ximelagatran and Hemorrhage

Cancer increases the risk of thromboembolic events, especially in people receiving anticoagulation treatments.. To compare the efficacy and safety of low molecular weight heparins (LMWHs), direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) for the long-term treatment of venous thromboembolism (VTE) in people with cancer.. We conducted a literature search including a major electronic search of the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 1), MEDLINE (Ovid), and Embase (Ovid); handsearching conference proceedings; checking references of included studies; use of the 'related citation' feature in PubMed and a search for ongoing studies in trial registries. As part of the living systematic review approach, we run searches continually, incorporating new evidence after it is identified. Last search date 14 May 2018.. Randomized controlled trials (RCTs) assessing the benefits and harms of long-term treatment with LMWHs, DOACs or VKAs in people with cancer and symptomatic VTE.. We extracted data in duplicate on study characteristics and risk of bias. Outcomes included: all-cause mortality, recurrent VTE, major bleeding, minor bleeding, thrombocytopenia, and health-related quality of life (QoL). We assessed the certainty of the evidence at the outcome level following the GRADE approach (GRADE handbook).. Of 15,785 citations, including 7602 unique citations, 16 RCTs fulfilled the eligibility criteria. These trials enrolled 5167 people with cancer and VTE.Low molecular weight heparins versus vitamin K antagonistsEight studies enrolling 2327 participants compared LMWHs with VKAs. Meta-analysis of five studies probably did not rule out a beneficial or harmful effect of LMWHs compared to VKAs on mortality up to 12 months of follow-up (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.88 to 1.13; risk difference (RD) 0 fewer per 1000, 95% CI 45 fewer to 48 more; moderate-certainty evidence). Meta-analysis of four studies did not rule out a beneficial or harmful effect of LMWHs compared to VKAs on major bleeding (RR 1.09, 95% CI 0.55 to 2.12; RD 4 more per 1000, 95% CI 19 fewer to 48 more, moderate-certainty evidence) or minor bleeding (RR 0.78, 95% CI 0.47 to 1.27; RD 38 fewer per 1000, 95% CI 92 fewer to 47 more; low-certainty evidence), or thrombocytopenia (RR 0.94, 95% CI 0.52 to 1.69). Meta-analysis of five studies showed that LMWHs probably reduced the recurrence of VTE compared to VKAs (RR 0.58, 95% CI 0.43 to 0.77; RD 53 fewer per 1000, 95% CI 29 fewer to 72 fewer, moderate-certainty evidence).Direct oral anticoagulants versus vitamin K antagonistsFive studies enrolling 982 participants compared DOACs with VKAs. Meta-analysis of four studies may not rule out a beneficial or harmful effect of DOACs compared to VKAs on mortality (RR 0.93, 95% CI 0.71 to 1.21; RD 12 fewer per 1000, 95% CI 51 fewer to 37 more; low-certainty evidence), recurrent VTE (RR 0.66, 95% CI 0.33 to 1.31; RD 14 fewer per 1000, 95% CI 27 fewer to 12 more; low-certainty evidence), major bleeding (RR 0.77, 95% CI 0.38 to 1.57, RD 8 fewer per 1000, 95% CI 22 fewer to 20 more; low-certainty evidence), or minor bleeding (RR 0.84, 95% CI 0.58 to 1.22; RD 21 fewer per 1000, 95% CI 54 fewer to 28 more; low-certainty evidence). One study reporting on DOAC versus VKA was published as abstract so is not included in the main analysis.Direct oral anticoagulants versus low molecular weight heparinsTwo studies enrolling 1455 participants compared DOAC with LMWH. The study by Raskob did not rule out a beneficial or harmful effect of DOACs compared to LMWH on mortality up to 12 months of follow-up (RR 1.07, 95% CI 0.92 to 1.25; RD 27 more per 1000, 95% CI 30 fewer to 95 more; low-certainty evidence). The data also showed that DOACs may have shown a likely reduction in VTE recurrence up to 12 months. For the long-term treatment of VTE in people with cancer, evidence shows that LMWHs compared to VKAs probably produces an important reduction in VTE and DOACs compared to LMWH, may likely reduce VTE but may increase risk of major bleeding. Decisions for a person with cancer and VTE to start long-term LMWHs versus oral anticoagulation should balance benefits and harms and integrate the person's values and preferences for the important outcomes and alternative management strategies.Editorial note: this is a living systematic review (LSR). LSRs offer new approaches to review updating in which the review is continually updated, incorporating relevant new evidence as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.

Topics: Administration, Oral; Anticoagulants; Azetidines; Benzimidazoles; Benzylamines; beta-Alanine; Dabigatran; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Oligosaccharides; Randomized Controlled Trials as Topic; Venous Thromboembolism; Vitamin K

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

The vitamin K antagonists (VKA) available for stroke prevention in patients with atrial fibrillation have many drawbacks due to their difficult clinical use and high risk of bleeding. Currently, several drugs are being developed as possible substitutes for VKA that have many advantages such as the lack of monitoring requirement and scarce pharmacologic and food interactions. The present article provides an update on the new oral anticoagulants that are in a more advanced stage of clinical research, their pharmacologic properties, advantages and disadvantages and their results in recent clinical trials.

Topics: Administration, Oral; Anticoagulants; Azetidines; Benzimidazoles; Benzylamines; beta-Alanine; Clinical Trials as Topic; Dabigatran; Drug Monitoring; Drugs, Investigational; Hemorrhage; Humans; Morpholines; Multicenter Studies as Topic; Patient Care Planning; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiophenes; Thrombophilia; Vitamin K

The oral direct thrombin inhibitor ximelagatran, and its active form, melagatran, have been tested in various clinical conditions as a promising alternative to conventional anticoagulant therapy (CAT), despite some concerns over potentially serious liver injury.. To assess its risk/benefit profile, a systematic review and meta-analysis of all randomised controlled trials (RCTs) comparing xi-/melagatran to CAT was performed.. Leading medical databases were searched. The rates of major adverse events (MAE: all cause death, nonfatal myocardial infarction, nonfatal thromboembolic stroke, nonfatal pulmonary embolism), major bleeds (MB), and hepatotoxicity were compared. Out of 140 potentially relevant citations, 13 RCTs enrolling 22,639 patients were included. Indications for treatment were: 1) perioperative prophylaxis of deep vein thrombosis (DVT); 2) management of DVT; and 3) stroke prevention in atrial fibrillation.. Overall, the risk of MAE (OR 0.98 [0.83-1.17]) and MB (OR 1.01 [0.69-1.47]) did not differ significantly between xi-/melagatran and CAT. There was a clear trend towards an increased risk of hepatotoxicity (OR 1.74 [0.50-6.01]), with an incidence of 5.8% with xi-/melagatran versus 2.3% with CAT (p<0.001); more specifically, the rate of hepatotoxicity was markedly augmented in the management of DVT (OR 5.16 [3.38-7.89]), for treatment durations > or = 3 months (OR 6.73 [5.01-9.05]), and in the prevention of atrial fibrillation-related stroke (OR 8.31 [5.65-12.23]). Two fatal cases of liver injury occurred with xi-/melagatran.. Although comparable to CAT in terms of MAE and MB, xi-/melagatran carries a prohibitive risk of hepatotoxicity that cannot be ignored. Newer long-term alternatives are urgently needed.

Topics: Anticoagulants; Azetidines; Benzylamines; Hemorrhage; Humans; Liver; Randomized Controlled Trials as Topic; Risk Assessment

Topics: Angina, Unstable; Anticoagulants; Azetidines; Benzimidazoles; Benzylamines; Brain Ischemia; Clinical Trials as Topic; Coumarins; Dabigatran; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Forecasting; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Morpholines; Myocardial Infarction; Peptide Fragments; Polysaccharides; Prothrombin; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Thiophenes; Thrombin; Thrombophilia; Thrombosis; 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

Old burdens and new perspectives of the long-term anticoagulant therapy. Long-term anticoagulant therapy (LAT) has increasingly improved the prognosis in various diseases thus becoming an indispensable tool in our day-to-day therapeutic arsenal. However its use is influenced by various uncertainty factors. The optimal range of anticoagulation can unfortunately only be partially achieved due to the several factors influencing it. Thromboembolic and bleeding episodes occur mainly at times when the state of anticoagulation diverges from the ideally set therapeutic range. Quality of the ongoing therapy can only partially be improved by increasing the frequency of the controls. This however is also inherent partly in the treatment indication and also in the personality of the given patient (compliance). Heparin preparations are rarely used for long-term anticoagulant therapy due to the inevitable injectable form of administration. The more easily applicable LMWH-s' actions are also influenced by several uncertainty factors. In cases of idiopathic deep vein thrombosis, extension of the LAT therapy could be beneficial and is recommended beyond 6 months in order to prevent recurrence of the acute event and postthrombotic syndrome, irrespective of the proof of the genetic predisposition. Several clinical observations suggest that LAT could hinder propagation of malignant tumors and this presumption has already been supported by experimental data. The favourable effect has primarily been associated with and experienced with the use of LMWH-s. Prolonged LAT may even change the perspectives of thrombolytic therapy in venous thrombosis, improving its late efficacy. A new and simply applicable anticoagulant may help further spreading of LAT.

Topics: Anticoagulants; Azetidines; Benzylamines; Coumarins; Drug Administration Schedule; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; International Normalized Ratio; Neoplasms; Patient Compliance; Thromboembolism; Thrombolytic Therapy; Thrombosis

Ximelagatran has been recently studied for prophylaxis in surgical orthopedic cases.. We proposed to establish whether interventions involving ximelagatran, as compared with warfarin, would increase thromboembolic prophylaxis in patients undergoing major orthopedic knee surgery.. Studies with random assignment were identified by an electronic search of the medical literature up to 2006. Data were double-entered into the Review Manager software, version 4.2.5.. We included three well-conducted clinical trials involving 4,914 participants. Sub-groups with two dosages of ximelagatran (24 mg and 36 mg, b.i.d.), were defined. Ximelagatran showed significantly lower frequency of total venous thromboembolism (VTE) than warfarin, but only with the 36-mg dosage (risk relative, RR: 0.72; 95% confidence interval, CI: 0.64-0.81; p < 0.00001). For the 24-mg subgroup, total VTE frequency was similar (RR: 0.86; 95% CI: 0.73-1.01; p = 0.06). No significant differences were shown with either ximelagatran dosage for deep vein thrombosis (DVT), pulmonary embolism, any bleeding or severe bleeding. At the end of the treatment, alanine aminotransferase (ALT) elevation was less frequent in the 24-mg ximelagatran sub-group (RR: 0.33; 95% CI: 0.12-0.91; p = 0.03], but during the follow-up period, the ALT elevation rate was greater in the 36-mg ximelagatran group (RR: 6.97; 95% CI: 1.26-38.50; p = 0.03].. Ximelagatran appears to be more effective than warfarin when used in higher dosages (36 mg b.i.d.), but at the expense of increased frequency of ALT elevation during the follow-up period.

Topics: Aged; Anticoagulants; Azetidines; Benzylamines; Brazil; Epidemiologic Methods; Hemorrhage; Humans; Knee; Orthopedic Procedures; Pulmonary Embolism; Thromboembolism; Venous Thrombosis; Warfarin

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

The oral direct thrombin inhibitor ximelagatran is the first oral anticoagulant since the introduction of the vitamin K antagonists in the early 1940s. A comparison of the discovery and early clinical development of the two classes of oral anticoagulants reveals some similarities but also several differences that illustrate the change in drug discovery over the last half century.

Topics: Animals; Anticoagulants; Azetidines; Benzylamines; Blood Coagulation; Cattle; Clinical Trials as Topic; Drug Design; Hemorrhage; History, 20th Century; Humans; Melilotus; Thrombin; Vitamin K; 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

Fibrinolysis is the reference treatment for most myocardial infarctions with ST-segment elevation; alternatives are angioplasty, with or without stent. The earlier fibrinolysis is performed (preferably before hospitalization), the more effective it is. It can be optimized by adjuvant antiplatelet therapy, such as aspirin, and probably by anticoagulant treatment as well. Because fibrinolytic therapy is accompanied by intensive thrombin generation and activation, immediate and continuous adjunctive simultaneous heparin therapy is recommended. The efficacy of subcutaneous low-molecular-weight heparin (LMWH) HBPM) is at least equivalent to that of intravenous unfractionated heparin (UFH), but its risk of severe (but not cerebral) hemorrhage is greater. Bolus LMWH on the other hand is associated with an increased risk of cerebral hemorrhage. Antithrombotic treatment thus appears optimal with bolus UFH at fibrinolysis and for at least 48 hours afterwards. An alternative after this bolus might be subcutaneous enoxaparin until discharge. Because the major drawback of both types of heparin is their rebound activation of thrombosis, oral anticoagulants are recommended thereafter. The combination of anticoagulant treatment + (low-dose) aspirin is not superior to aspirin alone when the target INR is below 2. Adequate anticoagulation with INRs greater than 2.0 consistently improves angiographic and clinical outcome. Bleeding (except intracerebral) is significantly increased whether the INR is greater than or less than 2.0. Other treatments are being investigated. Pentasaccharide (anti-Xa) combined with fibrinolysis seems to reduce reocclusion more effectively than UFH. Oral postinfarction treatment with ximelagatran (a thrombin inhibitor), combined with aspirin, is associated with fewer cardiovascular events than aspirin alone. More studies are needed.

Topics: Anticoagulants; Aspirin; Azetidines; Benzylamines; Cerebral Hemorrhage; Coronary Thrombosis; Drug Therapy, Combination; Factor Xa; Fibrinolytic Agents; Follow-Up Studies; Forecasting; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Injections, Intravenous; Injections, Subcutaneous; Myocardial Infarction; Myocardial Ischemia; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Risk Factors; Time Factors; Treatment Outcome

Vitamin K antagonists are effective oral anticoagulants, but they have limitations related to a narrow therapeutic range, food and drug interactions, slow onset of action and the need for routine coagulation monitoring. Ximelagatran is a promising new oral anticoagulant under investigation in advanced clinical trials. It is a prodrug that is converted after oral administration to melagatran, a direct thrombin inhibitor, with a peak effect after 2 hours and a half-life of approximately 3 hours with primarily renal excretion. Administration results in prolongation of coagulation tests, but routine monitoring is not required because of reliable absorption and predictable effects. A large clinical trials program has demonstrated effectiveness in prophylaxis of deep vein thrombosis (DVT) following major orthopedic surgery, treatment of symptomatic DVT, prevention of embolism in patients with atrial fibrillation, and prophylaxis of recurrent events after acute myocardial infarction. Bleeding complications have been similar to those with standard therapy, with no unexpected adverse effects except for elevation of serum transaminase levels in over 6% of patients beginning after 1 month of therapy. Ximelagatran may be an alternative oral anticoagulant for patients currently taking vitamin K antagonists.

Topics: Anticoagulants; Azetidines; Benzylamines; Heart Diseases; Hemorrhage; Humans; Liver Function Tests; Venous Thrombosis

Aging itself is a risk factor for venous thromboembolism, and the prevalence in the elderly of additional risk factors (e.g. cancer, orthopedic surgery, immobility) increase its intrinsic risk. Many in the medical community are reluctant to prescribe anticoagulation (for primary and secondary prevention of venous thromboembolism) to their geriatric patients for the fear that bleeding complications may outweigh the benefits. A thorough analysis of the data support the concept that the under-use of heparin in primary prevention in the elderly is more related to medical beliefs than to facts. The risk of bleeding due to oral anticoagulants (secondary prevention) is greatly reduced by keeping the International Normalized Ratio (INR) values within therapeutic ranges and carefully avoiding conditions/drugs that may interfere with such treatment. The oral direct thrombin inhibitor ximelagatran has been studied for primary (hip and knee replacement surgery) and for secondary prophylaxis of venous thromboembolism, and for acute venous thromboembolism treatment. The selective factor Xa inhibitor fondaparinux has been approved for primary prophylaxis of venous thromboembolism in hip and knee replacement surgery and in hip fracture surgery. Studies on the latter drugs, where most of the patients were > 65 years of age, further show that the fear of bleeding complications due to anticoagulation in the elderly is largely unjustified.

Topics: Age Factors; Aged; Aged, 80 and over; Aging; Anticoagulants; Azetidines; Benzylamines; Clinical Trials as Topic; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Humans; International Normalized Ratio; Polysaccharides; Risk Factors; Thromboembolism; Time Factors; Venous Thrombosis

Ximelagatran is a novel oral direct thrombin inhibitor (oral DTI) that is currently in advanced clinical development for the prevention and treatment of thromboembolic events in a wide range of patient populations and indications. The clinical development of novel anticoagulant therapies requires that treatments be assessed according to both their clinical benefit (reduction of risk of thromboembolic events) and safety profile (primarily bleeding). Definition and assessment of bleeding severity is thus an important factor in clinical trial design. Lack of consistency in bleeding definitions used in different clinical trial programmes makes comparison of bleeding event data difficult. Standard bleeding definitions would be required to make fair comparisons between clinical trials possible. The definitions of bleeding events used in clinical trials of ximelagatran are broadly consistent with those used in many other major trials. Results of phase II and III trials comparing ximelagatran with currently available anticoagulant therapies demonstrate that ximelagatran can be used with fixed dosing with no coagulation monitoring, dose titration, or dose adjustment, without compromising efficacy or safety. The incidences of major bleeding events in clinical trials of ximelagatran have been low and similar to those with other anticoagulant drugs. Adequate treatment in case of emergency situations such as serious bleeding should include cessation of treatment and maintenance of adequate diuresis.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Azetidines; Benzylamines; Hemorrhage; Humans; Incidence

Thrombin is a central bioregulator of coagulation and is therefore a key target in the therapeutic prevention and treatment of thromboembolic disorders, including deep vein thrombosis and pulmonary embolism. The current mainstays of anticoagulation treatment are heparins, which are indirect thrombin inhibitors, and coumarins, such as warfarin, which modulate the synthesis of vitamin K-dependent proteins. Although efficacious and widely used, heparins and coumarins have limitations because their pharmacokinetics and anticoagulant effects are unpredictable, with the risk of bleeding and other complications resulting in the need for close monitoring with their use. Low-molecular-weight heparins (LMWHs) provide a more predictable anticoagulant response, but their use is limited by the need for subcutaneous administration. In addition, discontinuation of heparin treatment can result in a thrombotic rebound due to the inability of these compounds to inhibit clot-bound thrombin. Direct thrombin inhibitors (DTI) are able to target both free and clot-bound thrombin. The first to be used was hirudin, but DTIs with lower molecular weights, such as DuP 714, PPACK, and efegatran, have subsequently been developed, and these agents are better able to inhibit clot-bound thrombin and the thrombotic processes that take place at sites of arterial damage. Such compounds inhibit thrombin by covalently binding to it, but this can result in toxicity and nonspecific binding. The development of reversible noncovalent DTIs, such as inogatran and melagatran, has resulted in safer, more specific and predictable anticoagulant treatment. Oral DTIs, such as ximelagatran, are set to provide a further breakthrough in the prophylaxis and treatment of thrombosis.

Topics: Administration, Oral; Amino Acid Chloromethyl Ketones; Anticoagulants; Arginine; Azetidines; Benzylamines; Binding Sites; Biological Availability; Blood Coagulation; Comorbidity; Coumarins; Drug Design; Embolism; Female; Forecasting; Glycine; Guanidines; Heart Diseases; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Hirudin Therapy; Humans; Neoplasms; Pipecolic Acids; Pregnancy; Pregnancy Complications, Hematologic; Prodrugs; Safety; Serine; Stroke; Sulfonamides; Thrombin; Thrombophilia; Thrombosis

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

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

Recurrent thromboembolic events may occur after termination of anticoagulant therapy for acute venous thromboembolism (VTE) using oral direct thrombin inhibitor ximelagatran.. Patients with VTE recruited at the German study centres were followed-up for an additional 18 months, treated initially with 2x36 mg ximelagatran daily or with enoxaparin/warfarin over 6 months (THRIVE Treatment study) and 2x24 mg ximelagatran daily or placebo over 18 months (THRIVE III study). Recurrent VTE and the combined outcome events consisting of recurrent VTE, other thrombotic complication, major bleeding and mortality were analysed.. In the THRIVE Treatment study, no patient suffered from a recurrent VTE, but 1 patient randomised to enoxaparin/warfarin experienced major bleeding. During follow-up, 4/32 and 3/32 patients initially randomised to ximelagatran and enoxaparin/warfarin developed recurrent VTE (p=0.7024). No major bleed occurred. One patient in each group died. The incidences of the combined outcome events were not different (p=0.9326). In the THRIVE III study, 0/9 versus 5/14 patients randomised to ximelagatran and placebo developed recurrent VTE including 1 fatal pulmonary embolism (p=0.0501). During follow-up, 3/9 and no patients initially randomised to ximelagatran and placebo developed recurrent VTE. One and 3 other outcome events occurred in patients initially randomised to ximelagatran or placebo. During follow-up, recurrent VTE (p=0.6893) and combined outcome events (p=0.3642) were not different between the groups.. The results of the follow-up studies suggest that thromboembolic events may re-occur in patients with acute VTE after termination of treatment with both vitamin K-antagonists and ximelagatran.

Topics: Administration, Oral; Anticoagulants; Arteries; Azetidines; Benzylamines; Drug Therapy, Combination; Enoxaparin; Follow-Up Studies; Germany; Hemorrhage; Humans; Incidence; International Normalized Ratio; Muscle, Skeletal; Prospective Studies; Recurrence; Retinal Vein Occlusion; Time Factors; Venous Thrombosis; 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

The oral direct thrombin inhibitor ximelagatran (24 mg twice daily) has been shown to significantly reduce the incidence of recurrent venous thromboembolism (VTE) vs. placebo over 18 months, with no significant influence on bleeding (THRIVE III). The influence of potential prognostic factors on the risk of recurrent VTE or major and/or minor bleeding and their impact on ximelagatran treatment was evaluated in the THRIVE III study population. The effect of sex, age, body weight, renal function, malignancy, type of initial VTE event, and history of previous VTE events was investigated in the intention-to-treat population using Cox proportionate hazard modelling. Ximelagatran was administered to 612 patients and placebo to 611 patients. Within the placebo group, risk of recurrent VTE was higher among men than women (hazard ratio [HR]: 2.50,95% confidence interval [CI] 1.49,4.17), and in patients with one or more than one previous VTE event (HR: 1.73,95% CI 1.00, 2.99). There was a higher risk of bleeding among women than men in both the ximelagatran (HR: 1.49, 95% CI 1.06, 2.09) and placebo (HR: 1.48, 95% CI 1.01, 2.15) groups, and in placebo-treated patients with an initial pulmonary embolism (HR: 1.53, 95% CI 1.06,2.23) compared to those with initial deep vein thrombosis. There were no significant interactions between treatment effect and any of the potential prognostic factors. In conclusion, the superior efficacy of ximelagatran vs. placebo was maintained in all subgroups. Long-term use of oral ximelagatran, without coagulation monitoring or dose adjustment, should be feasible and well tolerated in a wide cross-section of patients for the secondary prevention of VTE.

Topics: Adult; Aged; Anticoagulants; Azetidines; Benzylamines; Double-Blind Method; Female; Hemorrhage; Humans; Incidence; Male; Middle Aged; Pulmonary Embolism; Recurrence; Risk Factors; Sex Factors; Thromboembolism; Time Factors; Venous Thrombosis

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

We evaluated whether a postoperative regimen with melagatran followed by oral ximelagatran, two new direct thrombin inhibitors, was an optimal regimen for thromboprophylaxis in major orthopaedic surgery. In a double-blind study, 2788 patients undergoing total hip or knee replacement were randomly assigned to receive for 8 to 11 days either 3 mg of subcutaneous melagatran started 4-12 h postoperatively, followed by 24 mg of oral ximelagatran twice-daily or 40 mg of subcutaneous enoxaparin once-daily, started 12 h preoperatively. Ximelagatran was to be initiated within the first two postoperative days. The primary efficacy endpoint was venous thromboembolism (deep-vein thrombosis detected by mandatory venography, pulmonary embolism or unexplained death). The main safety endpoint was bleeding. Venous thromboembolism occurred in 355/1146 (31.0%) and 306/1122 (27.3%) patients in the ximelagatran and enoxaparin group, respectively, a difference in risk of 3.7% in favour of enoxaparin (p = 0.053). Bleeding was comparable between the two groups.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Cause of Death; Double-Blind Method; Drug Administration Schedule; Enoxaparin; Female; Glycine; Hemorrhage; Humans; Injections, Subcutaneous; Male; Middle Aged; Postoperative Complications; Prodrugs; Prospective Studies; Pulmonary Embolism; Safety; Thrombin; Treatment Outcome; Venous Thrombosis

Prophylaxis is recommended following total joint replacement because of the high risk of venous thromboembolism (VTE). Postoperative low-molecular-weight heparin (LMWH) reduces the incidence of venographically detected deep vein thrombosis (DVT) to about 10-15% in total hip replacement (THR) patients. Ximelagatran is a novel, oral direct thrombin inhibitor that selectively and competitively inhibits both free and clot-bound thrombin. We compared the efficacy and safety of ximelagatran with those of enoxaparin for the prevention of VTE in patients undergoing THR.. This was a prospective, randomized, multicenter, double-blind study conducted principally in the USA and Canada. Patients received fixed-dose oral ximelagatran 24 mg bid or subcutaneous enoxaparin 30 mg bid and matched placebo for 7-12 days; both regimens were initiated the morning after surgery. The incidence of VTE (by postoperative day 12) included thrombosis determined by mandatory venography of the leg on which surgery was performed and symptomatic, objectively proven DVT or pulmonary embolism (PE). VTE and bleeding events were interpreted by an independent central adjudication committee for primary analysis.. Of the 1838 patients randomized, 1557 had either adequate venography or symptomatic, proven VTE (efficacy population). Overall rate of venography acceptable for evaluation was 85.4%. Overall rates of total VTE were 7.9% (62 of 782 patients) in the ximelagatran group and 4.6% (36 of 775 patients) in the enoxaparin group, with an absolute difference of 3.3% and a 95% confidence interval for the difference of 0.9% to 5.7%. Proximal DVT and/or PE occurred in 3.6% (28 of 782 patients) in the ximelagatran group and 1.2% (nine of 774 patients) in the enoxaparin group. Major bleeding events were observed in 0.8% (seven of 906) of the ximelagatran-treated patients and in 0.9% (eight of 910) of the enoxaparin-treated patients (P > 0.95). Non-inferiority of ximelagatran 24 mg bid based on a prespecified margin of 5% was not met, resulting in superiority of the enoxaparin regimen.. Both ximelagatran and enoxaparin decreased the overall rate of VTE compared with that reported historically. However, in this study, enoxaparin 30 mg bid was more effective than ximelagatran 24 mg bid for prevention of VTE in THR. Oral ximelagatran was used without coagulation monitoring, was well tolerated, and had bleeding rates comparable to those of enoxaparin. Further refinement by testing a higher dose of ximelagatran in the patients undergoing THR is warranted.

Topics: Administration, Oral; Aged; Anticoagulants; Arthroplasty, Replacement, Hip; Azetidines; Benzylamines; Double-Blind Method; Enoxaparin; Female; Hemorrhage; Hemostatics; Humans; Male; Middle Aged; Prodrugs; Random Allocation; Thrombin; Thromboembolism; Venous Thrombosis; Wound Healing

In a previous study of the prevention of venous thromboembolism after total knee replacement, the efficacy of ximelagatran, an oral direct thrombin inhibitor that does not require monitoring of coagulation or dose adjustment, was found to be similar to that of warfarin at a dose of 24 mg of ximelagatran twice daily. The purpose of the present study was to determine whether a higher dose of ximelagatran is superior to warfarin.. This randomized, double-blind trial compared a regimen of 7 to 12 days of oral ximelagatran, at a dose of 24 or 36 mg twice daily, starting the morning after surgery, with warfarin therapy started the evening of the day of surgery. The composite end point of venous thromboembolism and death from all causes and the incidence of bleeding were the primary outcome measures.. Among the 1851 patients in the efficacy analysis, oral ximelagatran at a dose of 36 mg twice daily was superior to warfarin with respect to the primary composite end point of venous thromboembolism and death from all causes (20.3 percent vs. 27.6 percent; P=0.003). There were no significant differences between these two groups with respect to major bleeding (incidence, 0.8 percent and 0.7 percent, respectively), perioperative indicators of bleeding, wound characteristics, or the composite secondary end point of proximal deep-vein thrombosis, pulmonary embolism, and death (2.7 percent vs. 4.1 percent; P=0.17).. The efficacy of oral ximelagatran, administered starting the morning after total knee replacement, was superior to that of warfarin for prevention of venous thromboembolism. Rates of hemorrhagic complications with the two drugs were similar.

Topics: Administration, Oral; Aged; Anticoagulants; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Double-Blind Method; Drug Administration Schedule; Female; Hemorrhage; Humans; Male; Middle Aged; Prodrugs; Pulmonary Embolism; Thromboembolism; Treatment Outcome; Venous Thrombosis; Warfarin

For many patients with venous thromboembolism, secondary prevention with vitamin K antagonists is not extended beyond six months, since the risk of recurrence may be outweighed by the risk of major bleeding.. In a double-blind, multicenter trial, we randomly assigned 1233 patients with venous thromboembolism who had undergone six months of anticoagulant therapy to extended secondary prevention with the oral direct thrombin inhibitor ximelagatran (24 mg) or placebo, taken twice daily, for 18 months without monitoring of coagulation. At base line, bilateral ultrasonography of the legs and perfusion lung scanning were performed.. Data from 612 patients in the ximelagatran group and 611 in the placebo group were analyzed. The occurrence of the primary end point, symptomatic recurrent venous thromboembolism, was confirmed in 12 patients assigned to ximelagatran and 71 patients assigned to placebo (hazard ratio, 0.16; 95 percent confidence interval, 0.09 to 0.30; P<0.001). Death from any cause occurred in 6 patients in the ximelagatran group and 7 patients in the placebo group, and bleeding occurred in 134 patients and 111 patients, respectively (hazard ratio, 1.19; 95 percent confidence interval, 0.93 to 1.53; P=0.17). The incidence of major hemorrhage was low (six events in the ximelagatran group and five in the placebo group), and none of these hemorrhages were fatal. The cumulative risk of a transient elevation of the alanine aminotransferase level to more than three times the upper limit of normal was 6.4 percent in the ximelagatran group, as compared with 1.2 percent in the placebo group (P<0.001).. Oral ximelagatran was superior to placebo for the extended prevention of venous thromboembolism. There was no significant increase in the frequency of bleeding complications, but there was an increase in the number of patients with a transient elevation in the alanine aminotransferase level.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Azetidines; Benzylamines; Double-Blind Method; Female; Hemorrhage; Humans; Male; Middle Aged; Prodrugs; Pulmonary Embolism; Risk; Secondary Prevention; Thrombin; Thromboembolism; Venous Thrombosis

Ximelagatran and its subcutaneous (s.c.) form melagatran are novel direct thrombin inhibitors for the prevention and treatment of thromboembolic disease.. In a double-blind study, 2835 consecutive patients undergoing total hip or knee replacement were randomized to either melagatran/ximelagatran or enoxaparin. Melagatran 2 mg was started immediately before surgery; 3 mg was then administered postoperatively, followed by 24 mg of oral ximelagatran b.i.d. beginning the next day. Enoxaparin 40 mg, administered subcutaneously o.d., was started 12 h before surgery. Both treatments were continued for 8-11 days. The main efficacy outcome measures were major venous thromboembolism (VTE); [proximal deep vein thrombosis (DVT), non-fatal and/or fatal pulmonary embolism (PE), death where PE could not be ruled out], and total VTE (proximal and distal DVT; PE; death from all causes). DVT was detected by mandatory bilateral ascending venography at the end of the treatment period or earlier if clinically suspected. The main safety outcome was bleeding.. The rates of major and total VTE were significantly lower in the melagatran/ximelagatran group compared with the enoxaparin group (2.3% vs. 6.3%, P = 0.0000018; and 20.3% vs. 26.6%, P < 0.0004, respectively). Fatal bleeding, critical site bleeding and bleeding requiring reoperation did not differ between the two groups. 'Excessive bleeding as judged by the investigator' was more frequent with melagatran/ximelagatran than with enoxaparin.. In patients undergoing total hip or knee replacement, preoperatively initiated s.c. melagatran followed by oral ximelagatran was significantly more effective in preventing VTE than preoperatively initiated s.c. enoxaparin.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Double-Blind Method; Enoxaparin; Female; Glycine; Hemorrhage; Humans; Male; Middle Aged; Preoperative Care; Therapeutic Equivalency; Thrombin; Thromboembolism; Venous Thrombosis

Warfarin is used for prophylaxis of venous thromboembolism in patients undergoing total knee arthroplasty. However, it is associated with rates of deep venous thrombosis (DVT) of approximately 38% to 55% and requires routine coagulation monitoring and frequent dose adjustment. Ximelagatran, an oral direct thrombin inhibitor, has shown promising efficacy and tolerability in patients undergoing total hip or knee arthroplasty.. To compare the efficacy and safety of ximelagatran and warfarin for prophylaxis of venous thromboembolism after total knee arthroplasty.. Randomized, double-blind, parallel-group trial.. 74 North American hospitals.. 680 patients who had undergone total knee arthroplasty.. 7 to 12 days of treatment with oral ximelagatran, 24 mg twice daily, starting on the morning after surgery, or warfarin (target international normalized ratio, 2.5 [range, 1.8 to 3.0]), starting on the evening of the day of surgery.. Principal end points were asymptomatic DVT on mandatory venography; symptomatic DVT confirmed by ultrasonography or venography; symptomatic, objectively proven pulmonary embolism; and bleeding. All were assessed by blinded adjudication locally and at a central study laboratory.. On central adjudication, incidence of venous thromboembolism was 19.2% (53 of 276 patients) in the ximelagatran group and 25.7% (67 of 261 patients) in the warfarin group (difference, -6.5 percentage points [95% CI, -13.5 to 0.6 percentage points]; P = 0.070). On local assessment, incidence was 25.4% in the ximelagatran group and 33.5% in the warfarin group (P = 0.043). In the ximelagatran and warfarin groups, respectively, major bleeding occurred in 1.7% and 0.9% of patients and minor bleeding occurred in 7.8% and 6.4% of patients. No variables related to bleeding differed significantly between the two groups.. For prophylaxis of venous thromboembolism, fixed-dose ximelagatran started the morning after total knee arthroplasty is well tolerated and at least as effective as warfarin, but it does not require coagulation monitoring or dose adjustment.

Topics: Administration, Oral; Aged; Anticoagulants; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Double-Blind Method; Female; Hemorrhage; Humans; Male; Phlebography; Thrombin; Venous Thrombosis; 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

Thrombin amplifies the blood coagulation via factor V (FV)-mediated positive feedback loop. We hypothesised that factor Xa (FXa) inhibitors would interfere more gradually with this feedback activation loop than thrombin inhibitors, thereby achieving a better balance between haemostasis and prevention of thrombosis. In this study, we compared the effects of TAK-442, a novel FXa inhibitor, versus ximelagatran, a thrombin inhibitor, on FV-mediated positive feedback, venous thrombosis and bleeding. In normal plasma, TAK-442 delayed the onset of tissue factor-induced thrombin generation and prolonged prothrombin time (PT) with more gradual concentration-response curve than melagatran, the active form of ximelagatran. The effect of melagatran on the onset of thrombin generation decreased in an FVa-concentration-dependent manner in FV-deficient plasma supplemented with FVa. Furthermore, in FV-deficient plasma, the PT-prolonging potency of melagatran was markedly increased with a change in its concentration-response curve from steep to gradual. In the rat venous thrombosis model, TAK-442 (10 mg/kg, p.o.) prevented thrombus formation by 55% with 1.2 times prolongation of PT; a similar effect was observed in ximelagatran-treated (3 mg/kg, p.o.) rats. TAK-442 at 100 mg/kg prolonged PT by only 2.1 times with no change in bleeding time (BT), whereas ximelagatran at 10 mg/kg prolonged PT by 3.9 times and significantly increased BT. These results suggest that the differential effects of the two agents on FV-mediated amplification of thrombin generation may underlie the observation of a wider therapeutic window for TAK-442 than for ximelagatran.

Topics: Administration, Oral; Animals; Anticoagulants; Antithrombins; Azetidines; Benzylamines; Blood Coagulation; Disease Models, Animal; Dose-Response Relationship, Drug; Factor V; Factor Xa; Factor Xa Inhibitors; Feedback, Physiological; Hemorrhage; Humans; Male; Phospholipids; Prothrombin Time; Pyrimidinones; Rats; Rats, Sprague-Dawley; Risk Assessment; Sulfones; Thrombin; Thromboplastin; Venous Thrombosis

Several new oral anticoagulants are currently investigated in phase III programmes, mainly with inhibition of factor Xa or thrombin as their pharmacological target. Advantages are expected with these new drugs compared with vitamin K antagonists, but one potential drawback is the lack of specific antidotes. During the clinical studies with ximelagatran, an oral direct thrombin inhibitor withdrawn due to hepatic side effects, investigators were instructed to manage bleedings with routine measures. We have retrospectively tried to assess whether this was sufficient or whether there was a need for reversal strategies. The study population consisted of patients with major bleedings in three long-term studies (104 ximelagatran, 155 warfarin). All individual patient narratives were reviewed with respect to management of the bleeding. Complementary data were retrieved from the data-based case report forms. Approximately, two of three of the patients in both groups were subject to some kind of treatment. One-third (1/3) in both groups had transfusions documented and/or received specific medication. Vitamin K was given more often to warfarin patients. Two ximelagatran patients received prothrombin complex (four-factor concentrate), but one was a patient with a severe hepatopathy suspected to be drug-induced. Overall, the case descriptions did not reveal any apparent differences in the course of events between groups. We found no indications that the lack of an antidote posed a clinical problem in patients treated with ximelagatran as compared with warfarin. The relatively short half-life of melagatran, the active metabolite of ximelagatran, may have contributed to these results.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Azetidines; Benzylamines; Blood Transfusion; Disease Management; Female; Hemorrhage; Humans; Male; Middle Aged; Retrospective Studies; Thrombin; Treatment Outcome; Vitamin K; Warfarin

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

Anticoagulant therapy plays an important role in current medical practice. The main types of anticoagulant agents are: heparins, hirudins and vitamin K antagonists. None of the drugs used as anticoagulants meet the criteria of an ideal anticoagulant because they have side effects and they interact with other compounds. The main side effect of anticoagulant therapy is bleeding. The choice of a certain anticoagulant is made by the doctor based on the clinical context and also on the desired effect.

Topics: Anticoagulants; Azetidines; Benzylamines; Fondaparinux; Hemorrhage; Heparin; Hirudins; Humans; International Normalized Ratio; Polysaccharides; Thrombocytopenia; Vitamin K; Warfarin

The impact of prothrombotic abnormalities on the risk of recurrent venous thromboembolism (VTE) and bleeding in patients receiving long-term anticoagulation remains unclear. This analysis evaluated the influence of potential prothrombotic risk factors (antithrombin, protein C, protein S, factor V Leiden mutation, prothrombin gene G20210A mutation, cardiolipin antibodies, number of risk factors) on the risk of recurrent VTE or bleeding during treatment with oral ximelagatran (24 mg twice daily) or placebo for 18 months [THRombin Inhibitor in Venous thromboEmbolism (THRIVE) III trial]. Of the 1223 patients in the intention-to-treat population, prothrombotic state was analysed in 559 patients receiving ximelagatran and 540 patients receiving placebo. It is possible that patients at a high risk of recurrent VTE were poorly represented in this analysis because of selection bias. Prothrombotic risk factors were reported in 41% of patients (8% had > or = 2 factors). No significant interactions were found between ximelagatran treatment and potential prothrombotic risk factors for the risk of recurrent VTE or bleeding by Cox proportionate hazard modelling. There was no clear evidence for a higher risk of recurrent VTE or bleeding across subgroups according to the potential prothrombotic factors analysed in this study.

Topics: Antibodies, Anticardiolipin; Anticoagulants; Antithrombins; Azetidines; Benzylamines; Biomarkers; Blood Coagulation Tests; Ethnicity; Europe; Factor V; Hemorrhage; Humans; Proportional Hazards Models; Protein S; Recurrence; Risk; Thromboembolism; Thrombophilia; Treatment Outcome

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

The antithrombotic and bleeding properties of the oral direct thrombin inhibitor ximelagatran and of warfarin were investigated in an experimental venous thrombosis and bleeding model in anaesthetized rats. Rats were randomized to receive ximelagatran (1-20 micromol/kg), warfarin (0.20-0.82 micromol/kg), or vehicle (tap water) once daily orally for 4 days before surgery. Thrombosis was induced by partial stenosis and application of ferric chloride to the wall of the abdominal vena cava under anaesthesia. Sixty minutes after thrombus induction, rats were sacrificed, thrombi harvested, and their fresh weight determined. Bleeding was determined as haemoglobin in fluid collected from the abdominal cavity. Blood samples were taken before thrombus induction and sacrifice for determination of coagulation parameters and plasma concentrations of melagatran, the active form of ximelagatran. Ximelagatran and warfarin dose-dependently reduced thrombus formation. The highest doses of ximelagatran and warfarin almost completely prevented thrombus formation; however, the increase in bleeding (versus vehicle) was significantly lower with the highest dose of ximelagatran than with the highest dose of warfarin. The oral direct thrombin inhibitor ximelagatran is thus as at least as effective as warfarin in the prevention of thrombus formation in this animal model, but with a wider separation between antithrombotic effects and bleeding.

Topics: Animals; Azetidines; Benzylamines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Glycine; Hemorrhage; Male; Rats; Rats, Sprague-Dawley; Venae Cavae; Venous Thrombosis; Warfarin

Therapy for venous thromboembolism (VTE) currently involves a minimum of 3 months of anticoagulation. After cessation of therapy, however, recurrent venous thrombosis occurs at rates of 6 to 9% per year. Clinical trials have demonstrated the benefits of extending anticoagulation beyond 3 months for the prevention of recurrent VTE events. Despite this, many eligible patients do not receive the required thromboprophylaxis and the incidence of recurrent VTE remains too high for a preventable condition. A reason for failure to use prophylaxis is the fear of bleeding complications with current oral anticoagulants such as warfarin. Warfarin has an unpredictable pharmacokinetic profile and a variable dose-response relationship that requires frequent coagulation monitoring and dose adjustments to maintain a target intensity that is both safe and effective. Alternative strategies for long-term prophylaxis, which may potentially provide more consistent anticoagulant responses and reduce coagulation monitoring requirements, include the use of low-molecular-weight heparin (LMWH), treatment with warfarin at a lower intensity, and the introduction of novel anticoagulants. The long-term use of LMWH has been found to be a particularly favorable treatment option for cancer patients in whom it is difficult to control the intensity of anticoagulation. In clinical trials, LMWH significantly reduced the risk of recurrent VTE without increasing bleeding risk. The parenteral administration of the LMWHs, however, is a drawback for long-term use in the outpatient setting. A clinical trial assessing the efficacy and safety of long-term low-intensity warfarin treatment found this therapy to be better than placebo, but another study showed that conventional intensity warfarin was significantly more efficacious than low-intensity warfarin. New therapies in development that may offer improved safety-efficacy profiles are the synthetic pentasaccharides fondaparinux and idraparinux and the oral direct thrombin inhibitor ximelagatran. Parenterally administered fondaparinux has been shown to be as effective as LMWH for the acute treatment (5 to 7 days) of symptomatic deep vein thrombosis. Idraparinux, with once-weekly parenteral dosing, is currently being assessed in phase III clinical trials for the long-term secondary prevention of VTE. Ximelagatran is the first oral agent in the new class direct thrombin inhibitors. With a fast onset of action and oral administration, ximelagatran is a

Topics: Anticoagulants; Azetidines; Benzylamines; Chemical and Drug Induced Liver Injury; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Myocardial Ischemia; Oligosaccharides; Polysaccharides; Recurrence; Thrombin; Time Factors; Venous Thrombosis; Warfarin

Topics: Anticoagulants; Antidotes; Antifibrinolytic Agents; Azetidines; Benzylamines; Drug Design; Estrogens; Forecasting; Hemorrhage; Hemostatics; Humans; Plasma; Platelet Aggregation Inhibitors; Platelet Transfusion; Transfusion Reaction

Topics: Administration, Oral; Aged; Anticoagulants; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Female; Hemorrhage; Humans; Male; Thrombin; Venous Thrombosis; Warfarin