Novel antithrombotic agents: indirect synthetic inhibitors of factor Xa and direct thrombin inhibitors. Evidences from clinical studies

The optimal drugs employed in the antithrombotic treatment and prophylaxis have ideally been suggested to have high efficacy and safety and to be easy to use as regards the administration route and the fashion of monitoring the anticoagulant effect. A number of agents are under development in order to improve such requirements. Among them, the present review is focussed on a selective factor Xa inhibitor (pentasaccharide fondaparinux) and the direct thrombin inhibitors now available on a clinical ground. Fondaparinux is the first of a new class of selective antithrombin-dependent factor Xa inhibitors; it does not interact with plasma proteins other than antithrombin, leading to a predictable pharmacokinetics, which renders monitoring and dose adjustment unnecessary. The efficacy and safety of fondaparinux has been assessed in a number of clinical trials. In patients undergoing major orthopaedic surgery, a 2.5 mg s.c administration once daily induced a 50% average relative risk reduction for overall venous thromboembolism in comparison with enoxaparin but also an increased rate of major bleeding. Parenteral direct thrombin inhibitors include hirudin, bivalirudin and argatroban. these inhibitors have been studied in patients with coronary heart disease. In particular, in patients undergoing percutaneous coronary interventions, bivalirudin showed equivalent or higher efficacy but lower bleeding in comparison with unfractionated heparin. Another series of molecules capable of inhibiting thrombin is derived from the site of fibrinogen to which thrombin binds. Inogatran and melagatran have a low bioavailability when given orally, whereas the chemically modified prodrug ximelagatran has a higher bioavailability. Ximelagatran is safe and effective at least as low molecular weight heparin in patients undergoing major orthopaedic surgery and is safe and effective also in prevention of recurrence in patients with venous thromboembolism or myocardial infarction; ximelagatran is more effective than oral anticoagulants in prevention of arterial embolism due to atrial fibrillation, with comparable safety.     

Bivalirudin: a new approach to anticoagulation

Bivalirudin is one of the first of a new class of anticoagulants known as direct thrombin inhibitors. These drugs are able to overcome many of the shortcomings of traditional heparin anticoagulation by virtue of this unique mechanism of action. Bivalirudin is a semisynthetic derivative of hirudin, a modified component of leech saliva. Hirudin has been plagued by bleeding complications, likely due to its high affinity for thrombin. Bivalirudin has lower thrombin affinity than hirudin and therefore is believed to be a much safer compound. Bivalirudin has been shown to be a very effective anticoagulant in laboratory models, though its clinical efficacy remains to be fully proven. Bivalirudin has been studied in the setting of coronary angioplasty, unstable angina, and acute myocardial infarction and has shown some promise in many of these settings, particularly in preventing complications of percutaneous coronary interventions. Bivalirudin has consistently shown less major bleeding compared with standard heparin, although limitations in study methodologies somewhat hinder an accurate interpretation of this finding. Larger-scale studies are indicated and are currently being performed, the results of which will more definitively define the role of bivalirudin for the treatment of cardiovascular disease.     

Direct thrombin antagonists

BACKGROUND: Inhibiting thrombin as a key enzyme of the coagulation cascade is therapeutically useful in thromboembolic diseases. In coronary thrombosis, direct thrombin inhibitors promise to be useful for an efficacious therapy. Hirudin and recombinant or synthetic mimetics like hirulog, argatroban and melagatran have proven their efficacy in clinical studies. CONCLUSION: Therapy with direct thrombin inhibitors such as hirudin and analogous substances reduces coronary events. Moreover, the agents are useful for therapy of thromboembolic diseases, especially in the case of heparin induced thrombocytopenia type II.     

Oral antithrombins and the future of antithrombotic therapy

The coagulation cascade leads, via thrombin activation, to the formation of fibrin (from its precursor fibrinogen) and platelet thrombus. Several drugs are able to interfere with some of the enzymatic factors involved in thrombin activation, but thrombin inhibitors (heparin, hirudin and hirulog [bivalirudin]) are of particular interest because they disrupt the coagulation cascade by acting upon one of its final steps. Among the thrombin inhibitors, oral antithrombins (ximelagatran) appear to hold great promise for the control of thrombogenicity in a number of clinical contexts. Oral antithrombins do not require the participation of cofactors to exert their action, and in contrast to thrombin inhibitors administered parenterally, they bind specifically to the active site of thrombin without interfering with other portions of the molecule. Their specificity makes these drugs safe and obviates the need to monitor coagulability. Moreover, they show a low rate of interaction with other drugs or with foods, and the response to fixed doses is predictable. A number of clinical studies have investigated antithrombins for prophylaxis prior to orthopedic surgery, in the prevention of cerebrovascular accidents associated with atrial fibrillation, and in the control of coronary artery disease. These studies have shown that antithrombins are superior to other habitually used treatment options. Surprisingly, their use in long-term studies has not been associated with an increased rate of bleeding events. Their interesting molecular characteristics and considerable therapeutic efficacy and safety suggest that oral antithrombins will in the near future become a valuable therapeutic option.     

Melagatran attenuates fibrin and platelet deposition in a porcine coronary artery over-stretch injury model.

Melagatran is the active form of the oral direct thrombin inhibitor, ximelagatran. The purpose of this study was to compare the effects of different doses of melagatran with heparin or placebo on platelet deposition and relative fibrin content after coronary angioplasty in pigs. After 125I-labelled fibrinogen and autologous 111Indium-labelled platelets had been infused a balloon injury was performed in the left anterior descending and the right coronary arteries. Pigs were randomized to receive either heparin 200 IU/kg bolus plus 20 IU/kg per h infusion (n = 7); melagatran 1 mg/kg bolus plus 0.33 mg/kg per h infusion (n = 7); melagatran bolus 0.5 mg/kg plus 0.17 mg/kg per h infusion (n = 7); melagatran 0.15 mg/kg bolus plus 0.05 mg/kg per h infusion (n = 6) or saline (n = 4). Seventy-five minutes after the angioplasty, the pigs were euthanized and the injured vessel segments were measured in a gamma counter. Compared with placebo, platelet deposition and relative fibrin content were reduced after both heparin and melagatran, in the latter case with a dose-response relationship. Melagatran reduced platelet deposition and relative thrombus size in a dose-dependent manner when compared with placebo after coronary angioplasty in pigs. No statistically significant difference between melagatran and heparin was found.     

Hirudin,a new therapeutic tool?

Summary Hirudin is the most potent natural inhibitor of thrombin known to date. It is gaining popularity as an anticoagulant now that recombinant and synthesized forms are available. It is a monospecific and co-factor-independent thrombin inhibitor with otherwise inert pharmacological properties. Being a surprisingly weak immunogen, its administration has exhibited no side effects, particularly on platelets. Bleeding complications are not to be expected at therapeutic doses. Effective anticoagulatory doses can be easily predicted and laboratory control is no problem. Application of hirudin or derivatives thereof may be indicated for: prophylaxis and treatment of postoperative venous thrombosis and diffuse microthrombosis; prevention of arterial thrombosis, especially in cardiac surgery; enhancement of fibrinolytic therapy and/or angioplasty to prevent reocclusion; extracorporeal circulation; and plastic surgery. Hirudin may be a particularly useful alternative anticoagulatory agent in patients sensitized to heparin or in patients with hereditary or acquired antithrombin III deficiency. However, whether hirudin is really an effective therapeutic tool and whether it can replace heparin in certain clinical indications can be judged only after extended clinical experience has been accumulated.     

Effects of ximelagatran,an oral direct thrombin inhibitor,r-hirudin and enoxaparin on thrombin generation and platelet activation in healthy male subjects

OBJECTIVES: The effects of ximelagatran, an oral direct thrombin inhibitor (DTI), recombinant hirudin (r-hirudin) and enoxaparin on thrombin generation and platelet activation were studied in humans. BACKGROUND: Recombinant hirudin (parenteral DTI) and enoxaparin (low molecular weight heparin) have been demonstrated to be clinically effective in acute coronary syndromes. Ximelagatran is currently under investigation for the prevention and treatment of thromboembolism. The shed blood model allows for the study of thrombin generation and platelet activation in humans in vivo. METHODS: This was an open-label, parallel-group study involving 120 healthy male volunteers randomized to receive one of three oral doses of ximelagatran (15, 30 or 60 mg), r-hirudin (intravenous) or enoxaparin (subcutaneous) at doses demonstrated to be clinically effective in acute coronary syndromes, or to serve as a control. Thrombin generation (prothrombin fragment 1+2 [F1+2] and thrombin-antithrombin complex [TAT]) and platelet activation (beta-thromboglobulin [beta-TG]) biomarkers were studied using a shed blood model involving blood collection from skin incisions made using standardized bleeding time devices. RESULTS: Oral ximelagatran, intravenous r-hirudin and subcutaneous enoxaparin rapidly and significantly (p < 0.05) decreased F1+2, TAT and beta-TG levels in shed blood, indicating inhibition of thrombin generation and platelet activation. Statistically significant concentration (melagatran, the active form of ximelagatran)-response relationships for F1+2 (p = 0.005), TAT (p = 0.005) and beta-TG (p < 0.001) levels, with IC(50)s of 0.376 (F1+2), 0.163 (TAT) and 0.115 (beta-TG) micromol/l, were detected. Melagatran showed dose-proportional pharmacokinetics with low variability. All drugs were well tolerated. CONCLUSIONS: Oral administration of the DTI ximelagatran resulted in a rapid inhibition of both thrombin generation and platelet activation in a concentration-dependent manner using a human shed blood model. The inhibition of thrombin generation by 60 mg ximelagatran was comparable to that observed with doses of r-hirudin and enoxaparin demonstrated to be effective for the treatment of acute coronary syndromes.     

Emerging anticoagulants: mechanism of action and future potential

Medical needs associated with diverse thromboembolic conditions are not fully met by currently available anticoagulants. Of those, unfractionated heparin (UFH) is gradually replaced by low molecular weight heparin (LMWH) for prevention and treatment of venous thromboembolism and acute coronary syndromes, along with supportive treatment with oral anticoagulants, such as warfarin derivatives. While generally effective these agents have several shortcomings involving compliance, delivery, efficacy and safety considerations in various disease settings, and for these reasons new anticoagulants are sought, to target more specifically the critical effectors and steps in the blood coagulation process, namely: (i) initiation, (ii) propagation and (iii) the phase of thrombin activity. The emerging agents that block tissue factor/factor VIIa-dependent initiation phase of the coagulation cascade, include: recombinant tissue factor pathway inhibitor (rTFPI), nematode anticoagulant peptide (NAPc2), active site-blocked factor VIIa (FVIIai) and TF targeting antibodies. Some of them are currently evaluated in clinical trials with promising results. Propagation phase of thrombus formation (e.g. the activity of factors IXa, Xa, VIIIa or Va) is targeted mainly by various indirect, direct and bimodal inhibitors, such as fondaparinux, indraparinux, tick anticoagulant peptide (TAP), antistatin (ANT) and antithrombin-heparin covalent complex (ATH), all endowed mostly with an anti-Xa activity. Although promising, some of these agents (TAP, ANT and ATH) have not progressed beyond animal testing while others (fondaparinux) was already assessed for prevention and treatment of venous thromboembolism and for treatment of arterial thrombosis. Lastly, inhibitors of thrombin activity are composed of either indirect (UFH, LMWH), or direct thrombin (FIIa) inhibitors including: hirudin, argatroban, melagatran, ximelagatran, dabigatran, and bivalirudin. These agents are either in advanced development or already approved for clinical use. Bimodal FIIa inhibitory activity of ATH was demonstrated in animal models of venous and arterial thrombosis, but is in need of further development. In conclusion, while some of these emerging anticoagulants, such as fondaparinux, idraparinux, ximelagatran and ATH appear to possess superior efficacy-safety profile, as compared to their conventional predecessors (UFH, LMWH and warfarin), their cost-effectiveness, side effects and antidote availability have to be considered. More importantly, coagulation factors that are targets of these inhibitory activities also affect coagulation independent processes, such as wound healing, inflammation, angiogenesis, mitogenesis and cell survival. Thus the consequences of both coagulation-dependent and -independent effects of new agents should be carefully considered before proper clinical indications are established.     

Direct thrombin inhibitors

Direct thrombin inhibitors interact with thrombin and block its catalytic activity on a wide range of substrates. Their action is in contrast to heparin and its derivatives, which inhibit thrombin and other coagulation serine proteases via antithrombin, and to the warfarin-type drugs that interfere with synthesis of the precursors of the coagulation serine proteases. There are three direct thrombin inhibitors approved for clinical use at present (lepirudin, bivalirudin, argatroban) and another in advanced clinical testing (melagatran/ximelagatran). The chemical structure, kinetics of thrombin inhibition, pharmacokinetics, and clinical use of each of these agents are discussed.     

Antithrombotic drugs in vascular medicine: a historical perspective

Many new antithrombotic and antiplatelet drugs have been developed that have markedly improved prophylaxis and treatment of thrombotic diseases. Clopidogrel, a potent new antiplatelet compound, is the first clinical alternative to aspirin for long-term oral treatment and prevention of arterial thrombosis. Another new, exciting category of antiplatelet compounds is the GPIIb/IIIa-antagonists, the first antiintegrins in clinical use and the most potent inhibitors of platelet aggregation. Low molecular weight heparins (LMWHs) are the quantitatively dominating group of new antithrombotics, which has replaced unfractionated heparin for the prophylaxis and treatment of venous thromboembolism. Current clinical evidence suggests that LMWHs might replace unfractionated heparin for the treatment and prophylaxis of atherothrombotic complications in acute coronary syndromes in the near future. Fondaparinux is the first synthetic pentasaccharide and a selective inhibitor of factor Xa with exciting clinical data; it could become an alternative LMWH for prophylaxis of arterial and venous thromboembolism in high-risk patients. The field of oral thrombin inhibitors is still dominated by the coumarins. However, much effort is being undertaken to develop new orally active drugs from which ximelagatran is currently the leading compound with a predicted better safety and efficacy profile. Alternatively, inhibitors of factor VIIa might be of interest as well. Open questions include, in particular, the possible individualization of drug therapy in dependence on the kind of disturbed platelet function or blood hypercoagulability, respectively.     

Bivalent direct thrombin inhibitors: hirudin and bivalirudin

Hirudin derivatives (e.g. lepirudin, desirudin) and hirudin analogues (e.g. bivalirudin) are bivalent direct thrombin inhibitors; that is, they bind to two distinct sites on thrombin-its active (catalytic) site and its fibrinogen-binding site (exosite 1). These bivalent binding properties contribute to their high affinity and high specificity for thrombin. This review compares the pharmacological properties of these agents, and describes studies of their efficacy and safety in diverse clinical settings such as immune heparin-induced thrombocytopenia, postoperative antithrombotic prophylaxis, and treatment of acute coronary syndrome. Certain disadvantages of hirudin, such as its predominant renal excretion and immunogenicity, have been overcome through development of the hirudin analogue, bivalirudin. Compared with hirudin derivatives, bivalirudin exhibits a shorter half-life (25 vs 80 minutes), predominant non-renal (enzymic) metabolism, and low immunogenicity. Further work is required to define the scope of clinical thrombosis problems that could benefit from these novel agents.     

Ximelagatran for treatment and prophylaxis of recurrent events in deep vein thrombosis.

The treatment of acute venous thromboembolism and prophylaxis of recurrent events with heparin/low molecular weight heparin followed by vitamin K antagonists is limited by several factors. Oral direct thrombin inhibitors (ODTIs) showed a better pharmacological activity and might be an alternative in the treatment of venous thromboembolism. The Thrombin Inhibition in Venous Thromboembolism (THRIVE) program performed some studies developing the ODTI ximelagatran for this indication, and it is presented in the overview. The aim of the THRIVE I study was the dose finding, and that of the THRIVE IV study the applicability in hemodynamic stabile pulmonary embolism. A prospective, randomized, double blind trial was performed to compare oral ximelagatran with enoxaparin/warfarin for a 6-month treatment of acute venous thrombosis (THRIVE II and V). A second double blind study compared ximelagatran with placebo over 18 months after a 6-month anticoagulant therapy of acute deep vein thrombosis. The efficacy and safety of treatment of patients with acute deep venous thrombosis who received 2 infinity 36 mg ximelagatran was not inferior to that of patients who received a conventional anticoagulant for prophylaxis of recurrent events over 6 months. Ximelagatran 2 infinity 24 mg significantly reduced recurrent thromboembolic events compared to placebo without increasing the risk for hemorrhage. A reversible symptomless increase of alanine aminotransferase occurs in 6% to 9.6% of patients between months 2 and 4. The results of the follow-up studies suggest that thromboembolic events may recur in patients with acute venous thromboembolism after termination of treatment with both vitamin K antagonists and ximelagatran.     

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.     

Mechanism of action of the oral direct thrombin inhibitor ximelagatran

Thrombin plays a central role in thrombus formation through its conversion of fibrinogen to fibrin and activation of platelets as well as amplifying its own generation by feedback activation via factors V, VIII, and XI. Consequently, thrombin represents a logical and promising target for therapeutic interventions against arterial and venous thromboembolic disorders. Ximelagatran is the first oral agent in the new class of direct thrombin inhibitors and is rapidly absorbed and bioconverted to the active moiety, melagatran, which inhibits fluid-phase and clot-bound thrombin with similar high potency. Binding to the active site of thrombin is direct and competitive and does not require the presence of co-factors. Inhibition of thrombin generation and platelet activation has been demonstrated in vitro with melagatran as well as ex vivo after oral administration of ximelagatran to healthy human volunteers. Oral ximelagatran dose dependently reduced the total thrombus area in an ex vivo flow chamber model of arterial thrombosis, reflecting the cumulative effect of inhibition of thrombin activity, thrombin generation, and platelet activation. Melagatran has also been shown to reduce thrombin-mediated inflammation in vitro. The combination of antithrombotic and anti-inflammatory activity with the practicality of oral dosing provided by ximelagatran represents an important new option for the treatment of arterial and venous thromboembolic disorders.     

Ximelagatran: a new oral anticoagulant

Although there have been many significant advances over the last 50 years with regards to anticoagulant therapy, warfarin remains the definitive standard for the long-term prevention of thromboembolic events in many patients at risk for these complications. Although effective, warfarin has a narrow therapeutic window, necessitating frequent laboratory monitoring for anticoagulant effect. Ximelagatran is an investigational anticoagulant that directly inhibits thrombin, unlike heparin or warfarin, which are indirect inhibitors. Although indirect thrombin inhibitors are mainly only effective at inhibiting circulating thrombin, direct thrombin inhibitors are able to inhibit both free and clot-bound thrombin, thereby producing more effective anticoagulation. Ximelagatran is the first orally available direct thrombin inhibitor to reach phase 3 clinical trials. Ximelagatran is a prodrug for the active metabolite melagatran, and has been demonstrated to have a relatively wide therapeutic window in terms of bleeding and antithrombotic effect compared with warfarin. Clinical studies have demonstrated ximelagatran to be comparable in efficacy to warfarin and low-molecular-weight heparins (LMWH) for prophylaxis of venous thromboembolism, comparable to warfarin for stroke prevention in the setting of atrial fibrillation, and, when combined with aspirin, possible more effective than aspirin alone at preventing major adverse cardiovascular events in patients with a recent myocardial infarction. Adverse effects with ximelagatran primarily involve bleeding complications, which are more frequent than with placebo, but appear comparable to those occurring with standard anticoagulant treatment (ie, warfarin and LMWH). Ximelagatran has also been demonstrated to cause transient increases in liver enzymes, the significance of which will need to be addressed in ongoing phase 3 studies. Should ongoing trials prove ximelagatran to have at least similar therapeutic efficacy and safety as warfarin, ximelagatran may become a first-line anticoagulant due to its ease of administration and lack of a need for drug monitoring. The results of these trials are eagerly awaited in helping to defining the place in therapy for this promising new agent.     

Hirudin: Its biology and clinical use

Over a century has passed since the anticoagulant properties of hirudin were identified. Our understanding of this unique and promising 65 amino acid polypeptide has grown steadily, allowing clinical experience to be gained. In acute myocardial infarction, hirudin has been associated with a higher incidence of early and sustained TIMI grade 3 flow, a higher rate of infarct-related artery patency at 18–36 hours with a decreased rate of reocclusion, and a lower incidence of in-hospital death and reinfarction as compared with heparin. Hirudin has also been associated with a stable level of anticoagulation and an acceptable hemorrhagic complication rate when given in carefully chosen doses. In acute coronary syndromes, the initial results indicate that hirudin can improve the resolution of coronary thrombus and reduce the incidence of recurrent ischemic events. Similarly impressive reductions in thrombotic complications and ischemia have been observed in the early balloon angioplasty experience. Promising results have also been seen with hirudin in preventing deep venous thrombosis following orthopedic surgery. The favorable effects of hirudin as compared with heparin in phase II clinical trials have prompted further investigation in two large phase III trials, TIMI 9 and GUSTO 2. It is hoped that these initial results can be confirmed and that hirudin can be proved to be a safe and effective treatment for thrombotic syndromes of the venous and arterial circulatory systems.     

Advances in anticoagulation therapy: the role of selective inhibitors of factor Xa and thrombin in thromboprophylaxis after major orthopedic surgery

A new generation of antithrombotic agents that target a single enzyme within the procoagulant cascade is making its way into mainstream clinical practice. Borrowing selectively from the properties of their parent anticoagulant, unfractionated heparin, as well as from those of peptide anticoagulants from reptile or insect venoms, designers of the new drugs have created targeted inhibitors of thrombin, factor Xa, or other specific factors in the procoagulant pathways. These new agents promise efficacy and safety profiles far more favorable than those of conventional anticoagulants for thromboprophylaxis after major orthopedic surgery and require no laboratory monitoring of drug efficacy in this setting. Ximelagatran, the oral "prodrug" of the direct thrombin inhibitor melagatran, is in phase III of clinical development. Clinical trials using various dosages of ximelagatran, sometimes preceded by subcutaneous melagatran, as thromboprophylaxis after total hip or knee replacement surgery have suggested efficacy equal to or better than that of warfarin and enoxaparin. The best dosing regimen and optimal timing of first dose for melagatran and ximelagatran remain to be determined, as do the mechanism and impact of drug disturbance of hepatic function. Fondaparinux, a selective, synthetic inhibitor of factor Xa, has been shown in large clinical trials to be superior to low-molecular-weight heparins and is approved as a fixed once-daily subcutaneous 2.5-mg dose for thromboprophylaxis for hip or knee replacement surgery and after hip fracture repair. Fixed-dose fondaparinux 2.5 mg initiated 6 to 8 hours after surgery achieved superior efficacy and comparable safety in head-to-head comparisons with enoxaparin for the prevention of venous thromboembolism after major orthopedic surgery. Fondaparinux is the only agent approved for use in hip fracture patients in the United States at this time and has recently gained approval for extended prophylaxis in this patient population.     

Hirudin in Acute Coronary Syndromes: When Cents Override Good Sense

Two large multicenter clinical trials comparing heparin with hirudin in the management of patients with acute coronary syndromes have recently been completed. Direct thrombin inhibition was reported to result in only a modest reduction in the incidence of primary endpoint in GUSTO IIb, and to be of no demonstrable benefit in TIMI 9b. However, closer examination of the performance of hirudin in these trials suggests it to have been harshly judged. Hirudin provided a consistently more reliable anticoagulant effect than heparin, was associated with a comparable risk of bleeding and minimal risk of allergy. Furthermore, direct thrombin inhibition was more effective in preventing events in patients with unstable angina and non-Q wave infarction, and resulted in a significant reduction in the incidence of reinfarction among all facets of the acute coronary syndromes. There was in addition a striking benefit of combining hirudin with streptokinase in patients with acute myocardial infarction. Based on these data, there is little doubt that hirudin rather than heparin should form the foundation on which to base future strategies for management of the acute coronary syndromes.     

Clinician Update: Direct Thrombin Inhibitors in Acute Coronary Syndromes

Antithrombotic therapy has become the cornerstone of the treatment for atherosclerotic cardiovascular disease. Unfractionated heparin (UFH) has been the thrombin inhibitor of choice for decades. UFH, however, has its deficiencies. To overcome these problems several direct thrombin inhibitors (DTIs) have been developed. These agents are capable of inactivating clot-bound thrombin more efficiently, and provide more predictable and safer anticoagulation in patients with of acute coronary syndromes (ACS). The initial studies of hirudin and bivalirudin in the clinical settings of acute myocardial infarction (AMI), unstable angina (UA) and percutaneous coronary interventions (PCI) conducted in the early 1990s proved to be disappointing. As the knowledge of more appropriate use of these drugs progressed, there is a renewed interest in DTIs. Herein we will review the clinical studies assessing hirudin, bivalirudin and argatroban in the settings of AMI, UA and PCI.     

Comparison of the oral direct thrombin inhibitor ximelagatran with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement: a phase 2 dose-finding study

BACKGROUND: Up to one third of patients who undergo total knee replacement develop deep vein thrombosis after surgery despite receiving low-molecular-weight heparin prophylaxis. Ximelagatran is a novel direct inhibitor of free and clot-bound thrombin. METHODS: We performed a randomized, parallel, dose-finding study of 600 adults undergoing elective total knee replacement at 68 North American hospitals to determine the optimum dose of ximelagatran to use as prophylaxis against venous thromboembolism after total knee replacement. Patients received either ximelagatran twice daily by mouth in blinded fixed doses of 8, 12, 18, or 24 mg or open-label enoxaparin sodium, 30 mg, subcutaneously twice daily, starting 12 to 24 hours after surgery and continuing for 6 to 12 days. We measured the 6- to 12-day cumulative incidence of symptomatic or venographic deep vein thrombosis, symptomatic pulmonary embolism, and bleeding. RESULTS: A total of 594 patients received at least 1 dose of the study drug; 443 patients were evaluable for efficacy. Rates of overall venous thromboembolism (and proximal deep vein thrombosis or pulmonary embolism) for the 8-, 12-, 18-, and 24-mg doses of ximelagatran were 27% (6.6%), 19.8% (2.0%), 28.7% (5.8%), and 15.8% (3.2%), respectively. Rates of overall venous thromboembolism (22.7%) and proximal deep vein thrombosis or pulmonary embolism (3.1%) for enoxaparin did not differ significantly compared with 24-mg ximelagatran (overall difference, -6.9%; 95% confidence interval, -18.0% to 4.2%; P=.3). There was no major bleeding with administration of 24 mg of ximelagatran twice daily. CONCLUSION: Fixed-dose, unmonitored ximelagatran, 24 mg twice daily, given after surgery appears to be safe and effective oral prophylaxis against venous thromboembolism after total knee replacement.