ximelagatran and Atrial-Fibrillation

This study was designed to compare efficacy and safety among novel oral anticoagulants (NOACs), which have not been directly compared in randomized control trials to date.. We performed network meta-analyses of randomized control trials in preventing thromboembolic events and major bleeding in patients with atrial fibrillation. PubMed, Embase, and the Cochrane Database of Systematic Reviews for published studies and various registries of clinical trials for unpublished studies were searched for 2002-2013. All phase III randomized controlled trials (RCTs) of NOACs (apixaban, edoxaban, dabigatran, rivaroxaban), idraparinux, and ximelagatran were reviewed.. A systematic literature search identified nine phase III RCTs for primary analyses. The efficacy of each NOAC was similar with respect to our primary composite endpoint following adjustment for open label designs [odds ratios (ORs) versus vitamin K antagonists: apixaban 0.79; dabigatran 150mg 0.77; edoxaban 60mg 0.87; rivaroxaban 0.86] except for dabigatran 110mg and edoxaban 30mg. Apixaban and edoxaban 30mg and 60mg had significantly fewer major bleeding events than dabigatran 150mg, ricvaroxaban, and vitamin K antagonists. All NOACs were similar in reducing secondary endpoints with the exception of dabigatran 110mg and 150mg which were associated with a significantly greater incidence of myocardial infarction compared to apixaban, edoxaban 60mg, and rivaroxaban.. Our indirect comparison with adjustment for study design suggests that the efficacy of the examined NOACs is similar across drugs, but that some differences in safety and risk of myocardial infarction exist, and that open label study designs appear to overestimate safety and treatment efficacy. Differences in study design should be taken into account in the interpretation of results from RCTs of NOACs.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Dabigatran; Hemorrhage; Humans; Myocardial Infarction; Odds Ratio; Oligosaccharides; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiazoles; Thromboembolism; Treatment Outcome; Vitamin K

Chronic anticoagulation with vitamin K antagonists (VKAs) prevents ischaemic stroke and systemic embolism in people with non-valvular atrial fibrillation (AF) but dose adjustment, coagulation monitoring and bleeding limits its use. Direct thrombin inhibitors (DTIs) are under investigation as potential alternatives.. To assess (1) the comparative efficacy of long-term anticoagulation using DTIs versus VKAs on vascular deaths and ischaemic events in people with non-valvular AF, and (2) the comparative safety of chronic anticoagulation using DTIs versus VKAs on (a) fatal and non-fatal major bleeding events including haemorrhagic strokes, (b) adverse events other than bleeding and ischaemic events that lead to treatment discontinuation and (c) all-cause mortality in people with non-valvular AF.. We searched the Cochrane Stroke Group Trials Register (July 2013), the Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library, May 2013), MEDLINE (1950 to July 2013), EMBASE (1980 to October 2013), LILACS (1982 to October 2013) and trials registers (September 2013). We also searched the websites of clinical trials and pharmaceutical companies and handsearched the reference lists of articles and conference proceedings.. Randomised controlled trials (RCTs) comparing DTIs versus VKAs for prevention of stroke and systemic embolism in people with non-valvular AF.. All three review authors independently performed data extraction and assessment of risk of bias. Primary analyses compared all DTIs combined versus warfarin. We performed post hoc analyses excluding ximelagatran because this drug was withdrawn from the market owing to safety concerns.. We included eight studies involving a total of 27,557 participants with non-valvular AF and one or more risk factors for stroke; 26,601 of them were assigned to standard doses groups and included in the primary analysis. The DTIs: dabigatran 110 mg twice daily and 150 mg twice daily (three studies, 12,355 participants), AZD0837 300 mg once per day (two studies, 233 participants) and ximelagatran 36 mg twice per day (three studies, 3726 participants) were compared with the VKA warfarin (10,287 participants). Overall risk of bias and statistical heterogeneity of the studies included were low.The odds of vascular death and ischaemic events were not significantly different between all DTIs and warfarin (odds ratio (OR) 0.94, 95% confidence interval (CI) 0.85 to 1.05). Sensitivity analysis by dose of dabigatran on reduction in ischaemic events and vascular mortality indicated that dabigatran 150 mg twice daily was superior to warfarin although the effect estimate was of borderline statistical significance (OR 0.86, 95% CI 0.75 to 0.99). Sensitivity analyses by other factors did not alter the results. Fatal and non-fatal major bleeding events, including haemorrhagic strokes, were less frequent with the DTIs (OR 0.87, 95% CI 0.78 to 0.97). Adverse events that led to discontinuation of treatment were significantly more frequent with the DTIs (OR 2.18, 95% CI 1.82 to 2.61). All-cause mortality was similar between DTIs and warfarin (OR 0.91, 95% CI 0.83 to 1.01).. DTIs were as efficacious as VKAs for the composite outcome of vascular death and ischaemic events and only the dose of dabigatran 150 mg twice daily was found to be superior to warfarin. DTIs were associated with fewer major haemorrhagic events, including haemorrhagic strokes. Adverse events that led to discontinuation of treatment occurred more frequently with the DTIs. We detected no difference in death from all causes.

Topics: Amidines; Antithrombins; Atrial Fibrillation; Azetidines; Benzimidazoles; Benzylamines; beta-Alanine; Dabigatran; Drug Administration Schedule; Embolism; Female; Humans; Male; Randomized Controlled Trials as Topic; Safety-Based Drug Withdrawals; Stroke; Vitamin K; Warfarin

For the last decades vitamin K antagonists have been the most effective anticoagulant treatment of atrial fibrillation. New molecules are being designed, mainly due to the great amount of disadvantages in the management of conventional anticoagulation. Dabigatran, rivaroxaban and apixaban will soon be available as an alternative to warfarin/acenocumarol. All of them have demonstrated to be non-inferior to warfarin in preventing stroke and systemic embolism, with even dabigatran 150 mg bid and apixaban being superior. They have also a lower risk of bleeding, especially regarding severe/fatal and intracranial hemorrhages. This is a real revolution. The advance of these new anticoagulants will be limited only by the higher cost, and will progressively become the protagonists of oral anticoagulation in patients with nonvalvular atrial fibrillation.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Azetidines; Benzimidazoles; Benzylamines; beta-Alanine; Dabigatran; Embolism; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Treatment Outcome; Warfarin

Dabigatran has been associated with greater risk of myocardial infarction (MI) than warfarin. It is unknown whether the increased risk is unique to dabigatran, an adverse effect shared by other oral direct thrombin inhibitors (DTIs), or the result of a protective effect of warfarin against MI. To address these questions, we systematically searched MEDLINE and performed a meta-analysis on randomized trials that compared oral DTIs with warfarin for any indication with end point of MIs after randomization. We furthermore performed a secondary meta-analysis on atrial fibrillation stroke prevention trials with alternative anticoagulants compared with warfarin with end point of MIs after randomization. A total of 11 trials (39,357 patients) that compared warfarin to DTIs (dabigatran, ximelagatran, and AZD0837) were identified. In these trials, patients treated with oral DTIs were more likely to experience an MI than their counterparts treated with warfarin (285 of 23,333 vs 133 of 16,024, odds ratio 1.35, 95% confidence interval 1.10 to 1.66, p = 0.005). For secondary analysis, 8 studies (69,615 patients) were identified that compared warfarin with alternative anticoagulant including factor Xa inhibitors, DTIs, aspirin, and clopidogrel. There was no significant advantage in the rate of MIs with the use of warfarin versus comparators (odds ratio 1.06, 95% confidence interval 0.85 to 1.34, p = 0.59). In conclusion, our data suggest that oral DTIs were associated with increased risk of MI. This increased risk appears to be a class effect of these agents, not a specific phenomenon unique to dabigatran or protective effect of warfarin. These findings support the need for enhanced postmarket surveillance of oral DTIs and other novel agents.

Topics: Amidines; Anticoagulants; Antithrombins; Atrial Fibrillation; Azetidines; Benzimidazoles; Benzylamines; beta-Alanine; Dabigatran; Humans; Myocardial Infarction; Randomized Controlled Trials as Topic; Stroke; Warfarin

Although several new antithrombotic agents have been developed for stroke prevention in patients with nonvalvular atrial fibrillation (AF), many patients will continue to be treated with warfarin worldwide. We performed a meta-analysis of safety and efficacy outcomes in patients with AF treated with warfarin for stroke prevention in large contemporary randomized controlled trials (RCTs).. We searched the MEDLINE, EMBASE, and Cochrane databases for relevant studies; RCTs comparing warfarin with an alternative thromboprophylaxis strategy with at least 400 patients in the warfarin arm and reporting stroke as an efficacy outcome were included.. Eight RCTs with 55,789 patient-years of warfarin therapy follow-up were included. Overall time spent in the therapeutic range was 55% to 68%. The annual incidence of stroke or systemic embolism in patients with AF taking warfarin was estimated to be 1.66% (95% CI, 1.41%-1.91%). Major bleeding rates varied from 1.40% to 3.40% per year across the studies. The risk of stroke per year was significantly higher in elderly patients (2.27%), female patients (2.12%), patients with a history of stroke (2.64%), and patients reporting no previous exposure to vitamin K antagonists (1.96%). There was a significant increase in the annual incidence of stroke with progressively increasing CHADS(2) (congestive heart failure, hypertension, age, diabetes, and prior stroke) scores.. Current use of warfarin as a stroke prevention agent in patients with AF is associated with a low rate of residual stroke or systemic embolism estimated to be 1.66% per year. Compared with a previous meta-analysis, there has been significant improvement in the proportion of time spent in therapeutic anticoagulation, with a resultant decline in observed stroke rates.

Topics: Anticoagulants; Aspirin; Atrial Fibrillation; Azetidines; Benzylamines; Brain Ischemia; Clopidogrel; Female; Humans; Incidence; Male; Oligosaccharides; Primary Prevention; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Stroke; Ticlopidine; Treatment Outcome; United States; Warfarin

To assess whether the combined analysis of all phase III trials of nonvitamin-K-antagonist (non-VKA) oral anticoagulants in patients with atrial fibrillation and previous stroke or transient ischemic attack shows a significant difference in efficacy or safety compared with warfarin.. We searched PubMed until May 31, 2012, for randomized clinical trials using the following search items: atrial fibrillation, anticoagulation, warfarin, and previous stroke or transient ischemic attack. Studies had to be phase III trials in atrial fibrillation patients comparing warfarin with a non-VKA currently on the market or with the intention to be brought to the market in North America or Europe. Analysis was performed on intention-to-treat basis. A fixed-effects model was used as more appropriate than a random-effects model when combining a small number of studies.. Among 47 potentially eligible articles, 3 were included in the meta-analysis. In 14 527 patients, non-VKAs were associated with a significant reduction of stroke/systemic embolism (odds ratios, 0.85 [95% CI, 074-0.99]; relative risk reduction, 14%; absolute risk reduction, 0.7%; number needed to treat, 134 over 1.8-2.0 years) compared with warfarin. Non-VKAs were also associated with a significant reduction of major bleeding compared with warfarin (odds ratios, 0.86 [95% CI, 075-0.99]; relative risk reduction, 13%; absolute risk reduction, 0.8%; number needed to treat, 125), mainly driven by the significant reduction of hemorrhagic stroke (odds ratios, 0.44 [95% CI, 032-0.62]; relative risk reduction, 57.9%; absolute risk reduction, 0.7%; number needed to treat, 139).. In the context of the significant limitations of combining the results of disparate trials of different agents, non-VKAs seem to be associated with a significant reduction in rates of stroke or systemic embolism, hemorrhagic stroke, and major bleeding when compared with warfarin in patients with previous stroke or transient ischemic attack.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials, Phase III as Topic; Humans; Ischemic Attack, Transient; Randomized Controlled Trials as Topic; Stroke; Vitamin K; Warfarin

The Randomized Evaluation of Long-term anticoagulation therapY (RE-LY) study demonstrated a significant increase in myocardial infarction events with dabigatran compared with warfarin, provoking renewed interest in whether vitamin K antagonists are useful drugs for the prevention of myocardial infarction in high-risk patients with atrial fibrillation. Present analyses examined whether there was an increased risk of myocardial infarction associated with non-warfarin anticoagulants (Stroke Prevention with the ORal direct Thrombin Inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial Fibrillation III and IV, RE-LY, Amadeus) or "anticoagulant equivalents" (Atrial fibrillation Clopidogrel Trial with Irbesartan for the prevention of Vascular Events) in patients with atrial fibrillation who are prescribed anticoagulation for stroke thromboprophylaxis. The overall annual event rate for those receiving warfarin was 0.98% compared with 1.32% for those receiving comparators. Warfarin was associated with a significant reduction in myocardial infarction (relative risk 0.77; 95% confidence interval (CI), 0.63-0.95), an effect largely driven by the RE-LY trial. Sensitivity analyses, excluding RE-LY, revealed a nonsignificant reduction in myocardial infarctions (relative risk 0.83; 95% CI, 0.62-1.10); an analogous analysis excluding the Atrial fibrillation Clopidogrel Trial with Irbesartan for the prevention of Vascular Events demonstrated a significant reduction in myocardial infarctions (relative risk 0.80; 95% CI, 0.64-1.00). Warfarin might provide a protective effect against myocardial infarction compared with non-warfarin anticoagulants or "anticoagulation equivalents" in patients with atrial fibrillation who are prescribed anticoagulation for stroke thromboprophylaxis.

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzimidazoles; Benzylamines; Biphenyl Compounds; Dabigatran; Humans; Irbesartan; Myocardial Infarction; Pyridines; Randomized Controlled Trials as Topic; Stroke; Tetrazoles; Warfarin

The most frequent cardiac arrhythmia and main cause for cardio-embolic stroke is atrial fibrillation. Prophylaxis for thrombembolic events is performed regarding individual risk of patients with either ASS or vitamin-K-antagonists. Efficacy and safety of oral anticoagulation is limited by a narrow therapeutical range as well as by inter- and intraindividual variability of INR-values due to genetic disposition, differences in alimentation, dosage errors, rare control of INR-levels and drug-interactions. New oral anticoagulants with different mechanisms of action may be a promising therapeutic option in future. This review addresses the new anticoagulants Apixaban, Rivaroxban and Dabigatranetexilat with the design and as available the results of the corresponding phase-III-trials in atrial fibrillation (ARISTOTLE, ROCKET-AF, RE-LY).

Topics: Anticoagulants; Antithrombins; Atrial Fibrillation; Azetidines; Benzimidazoles; Benzylamines; Clinical Trials, Phase III as Topic; Dabigatran; Factor Xa Inhibitors; Fibrinolytic Agents; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiophenes; Thromboembolism

Indirect systemic and direct oral factor Xa and direct oral factor IIa inhibitors with improved pharmacologic profiles compared with heparins and vitamin K antagonists are currently in clinical development. This overview focuses on the indirect antithrombin dependent pentasaccharide derivatives of idraparinux and on the most advanced oral direct inhibitors to factor Xa (rivaroxaban and apixaban) and IIa (dabigatran). Specifically, the results of dose-finding studies for the prevention of venous thromboembolism after elective orthopedic surgery, the results of dose-finding studies for treatment of acute venous thromboembolism including prolonged prophylaxis of recurrent events, and the designs of ongoing clinical trials are reviewed.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Atrial Fibrillation; Azetidines; Benzimidazoles; Benzylamines; Clinical Trials as Topic; Dabigatran; Factor Xa Inhibitors; Glycine; Humans; Infusions, Parenteral; Morpholines; Oligosaccharides; Piperazines; Prothrombin; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; Thrombin; Thrombosis; Venous Thromboembolism

Nonvalvular atrial fibrillation is the most common cardiac arrhythmia associated with a substantial risk of thromboembolism and stroke. Despite numerous disadvantages that limit its efficacy and safety, warfarin is widely used in the prevention and treatment of thromboembolism related with atrial fibrillation. Ximelagatran, an oral direct thrombin inhibitor has the potential to be an alternative choice in the prevention and therapy of thromboembolism related with atrial fibrillation. Studies compared ximelagatran with warfarin in nonvalvular atrial fibrillation at risk for stroke showed that fixed dose oral ximelagatran is effective as adjusted dose warfarin in stroke prevention. Ximelagatran has numerous advantages over warfarin in clinical practice. Although it seems as a promising option for the prevention and therapy of thromboembolism, its safety and efficacy need to be determined definitely by further clinical trials.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Humans; Stroke; Thromboembolism; Warfarin

To compare the effectiveness of aspirin, warfarin, and ximelagatran as thromboprophylaxis in patients with non-valvular atrial fibrillation (NVAF).. Systematic review of randomised controlled trials in patients with NVAF treated with adjusted-dose warfarin and aspirin, fixed low-dose (FLD) warfarin, ximelagatran or placebo. Outcome measures studied were ischaemic stroke, systemic embolism, mortality and haemorrhage. Meta-analysis was performed using a fixed effects model.. We identified 13 trials (n=14,423 participants) of sufficient quality to be included in the analysis. Adjusted-dose warfarin significantly reduced the risk of ischaemic stroke or systemic embolism compared with aspirin (relative risk [RR] 0.59; 95% confidence interval [CI]: 0.40 to 0.86), FLD warfarin (RR 0.36; 95% CI: 0.23 to 0.58), or placebo (RR 0.33; 95% CI: 0.24 to 0.45). However, aspirin and placebo had a lower risk of major bleeding compared to warfarin (RR 0.58; 95% CI: 0.35 to 0.97 and RR 0.45; 95% CI: 0.25 to 0.82, respectively). The oral direct thrombin inhibitor, ximelagatran was as effective as adjusted-dose warfarin in the prevention of ischaemic strokes or systemic emboli (RR 1.04; 95% CI: 0.77 to 1.40) with less risk of major bleeding (RR 0.74; 95% CI: 0.56 to 0.96). Adjusted-dose warfarin significantly reduced mortality compared to placebo (RR 0.69; 95% CI: 0.53 to 0.89), but not for any of the other comparisons (aspirin: RR 0.87; 95% CI: 0.67 to 1.13; FLD warfarin: RR 1.11; 95% CI: 0.81 to 1.52; ximelagatran: RR 1.04; 95% CI: 0.86 to 1.26).. We have extended previous analyses, making this the largest systematic review and meta-analysis of thromboprophylaxis trial data in AF--and have included recent trials with the new oral direct thrombin inhibitor, ximelagatran. This systematic review confirms the superiority of anticoagulation therapy over aspirin as thromboprophylaxis in patients with NVAF. The new oral direct thrombin inhibitor, ximelagatran, appears as effective as adjusted-dose warfarin for the prevention of thromboembolic events in NVAF, with a lower risk of bleeding.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Aspirin; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials as Topic; Comorbidity; Drug Combinations; Humans; Stroke; Treatment Outcome; Warfarin

The use of warfarin in the elderly, particularly for stroke prevention in chronic atrial fibrillation, is steadily increasing. Although the benefits of warfarin are greatest in the elderly, so are the risk of adverse outcomes and the difficulties of anticoagulant management. Clinical systems need to improve to counter this therapeutic dilemma, as warfarin is likely to remain the only widely available oral anticoagulant for the foreseeable future. Aspects that require attention are: the careful selection of patients in whom treatment with warfarin is appropriate; initiating therapy in a low dose (e.g., 2.5-5 mg/day); thorough education of patients and carers; close monitoring, especially with any change in the patient's regular drug therapy; involving patients more in the management of their warfarin therapy (self-monitoring/management in suitable patients); and ongoing review of the appropriateness of therapy as circumstances change.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Drug Interactions; Drug Monitoring; Fractures, Bone; Hemorrhage; Humans; Stroke; Warfarin

Shortcomings of the existing anticoagulants, vitamin K antagonists and heparins, have led to the development of newer anticoagulant therapies. In particular, Vitamin K antagonists' slow onset of action, numerous drug interactions, narrow therapeutic window and need for frequent monitoring make it the most obvious target for replacement. Targeting specific coagulation enzymes or steps in the coagulation pathway, new anticoagulants have been or are under evaluation in clinical trials for a number of clinical indications, namely the prevention and treatment of venous thromboembolism, the prevention of ischemic stroke in patients with atrial fibrillation, and in acute coronary syndromes. Following a brief review of pharmacological aspects, this article will summarize the results of Phase III clinical trials evaluating the novel anticoagulants fondaparinux, ximelagatran and idraparinux. At present, most attention is directed at developing an oral anticoagulant to replace vitamin K antagonists for prevention of systemic thromboembolism. A number of newer agents are in both early and advanced stages of investigation.

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials, Phase III as Topic; Fondaparinux; Humans; Oligosaccharides; Polysaccharides; Thromboembolism; Thrombosis; Venous Thrombosis

We aimed to identify different stroke prevention treatments for atrial fibrillation assessed in randomized controlled trials and to compare them within a single evidence synthesis framework.. We updated the Cochrane review on anticoagulants and antiplatelet therapy for nonrheumatic atrial fibrillation to include randomized controlled trials published between January 2000 and March 2005 identified via the CENTRAL database and MEDLINE. A mixed-treatment comparison method was used to combine direct within-trial, between-treatment comparisons with indirect trial evidence while maintaining randomization.. Data were combined from 19 clinical trials that included 17 833 patients randomized to 9 treatment strategies, including placebo. For prevention of ischemic stroke, adjusted standard-dose warfarin sodium (relative rate [RR], 0.35; 95% credible interval [CrI], 0.24 to 0.52), adjusted low-dose warfarin (RR, 0.35; 95% CrI, 0.19 to 0.60), ximelagatran (RR, 0.34; 95% CrI, 0.18 to 0.61), and aspirin (RR, 0.64; 95% CrI, 0.44 to 0.88) were all associated with a significantly lower rate of ischemic stroke compared with placebo. For major and fatal bleeding episodes, there was some evidence of an increased risk for all treatments but none were statistically significant. Assuming a baseline risk of 51 ischemic stroke events per 1000 person-years, it can be estimated that adjusted standard-dose warfarin could prevent 28 (95% CrI, -37 to -19) ischemic strokes at the expense of 11 (95% CrI, -1 to +39) major or fatal bleeding episodes. In comparison, aspirin could prevent 16 (95% CrI, -26 to -5) ischemic strokes at the expense of 6 (95% CrI, -3 to +27) major or fatal bleeding episodes.. A lower rate of ischemic stroke and a higher rate of major bleeding episodes were found to be associated with oral anticoagulants compared with aspirin, and both anticoagulants and aspirin were found to be associated with a reduction in the rate of stroke compared with placebo.

Topics: Anticoagulants; Aspirin; Atrial Fibrillation; Azetidines; Benzylamines; Drug Therapy, Combination; Humans; Incidence; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Retrospective Studies; Stroke; Treatment Outcome; Warfarin

Warfarin sodium is an effective oral anticoagulant drug. However, warfarin has a narrow therapeutic window with significant risks of hemorrhage at therapeutic concentrations. Dosing is difficult and requires frequent monitoring. New oral anticoagulant agents are required to improve current anticoagulant therapy. Furthermore, while warfarin is effective in venous disease, it does not provide more than 60% risk reduction compared with placebo in venous thrombosis prophylaxis and considerably lower risk reduction in terms of arterial thrombosis. Ximelagatran is an oral pro-drug of melagatran, a synthetic small peptidomimetic with direct thrombin inhibitory actions and anticoagulant activity. As an oral agent, ximelagatran has a number of desirable properties including a rapid onset of action, fixed dosing, stable absorption, apparent low potential for medication interactions, and no requirement for monitoring of drug levels or dose adjustment. It has a short plasma elimination half-life of about 4 hours in cases of unexpected hemorrhage or need for reversal. Its main toxicity relates to the development of abnormal liver biochemistry and/or liver dysfunction with "long-term" use of the drug. This usually occurs within the first 6 months of commencing therapy, with a small percentage of patients developing jaundice. The biochemical abnormality usually resolves despite continuation of the drug. The cause of this toxicity remains unknown. Clinical studies to date have shown that ximelagatran is noninferior to warfarin in stroke prevention in patients with nonvalvular atrial fibrillation, noninferior to standard therapy as acute and extended therapy of deep vein thrombosis (DVT), and superior to warfarin for the prevention of venous thromboembolism post-major orthopedic surgery. It has also been shown to be more effective than aspirin alone for prevention of recurrent major cardiovascular events in patients with recent myocardial infarction.

Topics: Acute Disease; Administration, Oral; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Heart Diseases; Hemostasis; Humans; Molecular Structure; Orthopedic Procedures; Patient Compliance; Patient Satisfaction; Platelet Aggregation; Prodrugs; Stroke; Syndrome; Thrombin; Thromboembolism; Treatment Outcome; Venous Thrombosis

Topics: Anti-Inflammatory Agents; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Humans; Inflammation; International Normalized Ratio; Stroke; Thrombin; Warfarin

Topics: Acute Disease; Angioplasty, Balloon, Coronary; Anticoagulants; Arginine; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials as Topic; Coronary Disease; Heparin; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Syndrome; Thrombin; Thromboembolism; Thrombosis; Venous Thrombosis

Chronic, nonvalvular atrial fibrillation occurs more frequently with increasing age, together with an increasing risk for ischemic stroke. Guidelines recommend oral anticoagulation with a vitamin K antagonist for patients >65 years without risk factors and patients <65 years with risk factors for cardiac diseases. Advancing age also increases the risk for bleeding complications under oral anticoagulants; thus, only a part of these patients receives anticoagulant therapy. The risk of falls in elderly patients is of advancing relevance for this therapeutic decision. Oral direct thrombin inhibitors like ximelagatran may be an alternative choice for therapy. Ischemic strokes and systemic embolism in the same frequency with 2x36 mg ximelagatran over 18 months (91/3664 patients: 1.6%/year, for study Sportif III and Sportif V) compared with warfarin (93/3665 patients: 1.6%/year for study Sportif III and Sportif V). All bleeding complications occurred less frequently under therapy with ximelagatran. This could be of importance for elderly patients with risk factors for bleeding or risk of falling.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Cerebral Infarction; Clinical Trials as Topic; Hemorrhage; Humans; Risk Factors; Thromboembolism; Vitamin K; Warfarin

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.

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials as Topic; Humans; Stroke; Warfarin

Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting an estimated 2.2 million Americans. The management of non-valvular AF is likely to become even more challenging over the coming decades. The treatment target of AF takes 3 forms: cardioversion, rate control, and minimization of embolic risk. Recently, rate, rather than rhythm control has emerged as a valid therapeutic option in patients with persistent AF. According to current guidelines, International Normalized Ratio-targeted oral anticoagulation and proper stratification of risk remain fundamental principles of management. This article reviews, in depth, the current therapeutic options for atrial fibrillation including oral anticoagulants and unfractionated heparin, as well as reviewing new therapeutic options including bridging therapy with low-molecular-weight heparins and the new oral antithrombotic drug, ximelagatran.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Combined Modality Therapy; Echocardiography, Transesophageal; Electric Countershock; Fibrinolytic Agents; Heparin, Low-Molecular-Weight; Humans

Antithrombotic agents have verified efficacy in reducing the thromboembolic risk associated with atrial fibrillation. This article focuses on the emergence of a new oral direct thrombin inhibitor, ximelagatran, into the arena of atrial fibrillation thromboprophylaxis. This review does not cover atrial fibrillation in the context of valvular heart disease. The efficacy of aspirin and warfarin will be discussed briefly.

Topics: Administration, Oral; Anticoagulants; Aspirin; Atrial Fibrillation; Azetidines; Benzylamines; Chemical and Drug Induced Liver Injury; Clinical Trials, Phase III as Topic; Humans; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Risk Factors; Stroke; Thrombin; Thromboembolism; Warfarin

The chemistry, pharmacology, pharmacokinetics, clinical efficacy, dosage and administration, contraindications, and adverse effects of ximelagatran are reviewed.. Ximelagatran is the first orally active direct thrombin inhibitor to be tested in Phase III clinical trials. After oral administration, ximelagatran is rapidly converted to its active metabolite, melagatran. Melagatran (after oral ximelagatran administration) predictably inhibits thrombin function without need for routine anticoagulation monitoring. Melagatran effectively inhibits both free and clot-bound thrombin-a potential pharmacodynamic advantage over heparin products. Melagatran has a half-life of 2.4-4.6 hours, necessitating twice-daily administration. Melagatran is primarily eliminated by the kidneys and has not been studied clinically in patients with severe renal failure. Ximelagatran has undergone 10 Phase III trials (6 for prophylaxis of venous thromboembolism [VTE] due to orthopedic surgery, 1 for initial treatment of VTE, 1 for long-term prevention of VTE recurrence, and 2 for stroke prophylaxis due to atrial fibrillation). Results were generally positive. AstraZeneca applied in December 2003 for marketing approval of ximelagatran for prevention of VTE after total knee replacement surgery, long-term prevention of VTE recurrence after standard therapy, and stroke prevention due to atrial fibrillation. FDA denied approval of ximelagatran for all indications, mainly because of increased rates of coronary artery disease events in ximelagatran recipients in some studies and the possibility of hepatic failure when the medication is used for long-term therapy.. Ximelagatran has shown promise as a possible alternative to warfarin and other anticoagulants but will require further study to ensure its safety.

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Biological Availability; Clinical Trials, Phase III as Topic; Drug Interactions; Half-Life; Humans; Metabolic Clearance Rate; Stroke; Thrombin; Thromboembolism; Venous Thrombosis; Warfarin

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.

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials as Topic; Humans; Stroke

The acute management of anticoagulation in patients with atrial fibrillation to prevent stroke and other thromboembolic complications includes the use of individualized strategies tailored to the patient and based on the situation (cardioversion, surgeries, dental procedures, cardiac interventions, other invasive procedures and initiation of, or adjustment to, warfarin dosing). The vast range of choices can cause confusion and few randomized controlled clinical trials in this area provide adequate guidance. Chronic anticoagulation management is more straightforward since clinical evidence is ample, randomized clinical trial data provides cogent informaiton and guidelines have been established. Acute management of anticoagulation in patients with atrial fibrillation to prevent thromboembolic complications is often unrecognized but is emerging as a crucial, but challenging, and increasingly complex aspect of the care of patients with atrial fibrillation. This review addresses issues regarding such patients who may be at risk for stroke and require acute adjustments of anticoagulation (in light of, or in lieu of, chronic anticoagulation). Several promising new strategies are considered in light of established medical care. This analysis provides practical recommendations based on available data and presents results from recent investigations that may provide insight into future strategies.

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Electric Countershock; Heparin; Humans; Risk Assessment; Risk Factors; Stroke

Effective atrial fibrillation (AF) management requires attention to adequate rate control, consideration for the need to maintain sinus rhythm, and deliberation regarding proper anticoagulation to prevent thromboemboli. When properly used, warfarin anticoagulation in patients with AF at high risk for stroke reduces stroke incidence markedly. Unfortunately, proper anticoagulation with warfarin is not easy. An anticoagulant drug for which there are few interactions with other drugs, food, or supplements; for which there can be uniform dosing; for which routine International Normalized Ratio monitoring is not required; and for which there is a lower risk for bleeding, will gain widespread and rapid acceptance. In two large randomized trials comparing fixed-dose ximelagatran with warfarin in noninferiority studies, ximelagatran appears to be as effective at preventing stroke and thromboembolic events as warfarin (based on intention-to-treat analysis) and with similar, if not better, long-term risk.

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Humans; International Normalized Ratio; Randomized Controlled Trials as Topic; Warfarin

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

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Chemical and Drug Induced Liver Injury; Hemorrhage; Humans; Risk Assessment; Stroke; Thrombin; Vitamin K; Warfarin

Several case studies are briefly introduced, followed by a description of the clinical problem from an epidemiological point of view. The evidence for established management strategies is reviewed and, finally, practical handling of the case is considered.

Topics: Aged; Aged, 80 and over; Anticoagulants; Arthroplasty, Replacement, Knee; Atrial Fibrillation; Azetidines; Benzylamines; Female; Humans; Male; Stroke; Venous Thrombosis

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.

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials as Topic; Humans; Randomized Controlled Trials as Topic; Stroke; Thrombin; Warfarin

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.

Topics: Administration, Oral; Age Factors; Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Anticoagulants; Aspirin; Atrial Fibrillation; Azetidines; Benzylamines; Clopidogrel; Drug Therapy, Combination; Electric Countershock; Humans; Hypolipidemic Agents; Incidence; Injections, Subcutaneous; Middle Aged; Oligosaccharides; Placebos; Platelet Aggregation Inhibitors; Prevalence; Prodrugs; Randomized Controlled Trials as Topic; Recurrence; Risk Factors; Stroke; Ticlopidine; Warfarin

The last decade witnessed major advances in the prevention and treatment of venous as well as of arterial thrombosis. Limitations of existing anticoagulants led to the development of novel therapeutic approaches. Ximelagatran is a new direct thrombin inhibitor (DTI) that is given orally, without the need for close monitoring. This compound was tried in the treatment of active venous thromboembolism, and the results were encouraging. Randomized trials suggest that ximelagatran is not inferior to warfarin in the prevention of stroke in patients with nonvalvular atrial fibrillation. Multiple controlled, prospective trials compared ximelagatran with low molecular weight heparin or warfarin in prevention of venous thromboembolism in patients undergoing major orthopedic procedures. The results of these clinical trials are reviewed in this article. Because of certain safety concerns (increased liver enzymes, potential hepatonecrosis, and increased coronary events) ximelagatran has not yet been approved by the FDA. Additional studies may be required to address these concerns. Ximelagatran has been approved, however, by the European regulatory authorities for short-term thromboprophylaxis. The success of ximelagatran or other oral antithrombin agents would provide significant proof of the concept for the long-term use of oral antithrombins in the prevention and treatment of both arterial and venous thrombosis.

Topics: Animals; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Heparin; Humans; Thrombosis

Atrial fibrillation is the most frequently encountered tachyarrhythmia requiring therapy. Treatment issues include therapy for any reversible cause; the identification and treatment of any underlying structural disorder; control of the ventricular rate, both for symptom reduction and prevention of tachycardic-induced cardiomyopathy; restoration and maintenance of sinus rhythm when symptoms persist despite rhythm control; and anticoagulation in patients with high-risk markers for systemic embolization: age over 65 years, hypertension, diabetes, ventricular failure, rheumatic valvular disease, and prior stroke or other embolic event. In such patients, anticoagulation with warfarin is currently recommended. Warfarin therapy carries significant risks (especially bleeding), inconveniences (the cost of prothrombin time monitoring, the need for rigid dietary stability, the concerns of drug and herbal interactions), and other concerns (the issue of generic formulation substitution).. Under development are oral thrombin inhibitors. The first to reach clinical approval will likely be ximelagatran. In clinical trials to date, ximelagatran has proven to be equal to or superior to warfarin in the prevention and treatment of thrombophlebitis. In atrial fibrillation patients, the Stroke Prevention Using Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) trials completed so far appear to show a similar or better efficacy for ximelagatran versus warfarin as regards both prevention of embolic events and lower risks of major bleeding, with no serious adverse effects except for apparently reversible alterations in liver function tests in approximately 6% of subjects, all occurring early in therapy to date. If the remaining SPORTIF trial (SPORTIF V) is confirmatory (results to be available in late 2003), it is expected that this exciting new product will be submitted this winter to the Food and Drug Administration for approval. Recent findings also include the observations in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) and Rate Control Versus Electrical Cardioversion (RACE) trials that anticoagulation should not be discontinued despite the restoration and maintenance of sinus rhythm.. Oral direct thrombin inhibitors, such as ximelagatran, appear likely to replace the use of warfarin in most patients in the near future, because of a better risk-benefit profile.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials as Topic; Embolism; Fibrinolytic Agents; Humans; Prothrombin Time; Randomized Controlled Trials as Topic; Stroke; Venous Thrombosis; Warfarin

Atrial fibrillation comprises a large and growing epidemic in the aging population. Stroke is the most feared complication of atrial fibrillation, and the risk of stroke increases markedly with age. Multiple clinical trials have proven that warfarin anticoagulation is effective in reducing this risk. However, the complex pharmacokinetics and narrow therapeutic window of warfarin make its use in clinical practice challenging. Novel approaches to anticoagulation, including more potent antiplatelet agents and direct thrombin inhibitors, are currently undergoing clinical trials. In addition, nonpharmacological approaches to stroke prevention in atrial fibrillation are also in development. These newer approaches may revolutionize the treatment of this common disorder.

Topics: Anticoagulants; Aspirin; Atrial Fibrillation; Azetidines; Benzylamines; Clopidogrel; Humans; International Normalized Ratio; Platelet Aggregation Inhibitors; Risk Factors; Stroke; Thrombin; Ticlopidine; Warfarin

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.

Topics: Administration, Oral; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials, Phase III as Topic; Drug Administration Schedule; Fibrinolytic Agents; Humans; Prodrugs; Randomized Controlled Trials as Topic; Stroke; Therapeutic Equivalency; Thromboembolism; Warfarin

Ximelagatran (Exanta, AstraZeneca) is a novel oral direct thrombin inhibitor that inhibits the final step in the coagulation process - namely, the conversion of fibrinogen to insoluble fibrin by thrombin. Recently completed large clinical trials have evaluated the efficacy and safety of ximelagatran compared to standard anticoagulation therapy with warfarin and heparins in several thrombotic disorders including the treatment and prevention of venous thromboembolism following major orthopaedic surgery; stroke prevention in atrial fibrillation; and after acute myocardial infarction. This article reviews these recent clinical trials and explores the therapeutic potential of ximelagatran to become the oral anticoagulant of first choice in medicine.

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials as Topic; Coronary Artery Disease; Drug Therapy, Combination; Glycine; Humans; Prodrugs; Stroke; Thrombin; Thromboembolism; Venous Thrombosis

Atrial fibrillation (AF) is now regarded as the arrhythmia for which patients are hospitalized the most frequently, an arrhythmia that is responsible for significant morbidity and mortality. Of particular importance is that the arrhythmia is associated with a significant incidence of thromboembolism which may induce disabling and incapacitating strokes, sometimes fatal. In the past, it was thought that in patients with AF restoration and maintenance of sinus rhythm prevent the development of strokes, a presumption that has not been vindicated by controlled clinical trials. On the other hand, over many decades, it has been established that appropriate anticoagulation especially with warfarin can reduce stroke rate in nonvalvular AF by about 70%, and mortality by 26%. Aspirin reduces stroke rate by 26%, mortality by about 10%. Thus, in AF oral anticoagulants have become the focal point of therapy for the prevention of strokes and the safety and efficacy of such a therapy has been established by controlled clinical trials; moreover, the subsets of patients with AF in whom anticoagulation is mandatory have been defined on the basis of defined risk factors. Warfarin is now the anticoagulant of choice although its limitations are considerable in terms of drug-drug interactions, narrow range of therapeutic index requiring strict monitoring of intensity of anticoagulation, among other limitations which influence compliance of therapy with the agent. In this review, the continuing role of warfarin in the prevention of stroke in patients with AF is discussed as a background for the development of newer anticoagulants. The issue is of particular importance in the older patients, in whom the development of safer antithrombotic therapies remain a major challenge. In this context, the potential role of the direct thrombin inhibitors hold promise for the future and the evolving data on leading compounds of this class which may be competitive with warfarin are discussed.

Topics: Aged; Ambulatory Care Facilities; Anticoagulants; Aspirin; Atrial Fibrillation; Azetidines; Benzylamines; Cerebral Hemorrhage; Drug Design; Factor Xa Inhibitors; Fibrinolytic Agents; Humans; Prospective Studies; Randomized Controlled Trials as Topic; Risk Factors; Self Care; Stroke; Thrombin; Warfarin

Ximelagatran is the first orally available direct thrombin inhibitor. Ximelagatran is a pro-drug with an antithrombotic effect comparable to that of warfarin. Clinical studies have demonstrated that ximelagatran is as effective as warfarin in the prevention of deep-vein thrombosis, of stroke in patients with nonvalvular atrial fibrillation, and of the adverse cardiovascular events in patients with recent myocardial infarction. Ximelagatran can be administered without any need of laboratory test.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials as Topic; Humans; Myocardial Ischemia

Oral direct thrombin inhibitors (DTIs) are a potential alternative to vitamin K antagonists, such as warfarin, for anticoagulant therapy. The oral DTI at the most advanced stage of clinical development is ximelagatran, which is rapidly absorbed and bioconverted to the active form melagatran. Oral ximelagatran has been evaluated in randomized, controlled trials for several indications, including stroke prevention in atrial fibrillation (AF). Recently, two pivotal phase III trials demonstrated that fixed-dose oral ximelagatran, 36 mg twice daily without coagulation monitoring, prevents stroke and systemic embolic events in patients with nonvalvular AF as effectively as well-controlled, adjusted-dose warfarin. Oral ximelagatran was generally well tolerated and caused less total (major plus minor) bleeding than warfarin. In a minority of ximelagatran-treated patients, elevated serum alanine aminotransferase levels were reported, but were typically not associated with specific symptoms, and returned toward the pretreatment baseline whether treatment was continued or discontinued. In AF, oral ximelagatran promises a better benefit to risk ratio than warfarin.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Brain Ischemia; Clinical Trials as Topic; Humans; Stroke; Thrombin

Treatment strategies in patients with atrial fibrillation typically involve pharmacologic or interventional invasive therapies to suppress the rhythm, control ventricular contraction rates, or prevent thromboembolic complications. Current therapies used for rhythm conversion in atrial fibrillation may have undesirable risks or side effects that limit this approach. Lifelong anticoagulation may be necessary to prevent the formation of thrombus in the left atrial chamber that can travel into the cerebral circulation to cause a stroke. Currently, warfarin is the most commonly prescribed anticoagulant for this purpose. Unfortunately, many patients with atrial fibrillation may not receive warfarin because of the difficulties in dosing and maintaining desirable target goals. The oral direct thrombin inhibitor ximelagatran has several pharmacologic properties that provide a unique and potentially desirable treatment option. Clinical studies have demonstrated that ximelagatran, administered in twice-daily doses of 36 mg, is non-inferior to warfarin for thromboprophylaxis against stroke or systemic embolism in atrial fibrillation. The pharmacology of ximelagatran and clinical trials with its use in atrial fibrillation is reviewed.

Topics: Animals; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials as Topic; Fibrinolytic Agents; Humans

Atrial fibrillation and heart failure are growing epidemics in the developed world and often coexist. From clinical trials, warfarin is highly effective in reducing stroke in patients with atrial fibrillation. Equally important is the fact that in spite of well-designed trials, translation of the results of the data from the trials into clinical practice has been less than optimal. One of the reasons is that warfarin is a difficult drug to use. Thus there has been a concerted effort to develop an alternative to warfarin. Ximelagatran and Dabigatran, both direct thrombin inhibitors, are the furthest along in clinical development. Ximelagatran, while highly effective as an anticoagulant and safe with regard to bleeding, has been associated with liver function abnormalities; the importance of which needs resolution. Dabigatran is much earlier in development and is currently of unproven value. It is highly likely that alternatives to warfarin for stroke prevention will be available in the future and will likely result in a higher utilization rate of anticoagulants in patients with atrial fibrillation.

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials as Topic; Humans; Stroke; Thrombin; Warfarin

Non-rheumatic atrial fibrillation (NRAF) is one among the major public health problems, because it is associated with a high incidence of stroke or systemic thromboembolism. Warfarin significantly reduces cerebral/systemic events mainly in high-risk patients; unfortunately such drug is often as well under-used in eligible patients as under-dosed in treated patients. Traditional therapy with oral anticoagulants has several disadvatages: narrow therapeutic window, and often unpredictable dose-response so that frequent monitoring of the INR is required. It is therefore crucial that patients preferences and education be integrated into the decision-making process. Physicians often underprescribe oral anticoagulants since they perceive the risk of major bleeding as unacceptable because of some well known risk factors (e.g. previous bleedings, severe hypertension), and of qualms about drug interactions or alleged poor compliance. Therefore, the development of easy-to-use antithrombotic agents is still a challenge. New agents such as oral direct thrombin inhibitors are going to hold the promise for the next future. Ximelagatran is an orally active small molecule; being the first new oral anticoagulant used in large clinical trials. This molecule has many advantages in comparison to warfarin, such as the rapid onset/offset of action, the fixed oral dose, the no need of dose adjustment or of anticoagulation monitoring, as well the lack of food/alcohol intake interference as of drug interactions. The SPORTIF III and V trials have shown that ximelagatran is not inferior to warfarin in the prevention of strokes in patients with NRAF (both persistent and paroxysmal), but a side effect--consisting in the significant elevation of liver enzymes (> 3 times the upper limit of normal) in 6% of patients--was found. Further randomized trials are clearly needed, while current data suggest that ximelagatran will be able to represent a future viable therapeutic option for prevention of thromboembolism in patients with NRAF, offering huge advantages with respect to classic oral anticoagulants.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials as Topic; Drug Combinations; Humans; Patient Education as Topic; Patient Satisfaction; Stroke; Thromboembolism; Treatment Outcome; Warfarin

Several antithrombotic agents in development have the potential to greatly simplify the management of patients with AF or at risk for DVT/PE. Ximelagatran has already completed several phase 3 clinical studies in both of these high-risk, high-cost clinical settings and is poised to become the first practical alternative to warfarin. Although the exact therapeutic roles of ximelagatran and other novel antithrombotics further back in the pipeline remain to be determined, the impact of these nonwarfarin alternatives on the current labor-intensive system of anticoagulation clinics seems certain. Most important, the introduction of safer and equally effective oral anticoagulants that do not require monitoring may increase the percentage of high-risk patients who actually receive preventive therapy. If the institutional energy and resources previously spent on anticoagulation clinics, thrombotic disease management, and quality benchmarking can now be redirected to the delivery of the new generation of easier-to-administer and safer antithrombotic agents, the potential to increase rates of preventive therapy initiation and adherence in managed care populations may be within reach. Given the proven clinical value of anticoagulation, this potential increase in the rate of prophylaxis suggests the possibility that, even in the face of a rapidly aging US population, we are nonetheless entering into a period of reduced morbidity, mortality, and costs from stroke and DVT/PE.

Topics: Atrial Fibrillation; Azetidines; Benzimidazoles; Benzylamines; Clopidogrel; Fibrinolytic Agents; Fondaparinux; Humans; Oligosaccharides; Platelet Aggregation Inhibitors; Polysaccharides; Prodrugs; Pyridines; Stroke; Ticlopidine

The topic of anticoagulant prescription in patients with nonvalvular atrial fibrillation, for the primary and secondary prevention of stroke, provides a forum for discussion of current challenges in anticoagulation management and ways in which the introduction of ximelagatran will provide an opportunity to overcome many of them. Anticoagulation with warfarin has been shown to reduce stroke rates by 68%, providing significant net monetary savings. However, physician fear of hemorrhagic side effects, the need for regular INR monitoring, food and drug interactions, and patient noncompliance have all played a part in either suboptimal utilization or complete avoidance of anticoagulant therapy, even in patients at high risk for stroke. Ximelagatran, a new oral direct thrombin inhibitor, circumvents most of these problems and provides a more physician- and patient-friendly method of stroke prophylaxis. With the utilization of this new anticoagulation method, the incidence of stroke in high risk groups, and the corresponding quality-of-life and economic impact, can potentially be greatly reduced.

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Cost-Benefit Analysis; Humans; Risk Factors; Stroke; United States; Warfarin

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.

Topics: Anticoagulants; Aspirin; Atrial Fibrillation; Azetidines; Benzylamines; Clopidogrel; Humans; Oligosaccharides; Platelet Aggregation Inhibitors; Stroke; Ticlopidine; Warfarin

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.

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials as Topic; Humans; Randomized Controlled Trials as Topic; Stroke; Treatment Outcome; Warfarin

Atrial fibrillation (AF) is common, and it increases the risk of stroke. Placebo-controlled trials consistently showed that warfarin reduces the risk of stroke by two thirds, and a meta-analysis of trials of aspirin show a one-fifth reduction. Meta-analysis of trials directly comparing warfarin and aspirin shows that warfarin reduces the risk of stroke compared with aspirin by about one third. Major advisory bodies recommend risk stratification of patients with AF and prophylactic therapy with warfarin for patients at higher risk. There are several problems with warfarin therapy, which have resulted in a widely documented underuse. These problems include a narrow therapeutic window, marked variability in pharmacokinetics, and contraindications. There are new promising approaches to stroke prevention in AF. One of these is combination antiplatelet therapy. In a large randomized trial, the combination of dipyridamole and aspirin has been shown to have additive benefits against stroke. The combination of clopidogrel and aspirin results in additive benefits against vascular events, with only a modest increase in bleeding. A trial of combined antiplatelet therapy in AF is warranted. Occlusion of the left atrial appendage, either with a transvenous device or with surgery, is another strategy that is being explored. A direct thrombin inhibitor, ximelagatran, has been shown to have an excellent pharmacokinetic profile and is being developed as an oral agent for stroke prevention in AF, and it will not need regular monitoring.

Topics: Aspirin; Atrial Appendage; Atrial Fibrillation; Azetidines; Benzylamines; Clopidogrel; Dipyridamole; Drug Therapy, Combination; Fibrinolytic Agents; Humans; Platelet Aggregation Inhibitors; Prodrugs; Randomized Controlled Trials as Topic; Risk Factors; Stroke; Ticlopidine; Treatment Outcome; Warfarin

Ximelagatran, an oral direct thrombin inhibitor, has been investigated for the prevention and treatment of venous thromboembolism as well as for anticoagulation in atrial fibrillation. Unique properties of ximelagatran are that it is a prodrug, it does not require routine laboratory monitoring and it has minimal drug interactions. The dose of ximelagatran needs to be modified in patients with renal failure; however, dosing guidelines in this specific patient population have not been established. Preliminary and emerging data suggest that ximelagatran is superior or at least as effective as low molecular weight heparins and warfarin in the setting of venous thromboembolism prevention and treatment. Ximelagatran has comparable bleeding rates to low molecular weight heparins and warfarin; however, it is associated with transient elevations in hepatic transaminases.

Topics: Atrial Fibrillation; Azetidines; Benzylamines; Blood Coagulation; Drug Interactions; Humans; Myocardial Infarction; Thrombosis

Anticoagulants are widely used for the prevention and treatment of venous and arterial thrombosis. Current treatment strategies often employ a combination of parenteral and oral agents because the only available orally active anticoagulants, vitamin K antagonists, have a delayed onset of action. Furthermore, vitamin K antagonists have a narrow therapeutic window that necessitates careful anticoagulation monitoring, and dosing is problematic because of multiple food and drug interactions. These limitations highlight the need for oral anticoagulants that produce a more predictable anticoagulant response than vitamin K antagonists, thereby obviating the need for laboratory monitoring. Ximelagatran has the potential to meet this need. A prodrug of melagatran, an agent that targets thrombin, ximelagatran exhibits many of the characteristics of an ideal anticoagulant. This article (1). reviews the limitations of vitamin K antagonists, (2). lists the characteristics of an ideal anticoagulant, (3). rationalizes thrombin as a target for new anticoagulants, (4). reviews the preclinical and clinical data with ximelagatran, and (5). provides clinical perspective as to the future of ximelagatran and other orally active anticoagulants currently under development.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Blood Coagulation; Drug Monitoring; Glycine; Humans; International Normalized Ratio; Postoperative Complications; Prodrugs; Stroke; Thrombin; Thrombosis; Venous Thrombosis; Vitamin K

Obesity is well-established as a major cardiovascular (CV) risk factor. Obesity confers a greater risk for developing atrial fibrillation (AF), but the relation between obesity and established nonvalvular AF for stroke and all-cause death is still unclear. To ascertain the prevalence of overweight and obesity in patients with nonvalvular AF, their influence on adverse events, and the relation with anticoagulation control, we performed this post hoc analysis of the pooled Stroke Prevention using an Oral Thrombin Inhibitor in patients with atrial Fibrillation (SPORTIF) III and V data sets. For this study, we analyzed all patients assigned to the warfarin arm with data on body mass index (BMI). Time in therapeutic range was used as an index of the quality of anticoagulation control. The 3,630 patients eligible for this analysis were categorized as follows: (1) BMI 18.5 to 24.9 ("normal weight") in 24.1%; (2) BMI 25.0 to 29.9 ("overweight") in 39.8%; and BMI ≥30 ("obese") in 36.1%. Both overweight (hazard ratio [HR] 0.70) and obese (HR 0.59) categories were inversely associated with the composite outcome of stroke/all-cause death. A similar inverse association was seen for the end point of stroke (HR 0.61 and 0.47, respectively). Good anticoagulation control also attenuated the association between BMI categories and outcomes. In patients with time in therapeutic range >70%, BMI category was not significantly associated with the composite outcome of stroke/death and stroke. Stroke and all-cause death progressively reduced in overweight and obese anticoagulated patients with AF. The inverse relation of BMI categories to the risk of stroke and all-cause death was mitigated by good anticoagulation control.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Body Mass Index; Cohort Studies; Female; Humans; Male; Obesity; Prevalence; Stroke

AZD0837 and ximelagatran are oral direct thrombin inhibitors that are rapidly absorbed and bioconverted to their active forms, AR-H067637 and melagatran, respectively. This study investigated the antithrombotic effect of AZD0837, compared to ximelagatran and the vitamin K antagonist (VKA) phenprocoumon (Marcoumar), in a disease model of thrombosis in patients with non-valvular atrial fibrillation (NVAF).. Open, parallel-group studies were performed in NVAF patients treated with VKA, which was stopped aiming for an international normalized ratio (INR) of ≤ 2 before randomization. Study I: 38 patients randomized to AZD0837 (150,250 or 350 mg) or ximelagatran 36 mg twice daily for 10-14 days. Study II: 27 patients randomized to AZD0837 250 mg twice daily or VKA titrated to an INR of 2-3 for 10-14 days. A control group of 20 healthy elderly subjects without NVAF or anticoagulant treatment was also studied. Size of thrombus formed on pig aorta strips was measured after a 5-minute perfusion at low shear rate with blood from the patient/control subject.. Thrombus formation was inhibited by AZD0837 and ximelagatran. Relative to untreated patients, a 50% reduction of thrombus size was estimated at plasma concentrations of 0.6 and 0.2 μmol/L for AR-H067637 and melagatran, respectively. For patients receiving VKA treatment, the thrombus size was about 15% lower compared with healthy elderly controls.. Effects of AZD0837 and ximelagatran on thrombus formation were similar or greater than for VKA therapy and correlated with plasma concentrations of their active forms.

Topics: Administration, Oral; Aged; Amidines; Animals; Anticoagulants; Antithrombins; Atrial Fibrillation; Azetidines; Benzylamines; Female; Humans; In Vitro Techniques; Male; Middle Aged; Swine; Thrombosis; Treatment Outcome; Vitamin K

The purpose of this study was to investigate predictors of bleeding in a cohort of anticoagulated patients and to evaluate the predictive value of several bleeding risk stratification schemas.. The risk of bleeding during antithrombotic therapy in patients with atrial fibrillation (AF) is not homogeneous, and several clinical risk factors have been incorporated into clinical bleeding risk stratification schemas. Current risk stratification schemas for bleeding during anticoagulation therapy have been based on complex scoring systems that are difficult to apply in clinical practice, and few have been derived and validated in AF cohorts.. We investigated predictors of bleeding in a cohort of 7,329 patients with AF participating in the SPORTIF (Stroke Prevention Using an ORal Thrombin Inhibitor in Atrial Fibrillation) III and V clinical trials and evaluated the predictive value of several risk stratification schemas by multivariate analysis. Patients were anticoagulated orally with either adjusted-dose warfarin (target international normalized ratio 2 to 3) or fixed-dose ximelagatran 36 mg twice daily. Major bleeding was centrally adjudicated, and concurrent aspirin therapy was allowed in patients with clinical atherosclerosis.. By multivariate analyses, significant predictors of bleeding were concurrent aspirin use (hazard ratio [HR]: 2.10; 95% confidence interval [CI]: 1.59 to 2.77; p < 0.001); renal impairment (HR: 1.98; 95% CI: 1.42 to 2.76; p < 0.001); age 75 years or older (HR: 1.63; 95% CI: 1.23 to 2.17; p = 0.0008); diabetes (HR: 1.47; 95% CI: 1.10 to 1.97; p = 0.009), and heart failure or left ventricular dysfunction (HR: 1.32; 95% CI: 1.01 to 1.73; p = 0.041). Of the tested schemas, the new HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score performed best, with a stepwise increase in rates of major bleeding with increasing HAS-BLED score (p(trend) <0.0001). The c statistic for bleeding varied between 0.50 and 0.67 in the overall entire cohort and 0.68 among patients naive to warfarin at baseline (n = 769).. This analysis identifies diabetes and heart failure or left ventricular dysfunction as potential risk factors for bleeding in AF beyond those previously recognized. Of the contemporary bleeding risk stratification schemas, the new HAS-BLED scheme offers useful predictive capacity for bleeding over previously published schemas and may be simpler to apply.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Blood Coagulation; Double-Blind Method; Female; Follow-Up Studies; Hemorrhage; Humans; Male; Prognosis; Risk Assessment; Risk Factors; Stroke; Warfarin

The most common stroke subtype among atrial fibrillation (AF) patients not receiving anticoagulants is cardioembolic. In the SPORTIF III and V trials, the oral direct thrombin inhibitor ximelagatran was as effective as warfarin in reducing the risk of stroke in patients with nonvalvular AF. We assessed any differential effect of warfarin versus ximelagatran on the risk and outcome of cardioembolic and noncardioembolic stroke.. 7329 patients with AF and > or = 1 risk factors for stroke were randomized to treatment with warfarin (target international normalized ratio 2.0--3.0) or fixed-dose ximelagatran. Strokes were classified into specific subtypes. Therapeutic effect of warfarin and ximelagatran, adverse events, and stroke outcomes were assessed according to stroke subtype.. The annual stroke rate was low for both cardioembolic (ximelagatran, 0.39%; warfarin, 0.47%) and noncardioembolic stroke (ximelagatran, 0.57%; warfarin, 0.37%). In ischemic strokes, 33.9% (ximelagatran) and 34.3% (warfarin) had strokes of presumed cardioembolic origin. When fatal stroke, disabling stroke, myocardial infarction, and death from any cause were combined as poor outcome, patients with cardioembolic strokes had the highest rate of poor outcome (40%) but this was non- significant.. In SPORTIF III and V the efficacy of warfarin and ximelagatran were similar for prevention of cardioembolic and noncardioembolic strokes. Overall outcome tended to be worse following cardioembolic stroke. Ximelagatran has been withdrawn from the market due to hepatic side effects, but similar compounds are presently being studied.

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Chi-Square Distribution; Double-Blind Method; Female; Humans; Male; Stroke; Warfarin

In heart failure, digitalis increases exercise capacity and reduces morbidity, but has no effect on survival. This raises the suspicion that the inotropic benefits of digitalis may be counteracted by serious adverse effects. Patients with atrial fibrillation (AF) were studied to clarify this.. In the Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation (SPORTIF) III and V studies, 7329 patients with AF at moderate-to-high risk were randomised to preventive treatment of thromboembolism, either with warfarin or the oral direct thrombin inhibitor ximelagatran. The survival of users and non-users of digitalis was investigated.. At baseline, 53.4% of the study population used digitalis, and these patients had a higher mortality than non-users (255/3911 (6.5%) vs 141/3418 (4.1%), p<0.001; hazard ratio (HR) = 1.58 (95% CI 1.29 to 1.94)). Digitalis users also had more baseline risk factors. After multivariate risk factor adjustment, the increased mortality persisted (p<0.001; HR = 1.53 (95% CI 1.22 to 1.92 vs 1.23 to 1.92)).. The results suggest that digitalis, like other inotropic drugs, may increase mortality. This may be concealed in heart failure, but be revealed in patients with AF, who need the rate-reducing effect of digitalis, but do not benefit much from an increased inotropy. Cautious interpretation of the data is mandatory since the patients were not randomised with respect to digitalis use.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Cardiotonic Agents; Digitalis; Digitalis Glycosides; Double-Blind Method; Female; Humans; Kaplan-Meier Estimate; Male; Phytotherapy; Plant Preparations; Stroke; Thromboembolism; Warfarin

New-onset trial fibrillation (AF) occurs commonly after acute myocardial infarction (MI) and is associated with a poor prognosis due to stroke or death. The optimal antithrombotic therapy is unknown. The aim of this study was to investigate whether an oral direct thrombin inhibitor, ximelagatran, added to aspirin, reduced the risk of death, myocardial infarction (MI), and stroke in patients who developed AF after their qualifying MI in the efficacy and safety of the oral direct thrombin inhibitor ximelagatran in patients with recent myocardial damage (ESTEEM) trial.. The ESTEEM trial evaluated 6 months treatment with ximelagatran together with aspirin, compared to aspirin alone, for prevention of ischemic events in 1883 patients randomized within 14 days after an MI. After their qualifying MI, 174 (9%) patients developed AF in hospital. Multivariate hazard ratios for ximelagatran compared with placebo were calculated by presence AF.. Of 101 patients with AF treated with ximelagatran 7 (6.9%) had either death, MI, or stroke, compared with 15 (20.6%) in 73 patients allocated to placebo. Ximelagatran reduced the risk of death, MI, or stroke by 70% (hazard ratio 0.30, 95% CI 0.12-0.74). For the separate outcome events, we found similar, nonsignificant trends. One major bleeding event occurred in each treatment group.. For patients with MI complicated by AF, the combination of aspirin and an oral direct thrombin inhibitor seems beneficial. The high risk for death, MI, and stroke in this population and the increasing use of percutaneous interventions in MI patients may suggest a combination of long-term antiplatelet and anticoagulant therapy. Randomized clinical trials are warranted.

Topics: Administration, Oral; Aged; Anticoagulants; Aspirin; Atrial Fibrillation; Azetidines; Benzylamines; Drug Therapy, Combination; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Treatment Outcome

To test the hypothesis that stroke and systemic embolic events (SEE) in the stroke prevention using an oral thrombin inhibitor in atrial fibrillation (SPORTIF) III and V trials are different between paroxysmal and persistent atrial fibrillation (AF).. Data analysis from two cohorts of patients enrolled in the prospective SPORTIF III and V clinical trials (n = 7329); 836 subjects (11.4%) with paroxysmal AF [mean age 70.1 years (SD = 9.5)] were compared with 6493 subjects with persistent AF for this ancillary study.. The annual event rates for stroke/SEE are 1.73% for persistent AF and 0.93% for paroxysmal AF. In a multivariate analysis, after adjusting for stroke risk factors, gender and aspirin usage, the differences remained statistically significant with a higher hazard ratio (HR) for stroke/SEE in persistent AF [vs. paroxysmal AF, HR 1.87, 95% confidence interval (CI) 1.04-3.36; P = 0.037]. In 'high risk' patients (with >or=2 stroke risk factors) annual event rates for stroke/SEE were 2.08% for persistent AF and 1.27% for paroxysmal AF (adjusted HR = 1.68, 95% CI 0.91-3.1, P = 0.098). Elderly patients had annual event rates for stroke/SEE of 2.38% for persistent AF and 1.13% for paroxysmal AF (adjusted HR = 2.27, 95% CI 0.92-5.59, P = 0.075). Vitamin K antagonist (VKA)-naive paroxysmal AF patients had a 1.89%/year stroke/SEE rate, compared with 0.61% for previous VKA takers (HR = 0.33, 95% CI 0.11-1.01, P = 0.052).. In this large clinical trial cohort of anticoagulated AF patients, those with paroxysmal AF had stroke rates which were lower than for patients with persistent AF, although both groups had broadly similar stroke risk factors. Subjects with paroxysmal AF at 'high risk' had stroke/SEE rates that were not significantly different to persistent AF subjects.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Cohort Studies; Female; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Stroke; Warfarin

To test the hypothesis that stroke and systemic embolic events (SEE) in the Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation (SPORTIF) III and V trials were related to blood pressure, and that differences in event rates (stroke and SEE, bleeding) could also be related to the degree of hypertension.. A cross-sectional, longitudinal analysis was conducted, using data from the SPORTIF III and V trials. Results showed an increasing rate of stroke and SEE with increasing quartiles of systolic blood pressure (SBP) in AF patients. For the top quartile of SBP compared with the lowest quartile, the hazard ratio (HR) for stroke and SEE was 1.83 (95% confidence intervals [CI]: 1.22-2.74), whereas mortality was lower in the top quartile (HR 0.64; 95% CI: 0.49-0.83). In the combined SPORTIF III and V cohort, the event rate for stroke/SEE increased markedly at mean SBP of > 140 mmHg. There was no relationship between bleeding and quartiles of BP. The proportion of subjects with mean systolic BP > or = 140 mmHg was 35.8% (1220/3407) in SPORTIF III and 20.6% (807/3922) in SPORTIF V (P < 0.0001).. Hypertension contributes to increased stroke and SEE in AF. Event rates markedly increase at SBP levels of > or = 140 mmHg. The higher stroke rates observed in SPORTIF III compared with SPORTIF V may be related to the greater proportion of subjects with SBP > or = 140 mmHg during the trial.

Topics: Adult; Aged; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Cross-Sectional Studies; Double-Blind Method; Female; Hemorrhage; Humans; Hypertension; Longitudinal Studies; Male; Middle Aged; Risk Factors; Stroke; Thromboembolism; Warfarin

Warfarin prevents stroke in atrial fibrillation (AF); however, concerns regarding international normalized ratio control and hemorrhage limit its use in the elderly. The oral direct thrombin inhibitors (DTIs) are potential alternatives to warfarin, offering fixed dosing without drug and dietary interactions and the need for international normalized ratio monitoring. Although ximelagatran, a DTI studied in the Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation trials, has been withdrawn, development of other DTIs continues. We report our experience in elderly high-risk AF patients on ximelagatran compared with warfarin therapy.. Data from patients with AF and stroke risk factors randomized in Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation III and V trials to ximelagatran or warfarin were analyzed for stroke/systemic emboli, bleeding, and raised alanine aminotransferase levels in those >or=75 (n=2804) and <75 (n=4525) years.. Ximelagatran was as effective as warfarin in reducing stroke/systemic emboli in the elderly (2.23%/y with ximelagatran vs 2.27%/y with warfarin) as in younger patients (1.25%/y vs 1.28%/y). Total bleeds were significantly lower with ximelagatran compared with warfarin in elderly (40% vs 45%, P=0.01) and younger (27% vs 35%, P<0.001) patients. Raised alanine aminotransferase values (>3-fold elevation) among ximelagatran patients were more common in older (7.5% old vs 5.3% young) patients, particularly women (9.5% elderly women vs 6.1% elderly men).. In high-risk elderly AF patients, ximelagatran is as effective as warfarin with less bleeding, but alanine aminotransferase elevations are common, particularly in elderly women. Oral DTIs for stroke prevention show promise in elderly patients.

Topics: Administration, Oral; Age Factors; Aged; Aged, 80 and over; Alanine Transaminase; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Cerebral Hemorrhage; Double-Blind Method; Embolism; Female; Humans; Intracranial Thrombosis; Male; Middle Aged; Sex Characteristics; Sex Factors; Stroke; Thrombin; Treatment Outcome; Up-Regulation; Warfarin

Negative feedback regulation of pancreatic proteases controls pancreatic secretion in most species and pancreatic growth in rodents. Its mechanism involves the inhibition of intraluminal proteases, resulting in sustained elevation of plasma cholecystokinin (CCK) concentrations, producing a chronic trophic stimulus to the pancreas that leads to the formation of pancreatic nodules and adenomas. Ximelagatran, whose active form, melagatran, inhibits both thrombin and the serine protease trypsin, is under clinical development as an oral anticoagulant. Recent data indicate species differences in the expression of CCK receptor subtypes in the pancreas. CCK1 receptors are abundant in rat pancreas but are either absent or present at very low levels in human pancreas. As part of the clinical studies, we examined whether long-term ximelagatran administration causes CCK release and exerts possible trophic effects on the pancreas in humans.. One hundred thirty patients requiring anticoagulation treatment for atrial fibrillation randomly received, in a double-blind fashion, either 36 mg oral ximelagatran twice daily or warfarin dose adjusted to an international normalized ratio of 2.0 to 3.0. Before enrollment and after 12 months of treatment, computed tomography scans of the pancreas were performed, and pancreas volumes were quantified using the summation-of-areas technique. Three months after the initiation of drug treatment, plasma CCK concentrations were measured by radioimmunoassay 120 minutes after the patients drank 240 mL of a mixed liquid meal (Ensure).. After 3 months of treatment, plasma CCK concentrations did not differ between the ximelagatran and warfarin groups, 15 +/- 18 and 11 +/- 17 pmol/L (X +/- SD; P = 0.22), respectively. The initial average pancreas volumes were 82 +/- 31 and 88 +/- 28 mL in the ximelagatran and warfarin groups, respectively, and decreased to 70 +/- 25 and 75 +/- 28 mL, respectively, after 12 months of treatment. Although the decrease in pancreas volume with time was significant in each group (P = 0.0001), the magnitude of the volume reduction was similar in the 2 groups.. In contrast to rats, in which long-term oral administration of ximelagatran stimulates pancreatic growth and adenoma formation, in humans, ximelagatran does not increase plasma CCK concentrations and has no demonstrable trophic effect on the human pancreas.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Body Mass Index; Body Weight; Cholecystokinin; Double-Blind Method; Humans; Pancreas; Tomography, X-Ray Computed; Warfarin

Ximelagatran is a novel direct thrombin inhibitor that can be administered as a fixed oral dose, without the need for anticoagulant monitoring.. We undertook a pooled analysis of 7329 patients with nonvalvular atrial fibrillation from the Stroke Prevention Using Oral Thrombin Inhibitor in Atrial Fibrillation III and V trials to compare bleeding outcomes in patients who received ximelagatran, 36 mg twice daily, or warfarin sodium (target international normalized ratio, 2.0-3.0). We determined annual risk of bleeding (any, major), case-fatality rate, time course and anatomic sites of major bleeding, and risk factors for major bleeding with ximelagatran and warfarin treatment.. Annual incidence of any bleeding was 31.75% with ximelagatran and 38.82% with warfarin (relative risk reduction, 18.2%; 95% confidence interval [CI], 13.0-23.1; P<.001). Annual incidence of major bleeding was 2.01% with ximelagatran and 2.68% with warfarin (relative risk reduction, 25.1%; 95% CI, 3.2-42.1; P = .03). Case-fatality rate of bleeding was comparable in ximelagatran- and warfarin-treated patients (8.16% vs 8.09%; P = .98). Cumulative incidence of major bleeding was higher with warfarin than ximelagatran after 24 months of treatment (4.7% vs 3.7%; P = .04). Anatomic sites of bleeding were comparable with both treatments. Risk factors for bleeding with ximelagatran were as follows (hazard ratios and 95% CIs in parentheses): diabetes mellitus (1.81; 1.19-2.77; P = .006), previous stroke or transient ischemic attack (1.78; 1.16-2.73; P = .008), age 75 years or greater (1.70; 1.33-2.18; P<.001), and aspirin use (1.68; 1.08-2.59; P = .02). Risk factors for bleeding in warfarin-treated patients were previous liver disease (4.88; 1.55-15.39; P = .007); aspirin use (2.41; 1.69-3.43; P<.001); and age 75 years or greater (1.26; 1.03-1.52; P = .02).. Treatment with ximelagatran, 36 mg twice daily, is associated with a lower risk of bleeding than warfarin in patients with nonvalvular atrial fibrillation. Aspirin use and increasing age were associated with an increased risk of bleeding in ximelagatran- and warfarin-treated patients.

Topics: Adolescent; Adult; Aged; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Female; Follow-Up Studies; Hemorrhage; Humans; Incidence; Male; Middle Aged; Risk Factors; Survival Rate; Thrombosis; Time Factors; Treatment Outcome; Warfarin

The risk of stroke is greater among women with atrial fibrillation (AF) than men. Warfarin protects against stroke, but treatment-related bleeding occurs more often in women than in men.. SPORTIF III (open label, n=3410) and V (double-blind, n=3922) included 2257 women with AF and one or more stroke risk factors randomized to warfarin [target international normalized ratio (INR) 2.0-3.0] or ximelagatran (36 mg twice daily). Primary outcomes were all stroke (ischaemic/haemorrhagic) and systemic embolic event. Women were older, on average, than men, 73.4+/-8.0 vs. 69.8+/-9.0 years (P<0.0001). More women were >75-years old and women had more risk factors than men had (P<0.0001). The INR on warfarin (mean 2.5+/-0.7) was within target range for 67% of follow-up regardless of gender. Women more often developed primary events [2.08%/year, 95% confidence interval (CI) 1.60-2.56%/year vs. 1.44%/year, 95% CI 1.18-1.71%/year in men; P=0.016). Major bleeding rates were similar (P=0.766) but women experienced more overall (major/minor) bleeding (P<0.001). Warfarin was associated with more overall bleeding in both genders and more major bleeding in women than in men (P=0.001).. When compared with men with AF, women in these studies were older and had more stroke risk factors. Women were more prone to anticoagulant-related bleeding; the higher rate of thrombo-embolism among women was related to more frequent interruption of anticoagulant therapy.

Topics: Administration, Oral; Age Factors; Aged; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Chemical and Drug Induced Liver Injury; Double-Blind Method; Estrogen Replacement Therapy; Female; Hemorrhage; Humans; Male; Risk Factors; Sex Characteristics; Sex Factors; Stroke; Thromboembolism; Warfarin

In patients with nonvalvular atrial fibrillation, warfarin prevents ischemic stroke, but dose adjustment, coagulation monitoring, and bleeding limit its use.. To compare the efficacy of the oral direct thrombin inhibitor ximelagatran with warfarin for prevention of stroke and systemic embolism.. Double-blind, randomized, multicenter trial (2000-2001) conducted at 409 North American sites, involving 3922 patients with nonvalvular atrial fibrillation and additional stroke risk factors.. Adjusted-dose warfarin (aiming for an international normalized ratio [INR] 2.0 to 3.0) or fixed-dose oral ximelagatran, 36 mg twice daily.. The primary end point was all strokes (ischemic or hemorrhagic) and systemic embolic events. The primary analysis was based on demonstrating noninferiority within an absolute margin of 2.0% per year according to the intention-to-treat model.. During 6405 patient-years (mean 20 months) of follow-up, 88 patients experienced primary events. The mean (SD) INR with warfarin (2.4 [0.8]) was within target during 68% of the treatment period. The primary event rate with ximelagatran was 1.6% per year and with warfarin was 1.2% per year (absolute difference, 0.45% per year; 95% confidence interval, -0.13% to 1.03% per year; P<.001 for the predefined noninferiority hypothesis). When all-cause mortality was included in addition to stroke and systemic embolic events, the rate difference was 0.10% per year (95% confidence interval, -0.97% to 1.2% per year; P = .86). There was no difference between treatment groups in rates of major bleeding, but total bleeding (major and minor) was lower with ximelagatran (37% vs 47% per year; 95% confidence interval for the difference, -14% to -6.0% per year; P<.001). Serum alanine aminotransferase levels rose to greater than 3 times the upper limit of normal in 6.0% of patients treated with ximelagatran, usually within 6 months and typically declined whether or not treatment continued; however, one case of documented fatal liver disease and one other suggestive case occurred.. The results establish the efficacy of fixed-dose oral ximelagatran without coagulation monitoring compared with well-controlled warfarin for prevention of thromboembolism in patients with atrial fibrillation requiring chronic anticoagulant therapy, but the potential for hepatotoxicity requires further investigation.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Double-Blind Method; Female; Humans; Male; Prodrugs; Stroke; Survival Analysis; Warfarin

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Canada; Double-Blind Method; Hemorrhage; Humans; Risk; Stroke; Thrombin; Treatment Outcome; United States; Vitamin K; Warfarin

We sought to compare the tolerability and safety of three fixed doses of ximelagatran versus warfarin in patients with nonvalvular atrial fibrillation (NVAF).. Anticoagulants such as warfarin lower the risk of stroke in patients with NVAF. Ximelagatran is a novel, oral direct thrombin inhibitor with predictable pharmacokinetics and no known food or pharmacokinetic drug interactions.. This was a 12-week, randomized, parallel-group, dose-guiding study of NVAF patients with at least one additional risk factor for stroke. The primary end point was the number of thromboembolic events and bleedings. Three groups received ximelagatran (n = 187) at 20, 40, or 60 mg twice daily, given in a double-blind fashion, without routine coagulation monitoring. In a fourth group, warfarin (n = 67) was managed and monitored according to normal routines, aiming for an International Normalized Ratio of 2.0 to 3.0.. A total of 254 patients received study drug. One ischemic stroke (nonfatal) and one transient ischemic attack (TIA) occurred in the ximelagatran group. Two TIAs occurred in the warfarin group. No major bleeds were observed in the ximelagatran group. One major bleed occurred in a warfarin-treated patient. The number of minor and multiple minor bleeds was low, but there was a slight increase by ximelagatran dose. The 60-mg dose resulted in the same number of bleeding events as that with warfarin. S-alanine aminotransferase was increased in eight patients (4.3%) taking ximelagatran, but normalized with continuous treatment or cessation of the drug.. Fixed oral doses of ximelagatran up to 60 mg twice daily were well tolerated, without the need for dose adjustment or coagulation monitoring.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Stroke; Time Factors; Warfarin

Ximelagatran is a novel, oral direct thrombin inhibitor under investigation as an alternative to warfarin for prevention of thromboembolism in patients with nonvalvular atrial fibrillation (AF). Two long-term studies in patients with AF and at least one additional risk factor for stroke are underway to compare the safety and efficacy of fixed-dose ximelagatran (36 mg bid) without coagulation monitoring with dose-adjusted warfarin (international normalized ratio 2.0-3.0).. SPORTIF III is a randomized, open-label, parallel-group study with blinded event assessment involving 3407 patients at 259 sites in 23 countries. SPORTIF V is similar, but with double-blind treatment allocation involving 3922 patients at 409 North American sites. The primary end point in each study is the incidence of all strokes and systemic embolic events, and the objective is to establish the noninferiority of ximelagatran relative to warfarin. Secondary end point constellations include (1) death, stroke, systemic embolism, and myocardial infarction; (2) ischemic stroke, transient ischemic attack, and systemic embolism; and (3) bleeding and treatment discontinuation. Blinded central committees adjudicate all end points and monitor patient safety. The studies commenced July 2000; enrollment ended in December 2001. Each study will accrue > or =4000 patient-years and > or =80 primary end points with a minimum per-patient exposure of 12 months. Combined analysis of both studies is also planned.. The demographics of the 2 patient populations are similar and should allow the studies to meet the objective.. The program, the largest conducted in this indication, will determine the safety and antithrombotic efficacy of ximelagatran as an alternative to warfarin for prevention of thromboembolism in patients with AF.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Myocardial Infarction; Prodrugs; Thromboembolism; Warfarin

To investigate the influence of nonvalvular atrial fibrillation (NVAF) on the pharmacokinetic (PK) properties of the oral direct thrombin inhibitor ximelagatran and its active form, melagatran.. In an open study, 12 patients with persistent NVAF and 12 age- and gender-matched, healthy control subjects received a 10-min intravenous (i.v.) infusion of 2.66 mg melagatran followed by oral ximelagatran, 36 mg twice daily, for the subsequent five study days. Plasma and urine samples for PK analyses were collected after i.v. and single and repeated oral dosing.. The oral absorption of ximelagatran was rapid, and maximum plasma concentrations of ximelagatran (Cmax) were achieved at about 1 h post-dosing. There were no differences between NVAF patients and controls for the area under the plasma concentration versus time curve, Cmax, half-life (t1/2), or bioavailability (F) of melagatran after oral dosing with ximelagatran. The Cmax of melagatran, formed by the rapid bioconversion of ximelagatran, occurred approximately 3 h post-dosing. The geometric means of the t1/2 for melagatran were 4.0 h and 4.2 h for the first and last doses, respectively, in patients, and 3.5 h and 3.7 h, respectively, in controls. Geometric means of F of melagatran following oral administration of ximelagatran were 22% and 24% for the first and last doses, respectively, in patients and 21% and 23%, respectively, in controls. Approximately 80% of the i.v. dose of melagatran was excreted in urine in patients and in controls.. The PK properties of oral ximelagatran and i.v. melagatran in elderly patients with NVAF are consistent with those in matched, healthy controls.

Topics: Administration, Oral; Adult; Aged; Aging; Area Under Curve; Atrial Fibrillation; Azetidines; Benzylamines; Female; Glycine; Humans; Infusions, Intravenous; Male; Middle Aged; Thrombin

Warfarin prevents ischaemic stroke in patients with non-valvular atrial fibrillation, but dose adjustment, coagulation monitoring, and bleeding risk limit its use. The oral direct thrombin inhibitor ximelagatran represents a potential alternative. We aimed to establish whether ximelagatran is non-inferior to warfarin, within a margin of 2% per year, for prevention of stroke and systemic embolism.. We randomised 3410 patients with atrial fibrillation and one or more stroke risk factors to open-label warfarin (adjusted-dose, international normalised ratio [INR] 2.0-3.0) or ximelagatran (fixed-dose, 36 mg twice daily); patients were recruited from 259 hospitals, doctor's offices, or health-care clinics. Primary analysis was based on masked event assessment and was by intention to treat. Primary endpoint was stroke or systemic embolism.. During 4941 patient-years of exposure (mean 17.4 months, SD 4.1), 96 patients had primary events (56 in the warfarin group vs 40 in the ximelagatran group). The primary event rate by intention to treat was 2.3% per year with warfarin and 1.6% per year with ximelagatran (absolute risk reduction 0.7% [95% CI -0.1 to 1.4], p=0.10; relative risk reduction 29% [95% CI -6.5 to 52]). Rates of disabling or fatal stroke, mortality, and major bleeding were similar between groups, but combined minor and major haemorrhages were lower with ximelagatran than with warfarin (29.8% vs 25.8% per year; relative risk reduction 14% [4 to 22]; p=0.007). Raised serum alanine aminotransferase was more common with ximelagatran.. In high-risk patients with atrial fibrillation, fixed-dose oral ximelagatran was at least as effective as well-controlled warfarin for prevention of stroke and systemic embolism.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Female; Humans; Male; Middle Aged; Prodrugs; Stroke; Thromboembolism; Warfarin

Ximelagatran (Exanta, AstraZeneca), which is still investigational, is the first of a new category of direct inhibitors of thrombin which can be administered orally. SPORTIF III and V trials are both randomized studies; the first is open-label; the second, double-blind. They involved patients aged 18 or over with a non-valvular atrial fibrillation and, at least, one additional risk factor fot stroke (St) or systemic embolism (SE). They compared traditional warfarin anticoagulation (INR = 2-3) with fixed dose ximelagatran (36 mg twice daily) for the prevention of St/SE. These studies are non-inferiority trials. In the intention-to-treat analysis, SPORTIF III (3,407 patients [1,704 on on ximelagatran and 1,703 on warfarin]; mean follow-up of 17.4 months) observed 40 cases of St/SE in the ximelagatran group and 56 in the warfarin group. These data demonstrated the non-inferiority of ximelagatran. In addition, the per protocol analysis showed a superiority of ximelagatran (0.018). SPORTIF V (3,992 patients; mean follow-up of 20 months) observed 88 cases of St/SE. The incidence of these events was similar in both treatment-groups with an absolute difference no greater than 0.5%/yr. The non-inferiority of ximelagatran was thus confirmed. In both studies, bleedings were observed on both therapies with a slight trend in favor of ximelagatran. Additionally, some 6% of patients treated by ximelagatran experienced an increase to greater than three times the upper limit of normal of the liver enzyme alanine aminotransferase (ALT), compared to 0.7-0.8% in the warfarin group. Nearly all enzyme rises occurred during the first six months of therapy and decreased with or without drug discontinuation. The potential breakthrough that these data represent for oral anticoagulation is briefly outlined.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Female; Humans; Male; Middle Aged; Prodrugs; Randomized Controlled Trials as Topic; Risk Factors; Stroke; Thromboembolism; Warfarin

Topics: Anticoagulants; Antithrombins; Atrial Fibrillation; Azetidines; Benzylamines; Dabigatran; Factor Xa Inhibitors; Humans; Safety-Based Drug Withdrawals; Stroke; Warfarin

The effectiveness of oral anticoagulation therapy with warfarin (a vitamin K antagonist) in the treatment of thromboembolic disease, including stroke prophylaxis in patients with atrial fibrillation is well recognised. However, warfarin has a narrow therapeutic window and an unpredictable anticoagulation response, which make it difficult to achieve and maintain optimal anticoagulation. Various dietary factors, including sudden changes in eating patterns, can significantly alter anticoagulation control, thereby potentially exposing patients to the risk of bleeding or thromboembolic complications. Dietary vitamin K intake is a particularly important factor, given the mechanism of action of warfarin. Areas covered: In this article, we cover the sources of vitamin K and their potential effect of dietary vitamin K on anticoagulation response to warfarin. We also discuss the results of studies on the effect of vitamin K supplementation on anticoagulation stability. Expert commentary: A stable dietary vitamin K, promoted by daily oral vitamin K supplementation, can improve anticoagulation stability in patients on warfarin therapy. There is experimental evidence in animals that dietary vitamin K affects anticoagulation response to the direct thrombin inhibitor, ximelagatran. Whether dietary vitamin K affects anticoagulation response to the currently licensed direct oral anticoagulants (DOACs) in man remains to be investigated.

Topics: Administration, Oral; Animals; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Diet; Dietary Supplements; Food-Drug Interactions; Hemorrhage; Humans; Stroke; Thromboembolism; Vitamin K; Warfarin

The benefits and harms of oral anticoagulation therapy in patients with only one stroke risk factor (ie, CHA2DS2-VASc = 1 in males, or 2 in females) has been a subject of debate.. We analyzed all patients with only one stroke risk factor from the merged datasets of SPORTIF III and V trials. Anticoagulation control was defined according to time in therapeutic range (TTR).. Of the original trial cohort, 1097 patients had only one stroke risk factor. Stroke/systemic thromboembolic event had an incidence of 0.9 per 100 patient-years, with an incidence of 1.6 per 100 patient-years for all-cause death and 2.3%/patient-years for the composite outcome of stroke/systemic thromboembolic event/all-cause death. There were no significant differences in the risk for stroke/systemic thromboembolic event between sexes, nor between the different stroke risk factors amongst these atrial fibrillation patients with only one stroke risk factor. Cox regression analysis in patients treated with warfarin found only TTR to be inversely associated with stroke/systemic thromboembolic event (P = .034) and all-cause death (P = .015). Chronic heart failure was significantly associated with the outcome of all-cause death (P = .0019) and the composite outcome of stroke/systemic thromboembolic event/all-cause death (P = .021). There was a significant inverse linear association between TTR and the cumulative risk for both stroke/systemic thromboembolic event and all-cause death (both P <.001).. In atrial fibrillation patients with only one additional stroke risk factor (ie, CHA2DS2-VASc = 1 in males or 2 in females), rates of major adverse events (stroke/systemic thromboembolic event, mortality) were high, despite anticoagulation. TTR in warfarin-treated patients was inversely associated with the occurrence of both stroke/systemic thromboembolic event and all-cause death.

Topics: Aged; Anticoagulants; Antithrombins; Atrial Fibrillation; Azetidines; Benzylamines; Cause of Death; Chronic Disease; Comorbidity; Female; Heart Failure; Humans; Linear Models; Male; Middle Aged; Mortality; Prognosis; Proportional Hazards Models; Risk Factors; Stroke; Thromboembolism; Warfarin

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Azetidines; Benzimidazoles; Benzylamines; Blood Coagulation; Dabigatran; Humans; Pyridines; Thrombin; Venous Thromboembolism

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Digitalis; Digoxin; Drug Combinations; Hemorrhage; Humans; Phytotherapy

Patients with nonvalvular atrial fibrillation and prior stroke or transient ischemic attack (TIA) are at high risk for recurrent stroke. We investigated whether ximelagatran was noninferior to warfarin in patients with prior stroke or TIA.. We analyzed pooled data from the SPORTIF III and V trials in patients with prior stroke/TIA. The primary outcome was the composite annual rate of both ischemic and hemorrhagic strokes and systemic embolic events. Secondary analyses considered ischemic and hemorrhagic strokes separately, bleeding, and nonrandomized, concomitant therapy with aspirin < or =100 mg/d.. Patients from SPORTIF III (n=3407) and SPORTIF V (n=3922) trials were categorized by prior stroke/TIA (21%) versus no prior stroke/TIA (79%) and by treatment group (ximelagatran vs warfarin). The primary event rate in patients with prior stroke/TIA was 2.83%/y with ximelagatran and 3.27%/y with warfarin (absolute difference, -0.44%; 95% CI, -1.88 to1.01; P=0.625). In those without prior stroke/TIA, the primary event rate was 1.31%/y with ximelagatran and 1.26%/y with warfarin (P=NS). Ischemic strokes outnumbered cerebral hemorrhages with both warfarin (31 of 36) and ximelagatran (30 of 32) treatment (difference between treatments was not significant). Combining aspirin with either anticoagulant was associated with higher rates of major bleeding (1.5%/y with warfarin and 4.95%/y with warfarin plus aspirin, P=0.004; 2.35%/y with ximelagatran and 5.09%/y with ximelagatran plus aspirin, P=0.046) but not lower rates of primary events.. Ximelagatran was at least as effective as well-controlled warfarin for the secondary prevention of stroke. The nonrandomized, concomitant treatment with aspirin and anticoagulation was associated with increased bleeding without evidence of a reduction in primary outcome events.

Topics: Aged; Anticoagulants; Aspirin; Atrial Fibrillation; Azetidines; Benzylamines; Drug Therapy, Combination; Female; Humans; Male; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Stroke; Warfarin

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Humans; Stroke; Warfarin

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Humans; Warfarin

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Humans; Warfarin

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Humans; Warfarin

Patients with atrial fibrillation have a varied risk of stroke, depending on age and comorbid conditions. The objective of this study was to assess the predictive value of stroke risk classification schemes and to identify patients with atrial fibrillation who are at substantial risk of stroke despite optimal anticoagulant therapy.. Seven recognized classification schemes-the American College of Chest Physicians 2001, American College of Chest Physicians 2004, Stroke Prevention in Atrial Fibrillation (SPAF), Atrial Fibrillation Investigators, Framingham, van Walraven, and CHADS(2)-were compared for their ability to predict ischemic stroke in patients receiving anticoagulant therapy. Data came from the Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation III and V trials, which compared the efficacy of adjusted-dose warfarin and the direct thrombin inhibitor ximelagatran (36 mg twice daily) in preventing thromboembolic events in 7329 patients with chronic or paroxysmal nonvalvular atrial fibrillation who were at moderate or high risk of ischemic stroke. The main outcome measure was ischemic stroke, as determined by a central event adjudication committee.. During 11 245 patient-years of follow-up, 159 patients had an ischemic stroke (1.4%/year). As indicated by c statistics and hazard ratios, 3 of the classification schemes predicted stroke significantly better than chance: Framingham (c=0.64), CHADS(2) (c=0.65), and SPAF (c=0.61).. In a large cohort of atrial fibrillation patients at moderate or high risk of ischemic stroke treated with warfarin or ximelagatran, the CHADS(2), SPAF, and Framingham schemes had greater predictive accuracy than chance. This predictive ability may allow clinicians to target high-risk patients for more aggressive intervention.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Cohort Studies; Follow-Up Studies; Humans; Multicenter Studies as Topic; Predictive Value of Tests; Proportional Hazards Models; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Stroke; Warfarin

To show results of a prespecified pooled analysis of the studies SPORTIF III (open-label) and SPORTIF V (double-blind), to assess the homogeneity of the results and to explore subgroup analyses and adverse events.. 7,329 patients with atrial fibrillation (AF) and >or=1 additional stroke risk factor were randomized to warfarin (international normalized ratio 2.0-3.0) or ximelagatran (36 mg twice daily). Over 11,346 patient-years (mean 18.5 months/patient), 184 patients developed primary events of stroke and systemic embolism (ximelagatran 1.62 vs. warfarin 1.65%/year; p = 0.94). Heterogeneity between trials with respect to the primary event rate (study-by-treatment interaction p = 0.026) was found. This could not be explained statistically by baseline patient characteristics or by treatment (except perhaps by the better anticoagulation with warfarin in SPORTIF V) and was not evident for secondary end-points. There was no conclusive difference in major bleeding rates (ximelagatran 1.88 vs. warfarin 2.46%/year; p = 0.054), but combined minor plus major bleeding was lower with ximelagatran (31.7 vs. 38.7%/year; p < 0.0001). Elevation of liver enzymes occurred more frequently in patients taking ximelagatran (6.1% vs. warfarin 0.8%; p < 0.0001) and was reversible except in rare cases.. Fixed-dose oral ximelagatran without coagulation monitoring prevented stroke and systemic embolism as effectively as warfarin in patients with AF. Differences in the results of the two trials might relate to consistency of warfarin anticoagulation, different degree of blinding in the two trials, other concomitant therapies or chance. Further investigation is required to explore the long-term safety profile of ximelagatran.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Embolism; Female; Humans; Male; Middle Aged; Randomized Controlled Trials as Topic; Risk Factors; Stroke; Thrombin; Warfarin

Ximelagatran is an oral direct thrombin inhibitor for the prevention of thromboembolic disease. After oral administration, ximelagatran is rapidly absorbed and bioconverted to its active form, melagatran.. To characterise the pharmacokinetics of melagatran in patients with nonvalvular atrial fibrillation (NVAF) receiving long-term treatment for prevention of stroke and systemic embolic events.. A population pharmacokinetic model was developed based on data from three phase II studies (1177 plasma concentration observations in 167 patients, treated for up to 18 months) and confirmed by including data from two phase III studies (8702 plasma concentration observations in 3188 patients, treated for up to 24 months). The impact of individualised dosing on pharmacokinetic variability was evaluated by simulations of melagatran concentrations based on the pharmacokinetic model.. Melagatran pharmacokinetics were consistent across the studied doses and duration of treatment, and were described by a one-compartment model with first-order absorption and elimination. Clearance of melagatran was correlated to creatinine clearance, which was the most important predictor of melagatran exposure (explained 54% of interpatient variance in clearance). Total variability (coefficient of variation) in exposure was 45%; intraindividual variability in exposure was 23%. Concomitant medication with the most common long-term used drugs in the study population had no relevant influence on melagatran pharmacokinetics. Simulations suggested that dose adjustment based on renal function or trough plasma concentration had a minor effect on overall pharmacokinetic variability and the number of patients with high melagatran exposure.. The pharmacokinetics of melagatran in NVAF patients were predictable, and consistent with results from previously studied patient populations. Dose individualisation was predicted to have a low impact on pharmacokinetic variability, supporting the use of a fixed-dose regimen of ximelagatran for long-term anticoagulant therapy in the majority of NVAF patients.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials as Topic; Computer Simulation; Drug Administration Schedule; Drug Interactions; Female; Humans; Male; Middle Aged; Models, Biological; Prodrugs; Thrombin

Aspirin is used in combination with anticoagulant therapy in patients with atrial fibrillation (AF), but evidence of additional efficacy is not available.. We compared ischemic events and bleeding in the SPORTIF III and IV randomized trials of anticoagulation with warfarin (international normalized ratio 2-3) or fixed-dose ximelagatran. Low-dose aspirin (<100 mg/d) was allowed based on prevailing guidelines.. The 14% of patients receiving aspirin more often had diabetes (27.5% vs 23%, P < .01), coronary artery disease (69% vs 41%, P < .01), previous stroke or transient ischemic attack (26% vs 20%, P < .01), and left ventricular dysfunction (41% vs 36%, P < .01). Addition of aspirin to either warfarin or ximelagatran was associated with no reduction in stroke or systemic embolism. Major bleeding occurred significantly more often with aspirin plus warfarin (3.9% per year) than with warfarin alone (2.3% per year, P < .01), aspirin plus ximelagatran (2.0% per year), or ximelagatran alone (1.9% per year). The rate of myocardial infarction with aspirin and warfarin (0.6% per year) was not significantly different from that with ximelagatran alone (1.0% per year), warfarin alone (1.0% per year), or aspirin and ximelagatran (1.4% per year).. Aspirin combined with anticoagulant therapy was associated with no reduction in stroke, systemic embolism, or myocardial infarction in patients with AF. Aspirin combined with warfarin was associated with an incremental rate of major bleeding of 1.6% per year. No increased major bleeding occurred with aspirin and ximelagatran. These results suggest that the risks associated with addition of aspirin to anticoagulation in patients with AF outweigh the benefit.

Topics: Aged; Anticoagulants; Aspirin; Atrial Fibrillation; Azetidines; Benzylamines; Drug Therapy, Combination; Embolism; Female; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Risk Assessment; Stroke; Treatment Outcome; Warfarin

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.

Topics: Administration, Oral; Alanine Transaminase; Animals; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Dose-Response Relationship, Drug; Embolism; Humans; Randomized Controlled Trials as Topic; Stroke; Thrombin

Topics: Atrial Fibrillation; Azetidines; Benzylamines; Embolism; Humans; Randomized Controlled Trials as Topic; Warfarin

Recent trials have found that ximelagatran and warfarin are equally effective in stroke prevention for patients with atrial fibrillation. Because ximelagatran can be taken in a fixed, oral dose without international normalized ratio monitoring and may have a lower risk of hemorrhage, it might improve quality-adjusted survival compared with dose-adjusted warfarin.. To compare quality-adjusted survival and cost among 3 alternative therapies for patients with chronic atrial fibrillation: ximelagatran, warfarin, and aspirin.. Semi-Markov decision model.. Hypothetical cohort of 70-year-old patients with chronic atrial fibrillation, varying risk of stroke, and no contraindications to anticoagulation therapy.. Quality-adjusted life-years (QALYs) and costs in US dollars.. For patients with atrial fibrillation but no additional risk factors for stroke, both ximelagatran and warfarin cost more than 50,000 dollars per QALY compared with aspirin. For patients with additional stroke risk factors and low hemorrhage risk, ximelagatran modestly increased quality-adjusted survival (0.12 QALY) at a substantial cost (116,000 dollars per QALY) compared with warfarin. For ximelagatran to cost less than 50,000 dollars per QALY it would have to cost less than 1100 dollars per year or be prescribed to patients who have an elevated risk of intracranial hemorrhage (>1.0% per year of warfarin) or a low quality of life with warfarin therapy.. Assuming equal effectiveness in stroke prevention and decreased hemorrhage risk, ximelagatran is not likely to be cost-effective in patients with atrial fibrillation unless they have a high risk of intracranial hemorrhage or a low quality of life with warfarin.

Topics: Aged; Aged, 80 and over; Anticoagulants; Aspirin; Atrial Fibrillation; Azetidines; Benzylamines; Chronic Disease; Cost-Benefit Analysis; Decision Support Techniques; Humans; Prodrugs; Quality-Adjusted Life Years; Stroke; United States; Warfarin

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials as Topic; Coronary Artery Disease; Humans; Prodrugs; Risk; Stroke; Venous Thrombosis

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Cost-Benefit Analysis; Drug Costs; Humans; Safety; Thrombin; Thromboembolism; Warfarin

The growing epidemic of atrial fibrillation presents major challenges to the healthcare community, both clinical and financial.

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Humans; Patient Participation; Risk Assessment; Stroke; Thrombin; Treatment Outcome

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Cost-Benefit Analysis; Humans; Prodrugs; Quality-Adjusted Life Years; Stroke; Warfarin

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.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Female; Humans; Intracranial Embolism; Male; Meta-Analysis as Topic; Middle Aged; Randomized Controlled Trials as Topic; Risk Factors; Stroke; Treatment Outcome; Warfarin

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Angioplasty; Angiotensin-Converting Enzyme Inhibitors; Atrial Fibrillation; Azetidines; Benzylamines; Carotid Artery Diseases; Cyclic Nucleotide Phosphodiesterases, Type 4; Genetic Predisposition to Disease; Humans; Risk Factors; Stroke; Tissue Plasminogen Activator; Ultrasonography

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Humans; Prodrugs; Randomized Controlled Trials as Topic; Research Design; Risk; Stroke; Thromboembolism; Treatment Outcome; Warfarin

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Drug Administration Schedule; Humans; Prodrugs; Randomized Controlled Trials as Topic; Stroke; Treatment Outcome; Warfarin

Topics: Anticoagulants; Aspirin; Atrial Fibrillation; Azetidines; Benzylamines; Drug Therapy, Combination; Humans; Prodrugs; Randomized Controlled Trials as Topic; Stroke; Thromboembolism; Treatment Outcome; Vitamin K; Warfarin

Topics: Anticoagulants; Aspirin; Atrial Fibrillation; Azetidines; Benzylamines; Humans; Randomized Controlled Trials as Topic; Research Design; Stroke; Thromboembolism; Treatment Outcome; Warfarin

Topics: Aged; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Humans; Randomized Controlled Trials as Topic; Stroke; Thrombin; Warfarin

Anticoagulation with warfarin is the most effective means of reducing stroke in AF. The generally recommended INR goal is 2-3. Aspirin provides a modest degree of stroke protection in AF but is inferior to warfarin. Assessment of stroke risk is critical in determining whether to prescribe warfarin therapy to a patient with AF. The most important risk factors for stroke in AF are age over 65 years, hypertension, prior stroke, and left ventricular dysfunction or heart failure. The risk of warfarin may be less than commonly believed, but increases when warfarin is combined with aspirin. Patients with paroxysmal AF are not at lower risk of stroke than those with persistent AF and should be treated with warfarin. Apparently successful therapy with antiarrhythmic agents does not eliminate the need for anticoagulation. New antithrombotic therapies are being studied and may soon provide an alternative to warfarin.

Topics: Anticoagulants; Aspirin; Atrial Fibrillation; Azetidines; Benzylamines; Electric Countershock; Fibrinolytic Agents; Humans; Prodrugs; Stroke; Warfarin

While considering long-term oral anticoagulation one should assess benefit (i.e., reduction in thromboembolic events) and risks (i.e., bleeding complications) associated with therapy for each individual patient. The classic cardiac indications for oral anticoagulation include chronic atrial fibrillation, prosthetic heart valves, and left ventricular thrombus formation following anterior myocardial infarction. The value of anticoagulation in patients with impaired left ventricular function in stable sinus rhythm and in secondary prevention of coronary artery disease remains controversial. For decades warfarin has been the only compound available. Currently, promising results have been achieved with the oral thrombin inhibitor ximelagatran. In the future, oral anticoagulants, which are administered in fixed dose with no need for monitoring of the anticoagulation level, may replace warfarin. Safety and efficacy of double antiplatelet therapy (aspirin and clopidogrel) in the secondary prevention of thromboembolic events in patients with atrial fibrillation are currently being addressed in large-scale clinical trials.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials as Topic; Heart Valve Prosthesis Implantation; Heart Ventricles; Humans; Long-Term Care; Myocardial Infarction; Postoperative Complications; Risk Factors; Thromboembolism; Thrombosis

Topics: Advisory Committees; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Chemical and Drug Induced Liver Injury; Drug Approval; Embolism; Humans; Randomized Controlled Trials as Topic; Stroke; United States; United States Food and Drug Administration; Venous Thrombosis

Topics: Ambulatory Care Facilities; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Drug Utilization; Humans; Retrospective Studies; Risk Factors; Stroke; Warfarin

Topics: Administration, Oral; Age Factors; Aged; Aged, 80 and over; Anticoagulants; Aspirin; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials as Topic; Cohort Studies; Contraindications; Humans; Middle Aged; Platelet Aggregation Inhibitors; Prevalence; Recurrence; Risk Factors; Stroke; Time Factors

In two recent clinical trials, the effectiveness of ximelagatran, an oral thrombin inhibitor, was demonstrated as anticoagulant therapy for patients with atrial fibrillation and as secondary prophylaxis for patients following a myocardial infarction, respectively. This may be of relevance for the often life-long treatment of patients with anticoagulants, as with ximelagatran frequent monitoring of the anticoagulant status is not necessary, in contrast to treatment with warfarin-like drugs.

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Humans; Myocardial Infarction; Thrombin; Thrombosis

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Humans; Prodrugs; Stroke; Warfarin

Topics: Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials as Topic; Drug Monitoring; Fibrinolytic Agents; Humans; International Normalized Ratio; Intracranial Embolism; Prodrugs; Treatment Outcome; Warfarin