Bivalirudin: Pharmacology and Clinical Applications

Bivalirudin (Hirulog®, Angiomax®) is a specific, reversible and direct thrombin inhibitor with a predictable anticoagulant effect. It is cleared by both proteolytic cleavage and renal mechanisms, predominantly glomerular filtration. Bivalirudin inhibits both circulating thrombin and fibrin bound thrombin directly by binding to thrombin catalytic site and anion‐binding exosite I in a concentration‐dependent manner. Bivalirudin prolongs activated partial thromboplastin time, prothrombin time, thrombin time and activated clotting time (ACT). ACT levels with bivalirudin do not correlate with its clinical efficacy. Bivalirudin with a provisional GpIIb/IIIa inhibitor is indicated in elective contemporary percutaneous coronary intervention (PCI). In respect to combined ischemic and hemor‐rhagic endpoints of death, myocardial infarction, unplanned urgent revascularization and major bleeding during PCI (including subgroups of patients with renal impairment and diabetes) bivalirudin is not inferior to unfractioned heparin and planned GpIIb/IIIa inhibitors. In addition, bivalirudin has been consistently shown to have significantly less in‐hospital major bleeding than heparin alone or heparin in combination with‐a GpIIb/IIIa inhibitor. Bivalirudin appears to be also safe and effective during PCI in patients with heparin‐induced thrombocytopenia. Finally, data from PCI studies support the safety and efficacy of bivalirudin, although its direct randomized comparison with unfractionated heparin is lacking.     

Hirudin in acute coronary syndromes

Acute coronary syndromes are a major cause of morbidity and mortality in Western societies. The term describes a spectrum from unstable angina, the recently defined non-Q wave infarction (the Non ST-Elevation Myocardial Infarction [NSTEMI]), to acute transmural myocardial infarction. With regard to treatment, a series of recently published studies compared the specific direct thrombin inhibitor hirudin with standard unfractionated heparin. Initial small studies showed promising results and led to the initiation of large-scale clinical trials addressing patients with acute coronary syndromes. However, in these studies, an unacceptably high incidence of serious hemorrhagic complications prompted safety boards to stop trials. In those studies carried out according to the protocol, no significant clinical benefit of hirudin over standard heparin was proved. Here, hirudin has been shown to be equivalent to unfractionated heparin for the treatment of unstable coronary syndromes with or without ST elevation and as an adjunct to percutaneous coronary balloon angioplasty. Because of its narrow therapeutic window between clinical benefit and increased bleeding hazards, hirudin should be used cautiously. For patients with heparin-induced thrombocytopenia, hirudin is accepted as an important therapeutic alternative.     

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.     

Direct antithrombins: new perspectives in cardiovascular medicine

Thrombin converts fibrinogen to fibrin and is the most powerful activator of platelets thus playing a crucial role in arterial and venous thrombosis. The limitations of heparin, largely used in the therapy of arterial and venous thromboembolism, has prompted the development of new antithrombotic drugs, able to directly inhibit thrombin. They comprise hirudin, bivalirudin and argatroban, which are antithrombins for parenteral use, and the orally active ximelagatran which, once absorbed, is converted to the active compound melagatran. Hirudin is a polypeptide able to irreversibly block both the active site and the fibrin(ogen) binding site of thrombin; bivalirudin, a synthetic hirudin derivative, has the same binding sites of hirudin to thrombin but has a shorter pharmacological action and is safer for clinical use. Several clinical trials which tested these drugs in acute coronary syndromes, coronary angioplasty and venous thromboembolism. demonstrate that hirudin and bivalirudin are superior to heparin in significantly reducing cardiac major events. The advantage of hirudin and bivalirudin over heparin was also confirmed in adjuncts to thrombolytic therapy as well as in percutaneous angioplasty relating to thrombotic events but not to restenosis. Hirudin was also significantly better than both unfractionated heparin and low molecular weight heparin (LMWH) in the prophylaxis of venous thromboembolism in patients undergoing elective arthroplasty. Major bleeding associated to hirudin was not different from that observed with heparin. Preliminary data also indicate that melagatran/ximelagatran may be used in the prophylaxis of venous thromboembolism and in the prevention of arterial embolism in patients with non-valvular atrial fibrillation.     

Heparin management in acute myocardial infarction (AMI)

Antithrombotic agents have been shown to be beneficial in the setting of acute coronary syndromes, and as an adjunct to thrombolysis for acute myocardial infarction (AMI). The optimal type and dosing of antithrombotic drug, however, remains elusive. Heparin, the agent most commonly used, has several limitations, the most important of which may be its inability to inhibit clot-bound thrombin. Newer, direct thrombin inhibitors (such as hirudin) provide potent and predictable thrombin inhibition and are able to inhibit clot-bound thrombin. Both heparin and hirudin can carry a substantial risk of haemorrhage, however, and thrombin activity is likely to rebound after discontinuation of either agent. Further, the relationships of antithrombotic/thrombolytic dosing, measures of anticoagulation (such as APTT), and clinical outcomes are not always clear. Nonetheless, from the data available from large, randomised trials, intravenous heparin should remain a standard adjunct to thrombolytic therapy for AMI.     

Therapie des akuten Koronarsyndroms

Plaque rupture with consecutive formation of an intraluminal, platelet-rich thrombus is the central mechanism leading to critical reduction of coronary perfusion in the acute coronary syndrome. Current therapeutic strategies aim at the inhibition of activation of platelets and the coagulation cascade and the suppression of platelet aggregation and fibrin formation. The use of acetylsalicylic acid (ASA) is well established in the therapy of the acute coronary syndrome and its efficacy is documented in several large clinical studies. The results of a respective metaanalysis by the Antiplatelet Trialists' Collaboration are shown in Table 1. Further risk reduction has been achieved with the additional application of heparin during the early phase of treatment. Table 2 shows the results of the Montreal Heart Study of combined vs single drug treatment, and Figure 1 a metaanalysis by Oler et al. of combination therapy with heparin plus ASA compared to monotherapy with ASA. In the past, hirudin and analogues were not superior to heparin as adjunctive treatments to lysis in acute myocardial infarction, but bleeding complications were more frequent. In contrast, in the recently published OASIS-2 study, outcome in patients with unstable angina pectoris was significantly better with hirudin than with heparin. Several large studies have demonstrated at least equivalent efficacy of LMWHs compared to standard heparin. For the early phase of the acute coronary syndrome, the FRIC and ESSENCE studies have even demonstrated improved clinical outcome without increase in bleeding complications. However, in TIMI 11 and FRAXIS, long-term application of LMWH resulted in more bleeding complications and, in FRAXIS, in a trend to a worse clinical outcome. The use of GP-IIb/IIIa blockers, especially the chimeric antibody fragment abciximab, is well established in interventional cardiology. Figure 2 shows the mechanism of action of the GP-IIb/IIIa blockers on platelet aggregation. In addition, their use in conjunction with ASA and heparin in the acute coronary syndrome led to further significant reduction of cardiovascular events in several studies. For example, the reduction of events by abciximab in the CAPTURE-study is delineated in Table 3. The results obtained with several of the new competitive GP-IIb/IIIa receptor antagonists are shown in Table 4.     

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.     

Pharmacologic prevention of acute ischemic complications of coronary angioplasty

The risk of acute coronary occlusion following percutaneous transluminal coronary angioplasty (PTCA) has remained high despite the traditional use of heparin and aspirin. Interest has focused on newer strategies for preventing intracoronary thrombus formation, which is an important mechanism of abrupt vessel closure. Pretreatment with thrombolytic agents has failed vigorous testing in double-blind trials. Retrospective and observational studies have indicated that pretreatment with intravenous heparin is of benefit in patients with unstable symptoms, but prolonged infusion after angioplasty increases bleeding complications without improving outcomes. Subcutaneous heparin may be safer, but has not proved more effective. Oral dipyridamole has shown no advantage over aspirin, although there is evidence to suggest a benefit when given intravenously. Direct thrombin inhibitors (such as hirudin and hirulog) are associated with fewer early complications compared with heparin, but have yielded no apparent long-term benefit. The use of the antiplatelet drug ticlopidine is increasing, although long-term data are lacking. A great deal of recent interest has focused on newer antiplatelet agents, particularly the glycoprotein IIB/IIIa receptor inhibitor c7E3 Fab. In a large-scale trial, c7E3 significantly reduced the 30-day rate of mortality and cardiac events, and these benefits were maintained at 6 mo. This drug, unlike other antiplatelet agents, inhibits the final common pathway of platelet aggregation, which influences not only acute closure but has lasting effects for at least 6 mo. This may reflect a reduction in restenosis, although this remains to be proven. This article gives a brief overview of the pharmacologic agents available for the prophylaxis and treatment of acute ischemic complications of PTCA. Cathet. Cardiovasc. Diagn. 42:249–256, 1997.© 1997 Wiley-Liss, Inc.     

Efficacy of hirudin in reducing cardiovascular events in patients with acute coronary syndrome undergoing early percutaneous coronary intervention.

AIMS: Although hirudin is superior to unfractionated heparin for prevention of death, myocardial infarction, or refractory ischaemia in patients with non-ST-elevation acute coronary syndrome, it is not clear whether hirudin is also of benefit in acute coronary syndrome patients undergoing early percutaneous coronary intervention. METHODS AND RESULTS: In the OASIS 2 trial, 10 141 patients with non-ST-elevation acute coronary syndrome were randomized to 72 h of intravenous hirudin or unfractionated heparin. Percutaneous coronary intervention was performed at the discretion of the investigator. One hundred and seventeen patients underwent percutaneous coronary intervention within the first 72 h ("early percutaneous coronary intervention"). In patients undergoing early percutaneous coronary intervention, hirudin compared with unfractionated heparin was associated with a significantly lower incidence of death or myocardial infarction at 96 h (6.4% vs 21.4%, OR 0.30; 95% CI: 0.10-0.88) and 35 days (6.4% vs 22.9%, OR 0.25; 95% CI: 0.07-0.86). In the unfractionated heparin group, death or myocardial infarction was significantly higher at 35 days in patients undergoing early percutaneous coronary intervention compared with those managed conservatively (22.9% vs 7.3%, OR 3.14, P<0.001) but this early percutaneous coronary intervention-related hazard was not observed in hirudin-treated patients (6.4% vs 6.8%, OR 0.94 P=1.0). A time-dependent covariate for percutaneous coronary intervention was not significant in a Cox regression model, suggesting a similar treatment benefit with hirudin before and after percutaneous coronary intervention. After adjustment for percutaneous coronary intervention propensity, the benefits of hirudin remained significant. There were three major bleeds in patients undergoing early percutaneous coronary intervention, all in patients randomized to hirudin. CONCLUSION: In patients with non-ST-elevation acute coronary syndrome undergoing early percutaneous coronary intervention, a direct thrombin inhibitor such as hirudin may be more effective than heparin in reducing the incidence of ischaemic complications.     

Role of new anticoagulants as adjunctive therapy during thrombolysis

Procoagulant activity may persist during coronary thrombolysis and result in either delay in the time to recanalization or recurrent thrombosis. Although heparin and aspirin form the mainstay of current therapy, recurrent thrombosis occurs despite adjunctive heparin therapy during thrombolysis. Newer agents that inhibit thrombin by antithrombin III-independent mechanisms, or that inhibit earlier steps in the coagulation cascade, have been shown to be effective in the experimental preparation of coronary thrombolysis. Because heparin-antithrombin III is a relatively inefficient inhibitor of thrombin bound to fibrin, agents such as hirudin or small peptide inhibitors of the thrombin-active site appear to be more effective inhibitors of clot-associated thrombin activity. Inhibition of early steps in the coagulation cascade with the inhibitor of tissue factor-factor VIIa complex, or with activated protein C, also appears to be an effective anticoagulant strategy. In experimental preparations all of these agents have shown superiority in preventing recurrent thrombosis compared with heparin, and in some cases they appear to accelerate the rate of clot lysis.     

Hirudin in acute myocardial infarction

Summary The central role of thrombosis in the pathogenesis of acute myocardial infarction has led to intense interest in developing more effective thrombolytic-antithrombotic regimens. Hirudin is 65 amino acid polypeptide that binds in a 11 relationship with thrombin, thereby inhibiting the final step in the coagulation cascade. Hirudin has several potential advantages over the current antithrombin agent heparin: It is a direct inhibitor that does not require a cofactor, it has no known inhibitors that would attentuate its anticoagulant effects, and it can inhibit clot-bound thrombin, thereby achieving an antithrombotic effect at the site of potential rethrombosis. Initial clinical trials have shown promising results: Hirudin, as compared with heparin, provided a more consistent level of anticoagulation, as gauged by the activated partial thromboplastin time. As an adjunct to thrombolytic therapy in acute myocardial infarction, hirudin improved indices of coronary reperfusion and patency. Initial results with clinical end points, including death or myocardial infarction, also have shown favorable results for hirudin compared with heparin. In the first phases of the larger phase III trials, the rate of hemorrhagic events, including intracranial hemorrhage, was higher than expected in both the hirudin and heparin arms, indicating that a safety ceiling had been reached. The TIMI 9B and GUSTO IIb trials are using lower doses of intravenous hirudin and heparin, which should allow testing of the thrombin hypothesis: that more potent inhibition of thrombin will translate into improved clinical outcome for patients with acute MI.     

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.     

The TIMI 9b and GUSTO IIb Trials and the “Thrombin Hypothesis”

The "thrombin hypothesis" proposes that the clinical outcome of patients with unstable angina or acute myocardial infarction (MI) is related to the degree of thrombin inhibition, with greater inhibition resulting in improved outcome. Two recent trials (TIMI 9b and GUSTO IIb) tried to test this hypothesis by randomizing 15,000 patients with MI or unstable angina to a 3-to-5 day intravenous administration of either the powerful thrombin inhibitor hirudin, or standard heparin. In both studies, after 30 days, there was no significant difference in the rates of death or nonfatal infarction between the 2 treatment arms. More than one reason may explain these findings. In both trials the anticoagulant regimens were carefully tailored to prevent excessive bleeding complications and to achieve a predetermined level of efficacy, as measure by aPTT. It is possible that similar aPTTs and similar bleeding rates will result in similar clinical outcomes, regardless of the anticoagulant agent used. It is also possible that patients already receiving fibrinolytic drugs and aspirin did not derive such additional thrombolytic benefit from anticoagulants to compensate for the increased bleeding risk associated with their use. Finally, thrombin may not always play the crucial role that has been attibuted to it: marked thrombin generation may occur only in subgroups of patients, or as a secondary response to a primary trigger that fails to be antagonized by antithrombin therapy or that re-emerges after stopping treatment. The true role played by anticoagulants in the management of acute coronary syndromes is not clear from TIMI 9b or GUSTO IIb because neither study included a control group not receiving anticoagulants. These trials, however, raise important issues that deserve further investigation: for example, the definition of what drives thrombin generation in patients with acute coronary syndromes and the identification of possible subgroups of patients deriving true clinical benefit from anticoagulant therapy.     

Hirudin and hirudin fragments]

Hirudin is a potent and specific thrombin inhibitor: compared with heparin thrombin inhibition occurs directly and does not require the presence of plasma cofactors. Recombinant hirudin is well tolerated in animals and in healthy volunteers. Its clearance half-life after IV administration range from 1 to 2 hours and its bioavailability after subcutaneous administration reaches 75%. In most of the experimental models the ratio of the haemorrhagic side effect against the antithrombotic efficacy is satisfactory. Hirudin analogs are mono or bivalent according to their recognition site on thrombin. Bivalent derivatives (Hirulogs) have been mostly evaluated: they exhibit pharmacologic properties similar experimental to that of recombinant hirudin and have been successfully used in several thrombosis models and in healthy volunteers. Taking into account these data the most appropriate use for hirudin and hirudin derivatives should be clinical situations where the role of thrombin is important or which are only partially controlled by heparin therapy.     

Bivalirudin versus heparin and glycoprotein IIb/IIIa inhibition among patients with renal impairment undergoing percutaneous coronary intervention (a subanalysis of the REPLACE-2 trial)

Among patients who undergo percutaneous coronary intervention, renal impairment is associated with an excessive risk of bleeding and ischemic events. Bivalirudin provides comparable suppression of ischemic events with a decrease in bleeding events compared with heparin and glycoprotein IIb/IIIa inhibition. We examined the relation between adverse events, renal impairment, and antithrombotic therapy within a randomized comparison. The Second Randomized Evaluation in PCI Linking Bivalirudin to Reduced Clinical Events per-protocol study population was assessed. Renal function was defined as calculated creatinine clearance <60 ml/min. Events within the overall study population and within each study arm were assessed. Thirty-day events by renal function were compared by chi-square test and logistic regression. Late mortality was compared by log-rank test. Interaction analyses were performed. Among 5,710 patients, renal impairment was associated with increased ischemic events (hazard ratio 1.45, 95% confidence interval 1.13 to 1.88, p = 0.004), bleeding complications (hazard ratio 1.72, 95% confidence interval 1.06 to 2.80, p = 0.028), and excessive 12-month mortality (hazard ratio 3.85, 95% confidence interval 2.67 to 5.54, p <0.001). Bivalirudin provided suppression of ischemic events that was comparable to heparin and glycoprotein IIb/IIIa inhibition regardless of renal impairment. Fewer bleeding events with bivalirudin were also evident irrespective of renal dysfunction. No interaction between treatment assignment, bleeding or ischemic complications, and renal impairment was observed. The safety and efficacy of bivalirudin compared with heparin and planned glycoprotein IIb/IIIa inhibition in this high-risk group are comparable and consistent with the results of the overall trial.     

Effect of bivalirudin on coagulation function and prognosis in patients with coronary artery disease and renal insufficiency undergoing PCI

Background Renal insufficiency is associated with an excess risk of vascular complications and bleeding events in patients who undergo PCI. Heparin is still used commonly for PCI, but the bleeding complications is high. However, Bivalirudin is similar to heparin in ischemic complications and superior to the bleeding complications. Methods A total of 181 patients with coronary artery disease and renal insufficiency were randomly assigned two treatment groups: Bivalirudin(n = 90), unfractionated heparin(n = 91). Activated clotting time(ACT)was determined in patients at 5 min after undergoing PCI at the end of operation immediately(stopping drug immediately), and 30 min,1 h, 2 h after stopping drug. Activated partial thromboplastin time(APTT), thrombin time(TT), proth rombin time(PT), fibrinogen(FIB) index were measured before treatment, 6 h, 24 h and 72 h after the treatment through an automated coagulation analyzer. Platelet count was monitored before treatment and24 h after treatment. The end points were the proportion of net adverse clinical events(NACE)and stent thrombosis at 30 days. Results The use of bivalirudin was associated with a statistically significant higher at 5 min after treatment, end of operation immediately(P 0.05),with statistically significant lower at 1h after stopping drug, 2h after stopping drug(P 0.05). There were no differences between patients at blood coagulation and platelet after operation(P 0.05), no differences in the 30-day rates of stent thrombosis(0% vs. 0%, P = 1). Eleven patients(12.22%) treated with bivalirudin vs. 24(26.38%) treated with heparin experienced an adverse clinical events at 30 days(relative risk[RR], 0.46; 95%CI, 0.36-0.56; P 0.025). There were no differences in the major adverse cardiac or cerebral event at the 30-day end point(1.11% vs. 2.20%, P 0.05). The bleeding at 30 days was abated by using bivalirudin compared with unfractionated heparin(11.11% vs. 24.18%, P 0.05). Conclusions Compared with the unfractionated heparin, bivalirudin is more quickly in taking effect and recovering and more efficient for PCI in patients with coronary artery disease and renal insufficiency.     

Intracoronary macrothrombus formation during percutaneous coronary intervention despite optimal activated clotting time using bivalirudin--a case report

The occurrence of intracoronary thrombus during percutaneous coronary intervention (PCI) is a well-known complication. It has been estimated that it complicates approximately 6% of all coronary procedures. Patients at highest risk for this complication include those with acute ischemic syndromes or with angiographically apparent thrombus. Since the development of PCI, intravenous unfractionated heparin (UFH) has remained the primary antithrombotic therapy for the prevention of periprocedural ischemic complications. The availability of a rapid "point of care' test for dose individualization (the activated clotting time [ACT]) has facilitated this process. Other forms of antithrombotic therapies such as direct thrombin inhibitors or low-molecular-weight heparin have been proposed as more effective anticoagulants during PCI. Bivalirudin is a direct thrombin inhibitor proven to decrease post-PCI ischemic complication rate compared with UFH and have a lower vascular complication rate compared with glycoprotein IIb/IIIa receptor antagonists. We herein report a case of acute macrothrombus formation during PCI despite adequate ACT achieved with bivalirudin.     

Direct thrombin inhibitors as adjuncts to thrombolytic therapy

Thrombolytic therapy aims to achieve rapid and sustained Infarct-related artery patency, although this results in a procoagulant state. Heparin has limitations as an antithrombin agent, which has led to clinical investigation of alternative agents. Direct thrombin inhibitors, as adjuncts to thrombolytic therapy, have been shown to increase 90 minute Thrombolysis in Myocardial Infarction (TIMI)-3 flow rates and reduce reinfarction, when compared with heparin. These results have been achieved with an acceptable risk of bleeding, when administered in appropriate dosing regimens. When the direct thrombin inhibitor hirudin was administered at a mean of 34 and 50 minutes after thrombolytic therapy in large clinical trials, there was no reduction in mortality. In contrast, in several angiographic studies, direct thrombin inhibitors were administered prior to thrombolysis. The effect on mortality of the administration of hirulog prior to streptokinase is currently being examined.     

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.