The therapeutic potential of ximelagatran to become the anticoagulant of choice in medicine: a review of recently completed clinical trials

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.     

The therapeutic potential of ximelagatran to become the anticoagulant of choice in medicine: a review of recently completed clinical trials

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.     

More light at the end of the tunnel - apixaban in atrial fibrillation

INTRODUCTION: Subjects with atrial fibrillation are at risk of thromboembolic events. The vitamin K antagonists (e.g., warfarin) are useful at preventing coagulation in atrial fibrillation, but are difficult to use. One of the FXa inhibitors, oral apixaban, has been tested as an anticoagulant in atrial fibrillation. AREAS COVERED: In ARISTOTLE (Apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation) apixaban was compared to warfarin in subjects with atrial fibrillation, and shown to cause a lower rate of stroke or systemic embolism and of major bleeding, than warfarin. In the AVERROES (Apixaban versus acetylsalicylic acid [ASA] to prevent stroke in atrial fibrillations patients who have failed or are unsuitable for vitamin K antagonist treatment) trial, stroke or systemic embolism occurred less often with apixaban than aspirin, whereas the occurrence of major bleeding was similar in the groups. EXPERT OPINION: Apixaban is much easier for subjects with atrial fibrillation to use than warfarin, as it does not require regular monitoring by a health professional, with dosage adjustment. In addition to replacing warfarin in subjects with atrial fibrillation who are unable or not prepared to use warfarin, apixaban has the potential to replace warfarin more widely in the prevention of thromboembolism in subjects with atrial fibrillation.     

Ximelagatran--recent comparisons with warfarin

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

Direct thrombin inhibitors for treatment of heparin induced thrombocytopenia, deep vein thrombosis and atrial fibrillation

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

Ximelagatran, the new oral anticoagulant: would warfarin survive the challenge?

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.     

More light at the end of the tunnel – apixaban in atrial fibrillation

Introduction: Subjects with atrial fibrillation are at risk of thromboembolic events. The vitamin K antagonists (e.g., warfarin) are useful at preventing coagulation in atrial fibrillation, but are difficult to use. One of the FXa inhibitors, oral apixaban, has been tested as an anticoagulant in atrial fibrillation.

Areas covered: In ARISTOTLE (Apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation) apixaban was compared to warfarin in subjects with atrial fibrillation, and shown to cause a lower rate of stroke or systemic embolism and of major bleeding, than warfarin. In the AVERROES (Apixaban versus acetylsalicylic acid [ASA] to prevent stroke in atrial fibrillations patients who have failed or are unsuitable for vitamin K antagonist treatment) trial, stroke or systemic embolism occurred less often with apixaban than aspirin, whereas the occurrence of major bleeding was similar in the groups.

Expert opinion: Apixaban is much easier for subjects with atrial fibrillation to use than warfarin, as it does not require regular monitoring by a health professional, with dosage adjustment. In addition to replacing warfarin in subjects with atrial fibrillation who are unable or not prepared to use warfarin, apixaban has the potential to replace warfarin more widely in the prevention of thromboembolism in subjects with atrial fibrillation.     

Review of the rebound phenomenon in new anticoagulant treatments

BACKGROUND: The launch of new anticoagulant treatments has sparked debate as to the optimal drug to use for primary prevention of venous thromboembolism (VTE) in major orthopaedic surgery, for the treatment of VTE, and for stroke prevention in atrial fibrillation, taking into account both efficacy and tolerability. Newer drugs such as fondaparinux and ximelagatran have shown improvements in short-term efficacy or convenience, but such effects may be offset by reduced tolerability. They also raise the question of a possible delayed increase in thromboembolic events after these drugs are stopped, the so-called 'rebound effect'. OBJECTIVE: To review pharmacological and clinical data describing the rebound effect associated with new and standard anticoagulant drugs. RESEARCH DESIGN AND METHODS: Computerized searches, covering the period 1960-2005 for the historical background and physiopathology review, and from 1999 to 2005 for the clinical trial analysis, were performed on BIOSIS, PubMed and clinicaltrials.gov databases. The terms 'rebound', 'anticoagulant', and 'heparin' were used. Only articles written in English were reviewed. Articles with drug interactions from other therapeutic classes or types of vascular surgery and commentary articles were excluded. RESULTS: Available data in relation to a possible rebound phenomenon following cessation of active treatment are very limited. Results coming mainly from orthopaedic surgery trials suggest an increased rate of venous or arterial thromboembolic events with newer anticoagulants, compared with standard anticoagulant therapy. An increase in the rate of serious arterial adverse events has, for example, been observed in VTE patients treated with ximelagatran relative to those receiving warfarin/placebo (short-term exposure: 0.75% vs 0.26%, p < 0.05; long-term exposure: 1.70% vs 0.70%, p 相似文献   

Apixaban,an oral direct Factor Xa inhibitor: awaiting the verdict

For the last half-century, despite its many limitations warfarin has been the mainstay of treatment for patients with venous and arterial thromboembolic disease. During the past decade, a number of new oral anticoagulant agents have been developed that may offer an alternative to warfarin. Emerging data suggest that Factor Xa may be a target for inhibition. Apixaban is one such agent. It is a potent, selective, reversible, and orally bioavailable FXa inhibitor that demonstrates antithrombotic efficacy, with a favorable pharmacokinetic profile. At present, the safety and efficacy of apixaban for the prophylaxis and treatment of venous thromboembolism is being evaluated in Phase II and Phase III trials involving nearly 25,000 patients. Trials are also underway involving over 20,000 patients for secondary prevention after acute coronary syndromes and the prevention of stroke in patients with non-valvular atrial fibrillation. This review article discusses the discovery, pharmacokinetics, attributes, and current clinical trials of this emerging drug.     

Review of the rebound phenomenon in new anticoagulant treatments

ABSTRACT

Background: The launch of new anticoagulant treatments has sparked debate as to the optimal drug to use for primary prevention of venous thromboembolism (VTE) in major orthopaedic surgery, for the treatment of VTE, and for stroke prevention in atrial fibrillation, taking into account both efficacy and tolerability. Newer drugs such as fondaparinux and ximelagatran have shown improvements in short-term efficacy or convenience, but such effects may be offset by reduced tolerability. They also raise the question of a possible delayed increase in thromboembolic events after these drugs are stopped, the so- called “rebound effect”.

Objective: To review pharmacological and clinical data describing the rebound effect associated with new and standard anticoagulant drugs.

Research design and methods: Computerized searches, covering the period 1960–2005 for the historical background and physiopathology review, and from 1999 to 2005 for the clinical trial analysis, were performed on BIOSIS, PubMed and clinicaltrials.gov databases. The terms ‘rebound’, ‘anticoagulant’, and ‘heparin’ were used. Only articles written in English were reviewed. Articles with drug interactions from other therapeutic classes or types of vascular surgery and commentary articles were excluded.

Results: Available data in relation to a possible rebound phenomenon following cessation of active treatment are very limited. Results coming mainly from orthopaedic surgery trials suggest an increased rate of venous or arterial thromboembolic events with newer anticoagulants, compared with standard anticoagulant therapy. An increase in the rate of serious arterial adverse events has, for example, been observed in VTE patients treated with ximelagatran relative to those receiving warfarin/placebo (short-term exposure: 0.75% vs 0.26%, p < 0.05; long-term exposure: 1.70% vs 0.70%, p ≤ 0.1).

Conclusions: Further clinical trials or meta-analyses are needed before we can determine whether the unexpected thromboembolic events found with newer anticoagulants can be linked to a rebound effect on treatment cessation.     

Direct thrombin inhibitors for the prevention of venous thromboembolism after major orthopaedic surgery

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

慢性房颤华法令抗凝治疗的理想INR值探讨

目的:探讨慢性房颤华法令抗凝治疗的理想国际标准化比值(INR)。方法:对115例有血栓栓塞高危因素的慢性房颤患者给予华法令抗凝治疗,定期随访INR,同时观察治疗中发生的血栓栓塞和出血事件。结果:115例患者中有8例共10次发生血栓栓塞事件,7例7次发生与抗凝有关的出血事件,10次血栓栓塞事件中9次发生在INR<1.7,而所有的出血事件都发生在INR>3.5,INR 1.7～3.5时栓塞或出血发生率均较低。结论:INR 1.7～3.5是慢性房颤华法令抗凝治疗较理想的抗凝强度。     

Emerging anticoagulants

Warfarin, heparin and their derivatives have been the traditional anticoagulants used for prophylaxis and treatment of venous thromboembolism. While the modern clinician is familiar with the efficacy and pharmacokinetics of these agents, their adverse effects have provided the impetus for the development of newer anticoagulants with improved safety, ease of administration, more predictable pharmacodynamics and comparable efficacy. Research into haemostasis and the coagulation cascade has made the development of these newer anticoagulants possible. These drugs include the factor Xa inhibitors and IIa (thrombin) inhibitors. Direct and indirect factor Xa inhibitors are being developed with a relative rapid onset of action and stable pharmacokinetic profiles negating the need for close monitoring; this potentially makes them a more attractive option than heparin or warfarin. Examples of direct factor Xa inhibitors include apixaban, rivaroxaban, otamixaban, betrixaban and edoxaban. Examples of indirect factor Xa inhibitors include fondaparinux, idraparinux and idrabiotaparinux. Direct thrombin inhibitors (factor IIa inhibitors) were developed with the limitations of standard heparin and warfarin in mind. Examples include recombinant hirudin (lepirudin), bivalirudin, ximelagatran, argatroban, and dabigatran etexilate. This review will discuss emerging novel anticoagulants and their use for the prophylaxis and management of venous thromboembolism, for stroke prevention in nonvalvular atrial fibrillation and for coronary artery disease.     

Ximelagatran: an orally active direct thrombin inhibitor.

PURPOSE: The chemistry, pharmacology, pharmacokinetics, clinical efficacy, dosage and administration, contraindications, and adverse effects of ximelagatran are reviewed. SUMMARY: 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. CONCLUSION: Ximelagatran has shown promise as a possible alternative to warfarin and other anticoagulants but will require further study to ensure its safety.     

Ximelagatran: the first oral direct thrombin inhibitor

Oral anticoagulants are often prescribed for long-term prevention and treatment of venous or arterial thromboembolism. The only orally active anticoagulants currently available are the vitamin K antagonists. Although effective, they have a narrow therapeutic window and require routine coagulation monitoring to ensure that a therapeutic level has been achieved. Furthermore, genetic differences in metabolism and multiple food and drug interactions affect the anticoagulant response to vitamin K antagonists. These factors add to the need for routine coagulation monitoring, which is problematic for patients and physicians and costly for the healthcare system. Ximelagatran, the first oral direct thrombin inhibitor, was designed to overcome many of the drawbacks of vitamin K antagonists. Since it produces a predictable anticoagulant response, ximelagatran does not require coagulation monitoring. Phase III clinical trials have evaluated the efficacy and safety of ximelagatran for the prevention and treatment of venous thromboembolism and for the prevention of thromboembolic events in patients with atrial fibrillation. Focusing on ximelagatran, this review will discuss the appropriateness of thrombin as a target for new anticoagulants, compare and contrast direct and indirect thrombin inhibitors and describe the theoretical advantages of direct thrombin inhibitors. It will also review the pharmacology of ximelagatran, discuss the clinical trial results with ximelagatran and provide perspective on the advantages and potential limitations of ximelagatran.     

Ximelagatran: the first oral direct thrombin inhibitor

Oral anticoagulants are often prescribed for long-term prevention and treatment of venous or arterial thromboembolism. The only orally active anticoagulants currently available are the vitamin K antagonists. Although effective, they have a narrow therapeutic window and require routine coagulation monitoring to ensure that a therapeutic level has been achieved. Furthermore, genetic differences in metabolism and multiple food and drug interactions affect the anticoagulant response to vitamin K antagonists. These factors add to the need for routine coagulation monitoring, which is problematic for patients and physicians and costly for the healthcare system. Ximelagatran, the first oral direct thrombin inhibitor, was designed to overcome many of the drawbacks of vitamin K antagonists. Since it produces a predictable anticoagulant response, ximelagatran does not require coagulation monitoring. Phase III clinical trials have evaluated the efficacy and safety of ximelagatran for the prevention and treatment of venous thromboembolism and for the prevention of thromboembolic events in patients with atrial fibrillation. Focusing on ximelagatran, this review will discuss the appropriateness of thrombin as a target for new anticoagulants, compare and contrast direct and indirect thrombin inhibitors and describe the theoretical advantages of direct thrombin inhibitors. It will also review the pharmacology of ximelagatran, discuss the clinical trial results with ximelagatran and provide perspective on the advantages and potential limitations of ximelagatran.     

Clinical potential of oral direct thrombin inhibitors in the prevention and treatment of venous thromboembolism

Current antithrombotic therapies are associated with various practical limitations and risks that restrict their utility in the management of venous thromboembolism. The coagulation factor, thrombin, has been the focus of extensive investigation as a pharmacological target in efforts to improve the management of venous thromboembolism. Hirudin, desirudin, bivalirudin and argatroban are direct thrombin inhibitors that have been launched for limited indications as anticoagulants. Their usefulness for long-term prophylaxis is limited by a requirement for parenteral administration, restricted licensing and bleeding/tolerability profile. Ximelagatran--which, after oral administration, is rapidly converted to its active form, melagatran--is the first oral direct thrombin inhibitor and the first new oral anticoagulant to become available in 60 years. Clinical studies have shown that melagatran/ximelagatran, without coagulation monitoring, is effective and well tolerated for the prevention of venous thromboembolism after hip replacement and knee replacement surgery. Ximelagatran is also effective in the acute treatment of venous thromboembolism and long-term secondary prevention of recurrent venous thromboembolism, the prevention of stroke in patients with atrial fibrillation and in the prevention of cardiovascular events after myocardial infarction. Oral direct thrombin inhibitors have a promising role in the management of venous thromboembolism and other associated medical conditions.     

Ximelagatran--a promising new drug in thromboembolic disorders

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

Direct thrombin inhibitors

Heparins and vitamin K antagonists have been the primary agents used for anticoagulation in certain cardiovascular and thromboembolic diseases for over 50 years. However, they can be difficult to administer and are fraught with limitations. In response to the need for new anticoagulants, direct thrombin inhibitors (DTIs) have been developed and investigated for their utility in prophylaxis and treatment of venous thromboembolism (VTE), heparin-induced thrombocytopenia (HIT), acute coronary syndromes (ACS), secondary prevention of coronary events after ACS, and nonvalvular atrial fibrillation. Currently, four parenteral direct inhibitors of thrombin activity are FDA-approved in North America: lepirudin, desirudin, bivalirudin and argatroban. Of the new oral DTIs, dabigatran etexilate is the most studied and promising of these agents. This review discusses the clinical indications and efficacy of these direct thrombin inhibitors as well as future directions in anticoagulant therapy.