted. Brain CT disclosed a non-hemorrhagic occipital infarct. Platelets had fallen to 63,000 over eight days, and antibodies against a complex of heparin and platelet factor 4 were detected. These findings led to the diagnosis of heparin-induced thrombocytopenia and thrombosis syndrome (HITTS), an immune-mediated disorder in which venous and arterial thromboses occur. Right lower extremity deep venous thromboses were later diagnosed, and an MRI disclosed multiple cerebral infarcts of recent onset but different ages. Previous reports have documented brain arterial strokes in HITTS, mostly in the distribution of the middle cerebral artery, but clinical documentation is sparse, and there have been no imaging reports. This is the first report to document the clinical and imaging features of a HITTS stroke and the first to describe a stroke presumptively caused by a low molecular weight heparin. It emphasizes that HITTS may cause stroke even when the platelet count is normal. Diagnosis of HITTS should prompt immediate cessation of heparin treatment and substitution of a direct thrombin inhibitor or fondaparinux.
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PMID:Homonymous hemianopia caused by occipital lobe infarction in heparin-induced thrombocytopenia and thrombosis syndrome. 1614 26

Atrial fibrillation is the most common clinical arrhythmia and with an ageing population, it is an increasing cause of hospital admissions, morbidity and mortality. The most feared complication of atrial fibrillation is stroke. A number of studies have demonstrated that warfarin is at least moderately effective at reducing thromboembolic risk in stroke yet its use in both the community and in secondary care is suboptimal. Concerns about drug interactions, frequent blood monitoring and the risks of over and under coagulation have led to under prescription. Direct thrombin inhibitors are under investigation as an alternative to warfarin for thromboembolic prophylaxis in atrial fibrillation. Two large studies (SPORTIF III and SPORTIF V) have recently been published examining the effectiveness of the direct thrombin inhibitor ximelagatran at reducing thromboembolic risk. Ximelagatran was shown to be non-inferior to warfarin for the prevention of thromboembolic complications. Concerns however have arisen about long-term safety, particularly the possible effects on hepatic function. This review examines the data and discusses whether the introduction of these drugs could result in the end of the anticoagulation clinic for patients with atrial fibrillation.
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PMID:Will this be the end of the anticoagulation clinic for patients with atrial fibrillation? 1624 32

Atrial fibrillation (AF) is the most potent common risk factor for ischemic stroke. The number of Americans with nonvalvular AF is expected to increase markedly over the next several decades, making AF-related stroke an important public health concern. Given the individual and societal burden associated with AF-related stroke, efforts to identify and implement efficacious and acceptably safe therapeutic stroke prevention strategies are paramount. This article reviews the existing randomized trial evidence supporting the efficacy of oral vitamin K antagonists (ie, warfarin) or aspirin for preventing thromboembolism in AF, as well as completed and ongoing studies exploring novel antithrombotic agents including the oral direct thrombin inhibitor, ximelagatran, other antiplatelet agents (eg, clopidogrel), factor Xa inhibitors, and other pharmacological agents and additional therapeutic approaches such as mechanical devices and surgical procedures to obliterate the left atrial appendage.
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PMID:Antithrombotic therapy for stroke prevention in atrial fibrillation. 1625 51

Atrial fibrillation, the most commonly encountered arrhythmia in clinical practice, is associated with substantial morbidity and mortality. Its incidence and prevalence are increasing, and it represents a growing clinical and economic burden. Recent research has highlighted new approaches to both pharmacological and non-pharmacological management. Pooled data from trials comparing antithrombotic treatment with placebo show that warfarin reduces the risk of stroke by 62% and that aspirin alone reduces the risk by 22%. Overall, in high-risk patients, warfarin was better than aspirin in preventing strokes, with a relative risk reduction of 36%, but the risk of major hemorrhage with warfarin was twice that with aspirin. Anticoagulation treatment needs to be tailored individually for patients on the basis of age, comorbidities, and contraindications. However, warfarin remains under-prescribed in clinical practice, for reasons related to patients (comorbidities) and physicians. The limitations of warfarin treatment have prompted the development of new anticoagulants with predictable pharmacokinetics that do not require as frequent monitoring. Ximelagatran, an oral direct thrombin inhibitor, was compared with warfarin in the SPORTIF program, which found both agents to be broadly effective in the prevention of embolic events, but observed abnormal liver function tests in 6% of patients on ximelagatran. Liver function monitoring during treatment is thus needed. Idraparinux, a factor Xa inhibitor administered by once weekly subcutaneous injections, is being evaluated in patients with atrial fibrillation. The ACTIVE trial is currently assessing the role of aspirin plus clopidogrel, compared with adjusted dose warfarin, in the prevention of vascular events in high-risk patients with atrial fibrillation. Angiotensin-converting enzyme inhibitors and angiotensin II receptor-blocking drugs interfere with atrial remodeling and show promise in atrial fibrillation, as suggested in the LIFE trial. Preliminary studies suggest that statins may reduce the risk of recurrence after electrical cardioversion. Finally, percutaneous methods for occlusion of the left atrial appendage are currently under investigation in patients at high risk of thromboembolism but with contraindications for chronic warfarin.
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PMID:[Preventing cerebrovascular accidents during atrial fibrillation]. 1626 96

Unfractionated heparin, low-molecular-weight heparins and vitamin K antagonists are established antithrombotic agents, but all have a number of limitations. Unfractionated heparin requires parenteral administration, has a short half-life and variable dose-response relationship. Low molecular weight heparins are more effective than low-fixed-dose unfractionated heparin in the prevention of postoperative venous thromboembolism in high-risk surgical patients but they still require subcutaneous administration. Vitamin K antagonists have a narrow therapeutic window and require a careful laboratory monitoring to minimize the risk of bleeding or thrombosis. Direct thrombin inhibitors are selective inhibitors of this key enzyme. Direct thrombin inhibitors inactivate thrombin without requiring any plasma cofactor, inhibit both free and fibrin-bound thrombin, and do not appreciably bind to plasma proteins. Ximelagatran, the first oral direct thrombin inhibitor, is rapidly absorbed and converted to its active form melagatran, which can itself be administered subcutaneously. Ximelagatran has been evaluated in the prevention of venous thromboembolism after major orthopaedic surgery, in the treatment of venous thromboembolism, in the prevention of stroke in patients with atrial fibrillation and in the prevention of recurrence after acute coronary syndromes. In the European studies in major orthopaedic surgery ximelagatran was administered orally after one or two days of melagatran, given subcutaneously. This review will report on the mechanism of action and clinical pharmacology of direct antithrombin agents and on the results of the clinical trials performed with direct thrombin inhibitors in the prevention of venous thromboembolism after major orthopaedic surgery. Taken together, these results indicate that direct thrombin inhibitors, ximelagatran in particular, have the potential to be a valid alternative to low molecular weight heparins and oral anticoagulants in the prevention of venous thromboembolism after major orthopaedic surgery.
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PMID:Direct thrombin inhibitors for the prevention of venous thromboembolism after major orthopaedic surgery. 1630 19

Thrombin is a central enzyme in hemostasis, exerting potent procoagulant effects and activating platelets. Recently, several small molecule direct thrombin inhibitors (DTI's) with important clinical applications have been developed. Both lepirudin and argatroban are effective in treatment of heparin-induced thrombocytopenia resulting in rapid normalization of platelet counts and a reduction in thrombotic events. Because of differences in clearance mechanisms, argatroban is preferable in patients with renal insufficiency and lepirudin if there is hepatic impairment. DTI's have also been evaluated in treatment of venous thromboembolism. Small studies with recombinant hirudin have shown promise. Ximelagatran is a new DTI in late-stage clinical trials with advantages for treatment of venous thromboembolism including oral administration and fixed dosing, making it convenient for long-term treatment. A Phase III trial demonstrated that ximelagatran was superior to placebo for preventing recurrent thrombosis in patients who had undergone six months of standard anticoagulant therapy for venous thromboembolism. Another large trial compared ximelagatran to standard treatment with enoxaparin and warfarin for treatment of symptomatic deep vein thrombosis in a Phase III trial of 2,528 patients. The results showed that ximelagatran administered twice daily was as effective as standard treatment in preventing recurrence with no increase in bleeding complications. Ximelagatran has also been evaluated in two Phase III trials in patients with atrial fibrillation. The primary analysis of both showed that ximelagatran was non-inferior to warfarin for preventing stroke and other embolic events with no increase in bleeding complications. Unexpectedly, elevated serum transaminase levels were observed in 5-10% of patients receiving ximelagatran for over 1 month, and routine monitoring may be necessary. The introduction of DTIs represents an important advance in treatment of heparin-induced thrombocytopenia. The oral direct thrombin inhibitor, ximelagatran, shows promise in providing simplified, effective therapy for venous thromboembolism and atrial fibrillation.
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PMID:Direct thrombin inhibitors for treatment of heparin induced thrombocytopenia, deep vein thrombosis and atrial fibrillation. 1630 22

Ximelagatran is a novel oral direct thrombin inhibitor that offers a number of advantages over the standard treatment, warfarin, in patients with atrial fibrillation. Two large clinical trials, one open-label (Stroke Prevention Using Oral Thrombin Inhibitor in Atrial Fibrillation [SPORTIF] III), one double-blind (SPORTIF V), have compared the efficacy and safety of fixed-dose ximelagatran without anticoagulation monitoring with dose-adjusted warfarin using a non-inferiority design. On the basis of the results, the investigators concluded that ximelagatran was just as effective as warfarin in preventing stroke or systemic embolism (the primary end point), because the pre-specified non-inferiority criterion was met. Reanalysis of the data with rather conservative interpretive criteria, however, revealed a number of deficiencies: 1) an unreasonably generous margin that was potentially biased toward non-inferiority, given the low baseline event rate of warfarin; 2) the inappropriateness of the analytical method used to estimate the non-inferiority margin; 3) a lack of confidence that ximelagatran retains at least 50% of warfarin's effect (a prerequisite to the establishment of non-inferiority); 4) significant heterogeneity in the magnitude of efficacy observed in the two trials; and 5) safety concerns regarding increased liver toxicity with ximelagatran without a significant offsetting advantage in major bleeding. This imbalance in the benefit-risk profile materially undermines the investigators' claim of non-inferiority of ximelagatran and led the Food and Drug Administration to reject the sponsor's application for ximelagatran. Despite published conclusions to the contrary, we conclude that ximelagatran has not been shown to be non-inferior to warfarin. Such determinations of non-inferiority are highly dependent on the underlying assumptions, and graphical sensitivity analyses make this dependence explicit.
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PMID:Trials and tribulations of non-inferiority: the ximelagatran experience. 1694 3


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