Direct Thrombin Inhibitors
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《新英格兰医药杂志》
Direct thrombin inhibitors (DTIs) are a new class of anticoagulants that bind directly to thrombin and block its interaction with its substrates. Some DTIs — such as recombinant hirudins, bivalirudin, and ximelagatran, either alone or in combination with melagatran — have undergone extensive evaluation in phase 3 trials for the prevention and treatment of arterial and venous thrombosis. The evidence concerning the clinical applicability of other DTIs, such as argatroban and dabigatran, is limited to phase 2 studies. Four parenteral DTIs have been approved by the Food and Drug Administration (FDA) in North America: hirudin and argatroban for the treatment of heparin-induced thrombocytopenia, bivalirudin as an alternative to heparin in percutaneous coronary intervention, and desirudin as prophylaxis against venous thromboembolism in hip replacement. This review discusses FDA-approved DTIs as well as those under evaluation in phase 2 or 3 clinical trials.
Mechanisms of Action
Coagulation Cascade and Generation of Thrombin
After injury to a vessel wall, tissue factor is exposed on the surface of the damaged endothelium. The interaction of tissue factor with plasma factor VII activates the coagulation cascade, producing thrombin by stepwise activation of a series of proenzymes (Figure 1). Thrombin is central in the clotting process: it converts soluble fibrinogen to fibrin; activates factors V, VIII, and XI, which generates more thrombin; and stimulates platelets. Furthermore, by activating factor XIII, thrombin favors the formation of cross-linked bonds among the fibrin molecules, stabilizing the clot. The coagulation cascade is regulated by natural anticoagulants, such as tissue factor pathway inhibitor, the protein C and protein S system, and antithrombin, all of which help to restrict the formation of the hemostatic plug to the site of injury.
Figure 1. Thrombin Generation.
The activation of coagulation proceeds through a stepwise activation of proteases that eventually results in the fibrin framework. After vascular injury, tissue-factor expression by endothelial cells is a critical step in the initial formation of fibrin, whereas the activation of factors XI, IX, and VIII is important to continue the formation of fibrin. The molecule of thrombin plays a central role within the coagulation cascade. The formation of the clot is highly regulated by natural anticoagulant mechanisms that confine the hemostatic process to the site of the injury to the vessel. Most of these natural anticoagulants are directed against the generation or action of thrombin and include antithrombin and the protein C system. Solid lines denote activation pathways, and dashed lines denote inhibitory pathways.
(This figure has been corrected from the version published on September 8, 2005.)
Differences from Heparins
Thrombin-inhibiting drugs can block the action of thrombin by binding to three domains: the active site or catalytic site and two exosites (Figure 2). Located next to the active site, exosite 1 acts as a dock for substrates such as fibrin, thereby orienting the appropriate peptide bonds in the active site. Exosite 2 serves as the heparin-binding domain.1 Thrombin is inhibited indirectly by low-molecular-weight heparins, because these drugs strongly catalyze the function of antithrombin. A heparin–thrombin–antithrombin complex is formed in which heparin binds simultaneously to exosite 2 in thrombin and to antithrombin. Furthermore, heparin can act as a bridge between thrombin and fibrin by binding both to fibrin and exosite 2 (Figure 2). Because both thrombin exosites are occupied within this fibrin–heparin–thrombin complex, the enzymatic activity of thrombin is relatively protected from inactivation by the heparin–antithrombin complex.2,3,4 Thus, heparins have a reduced capacity for the inhibition of fibrin-bound thrombin, which appears to be detrimental, because active thrombin further triggers thrombus growth.
Figure 2. Mechanism of Action of Direct Thrombin Inhibitors as Compared with Heparin.
In the absence of heparin, the rate of thrombin inactivation by antithrombin is relatively low, but after conformational change induced by heparin, antithrombin irreversibly binds to and inhibits the active site of thrombin. Thus, the anticoagulant activity of heparin originates from its ability to generate a ternary heparin–thrombin–antithrombin complex. The activity of DTIs is independent of the presence of antithrombin and is related to the direct interaction of these drugs with the thrombin molecule. Although bivalent DTIs simultaneously bind the exosite 1 and the active site, the univalent drugs in this class interact only with an active site of the enzyme. In the lower panel, the heparin–antithrombin complex cannot bind fibrin-bound thrombin, whereas given their mechanism of action, DTIs can bind to and inhibit the activity of not only soluble thrombin but also thrombin bound to fibrin, as is the case in a blood clot. An animated version of this figure is available with the full text of the article at www.nejm.org.
Since DTIs act independently of antithrombin, they can inhibit thrombin bound to fibrin or fibrin degradation products.3,4,5 Bivalent DTIs block thrombin at both the active site and exosite 1, whereas univalent DTIs bind only to the active site. The group of bivalent DTIs includes hirudin and bivalirudin, whereas argatroban, melagatran (and its oral precursor, ximelagatran), and dabigatran are univalent DTIs. Native hirudin and recombinant hirudins (lepirudin and desirudin) form an irreversible 1:1 stoichiometric complex with thrombin.6 In a similar way, bivalirudin, a synthetic hirudin, binds to the active site and exosite 1,7 but once bound, it is cleaved by thrombin, thereby restoring the active-site functions of thrombin.8 Therefore, in contrast to the hirudins, bivalirudin produces only a transient inhibition of thrombin.
By interacting only with the active site, univalent DTIs inactivate fibrin-bound thrombin.9,10 Argatroban and melagatran (like bivalirudin) dissociate from thrombin, leaving a small amount of free, enzymatically active thrombin available for hemostatic interactions.11,12
By reducing the thrombin-mediated activation of platelets, DTIs also have an antiplatelet effect.13,14 Since DTIs do not bind to plasma proteins, these agents should produce a more predictable response than does unfractionated heparin and should be more effective than low-molecular-weight heparins because they inhibit fibrin-bound thrombin.
Pharmacokinetics and Pharmacodynamics
The routes of administration, plasma half-lives, and main sites of clearance of the various DTIs are listed in Table 1. DTIs with a predominant renal clearance such as hirudin, melagatran, and dabigatran are likely to accumulate in patients with impaired renal function.12,15 Although excessive anticoagulation with hirudin in patients with renal insufficiency can be managed with high-volume hemofiltration with hirudin-permeable hemodialysis membranes,15 the available data remain scarce. Studies in animals suggest that excessive plasma concentrations of melagatran can be managed by either hemodialysis or the administration of activated prothrombin complex concentrates.12 Since patients with severe renal impairment have been excluded from the clinical trials, the safety of DTIs that are predominantly cleared by the kidneys remains to be established.
Table 1. Main Properties and Pharmacokinetic Characteristics of Direct Thrombin Inhibitors.
Bivalirudin is only partially excreted by the kidneys, as hepatic metabolism and proteolysis at other sites also contribute to its metabolism.16 However, the half-life of bivalirudin is prolonged with severe renal impairment, and dose adjustments are needed.17
Argatroban is predominantly cleared by hepatic metabolism and requires dose adjustments in patients with hepatic dysfunction.18 The use of aspirin does not appear to influence the plasma concentrations of DTIs.19,20
Studies in Arterial Thrombosis
Acute Coronary Syndromes with or without Percutaneous Coronary Intervention
Patients with acute coronary syndromes (acute myocardial infarction, either with or without ST-segment elevation, and unstable angina) remain at risk for recurrent myocardial ischemia, despite treatment with aspirin, clopidogrel, and heparin.21,22 The role of DTIs in the management of acute coronary syndromes was reviewed by the Direct Thrombin Inhibitor Trialists' Collaborative Group in a meta-analysis of data on individual patients.23 Eleven randomized trials were pooled, providing a total of 35,970 patients who were assigned to receive either DTIs or unfractionated heparin from 24 hours up to 7 days and then were followed for at least 30 days. As compared with heparin, DTIs reduced the incidence of the composite outcome of death and myocardial infarction both at the end of treatment and at 30 days (Table 2). The difference in risk appeared to be due mainly to a significant reduction in myocardial infarction, without a significant effect on death. The analysis by agent revealed that benefits were similar for hirudin and bivalirudin, whereas a nonsignificant, small increase in the risk of death or myocardial infarction was observed with univalent DTIs. Serious bleeding occurred less frequently among patients receiving DTIs than among those receiving heparin, but there was substantial heterogeneity for this outcome. Serious bleeding occurred more frequently with hirudin than with heparin but less often with bivalirudin and univalent inhibitors. The data on univalent DTIs should be interpreted with caution owing to the rather small number of events and the fact that these results are derived from dose-finding studies, with all dosage groups combined.
Table 2. Clinical Studies Comparing Direct Thrombin Inhibitors with Control Therapy in Patients with Coronary Syndromes (with or without Percutaneous Coronary Intervention) or Atrial Fibrillation.
In 2001, the data from another randomized clinical trial in acute coronary syndromes became available.24 In this study, patients with myocardial infarction characterized by ST-segment elevation were randomly assigned to receive either bivalirudin or unfractionated heparin combined with streptokinase.24 No difference was observed in the primary outcome of 30-day mortality between the two treatment groups, although a benefit of bivalirudin was observed for the secondary outcome of reinfarction within 96 hours. In contrast to the results of the meta-analysis, rates of serious bleeding were not lower with bivalirudin.
Some aspects regarding the role of DTIs in acute coronary syndromes require comment. In the trials reviewed in the meta-analysis23 and in the Hirulog and Early Reperfusion or Occlusion 2 (HERO-2) study,24 DTIs have been compared with unfractionated heparin. However, several analyses have suggested that low-molecular-weight heparin may be superior to unfractionated heparin in patients with unstable angina and myocardial infarction.29,30,31 Moreover, aggressive antiplatelet therapy has become the standard treatment in acute coronary syndromes, and the role of DTIs has not been established in the setting of the combined use of aspirin and clopidogrel, as well as glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors.
Therefore, hirudin is an unattractive alternative for the treatment of patients with acute coronary syndromes, given the lack of a clear efficacy benefit, the observed increase in bleeding, and the higher cost as compared with unfractionated heparin. In a similar manner, bivalirudin does not appear to be more efficacious or safer than unfractionated heparin and cannot be recommended in this setting.
Percutaneous Coronary Intervention
The meta-analysis mentioned above23 suggested that the prespecified subgroup of patients undergoing percutaneous coronary intervention had no significant efficacy benefit, but the incidence of serious bleeding was less with hirudin and bivalirudin than with unfractionated heparin.
Bivalirudin was compared with heparin during coronary angioplasty for unstable or postinfarction angina. Initial results suggested that there was a benefit,32 a finding that was supported in a longer-term follow-up using an intention-to-treat analysis.33 The combined outcome of death, myocardial infarction, and revascularization at 7 and 90 days occurred less frequently with bivalirudin, mainly owing to an effect on the need for revascularization. At 90 days, serious bleeding was significantly reduced in the bivalirudin group (3.7 percent vs. 9.3 percent).33
The meta-analysis23 pooled data from trials that were conducted before the introduction of newer therapies such as intracoronary stenting and the use of GPIIb/IIIa inhibitors. In the Randomized Evaluation in Percutaneous Coronary Intervention Linking Angiomax to Reduced Clinical Events 2 (REPLACE-2) study, patients undergoing urgent or elective percutaneous coronary intervention were randomly assigned to receive unfractionated heparin plus GPIIb/IIIa inhibitors or to receive bivalirudin to which GPIIb/IIIa inhibitors were added only if complications occurred during the procedure.25 Aspirin was prescribed to all patients, and the use of clopidogrel was encouraged. The composite efficacy and safety outcome of death, myocardial infarction, urgent repeat revascularization, and serious bleeding was not significantly different between the two groups. However, the use of bivalirudin was associated with a lower rate of serious bleeding. GPIIb/IIIa inhibitors were used in only 7.2 percent of the bivalirudin recipients, which may have contributed to the lower costs associated with this approach.34 The composite outcome remained not significantly different at six months35 and was not affected by concomitant clopidogrel treatment.36 A subanalysis of this trial confirmed the similar efficacy and the lower incidence of bleeding for bivalirudin, regardless of renal function.37
In summary, bivalirudin appears to be safer than heparin in patients undergoing percutaneous coronary intervention, provided that GPIIb/IIIa inhibitors are administered if complications occur during the procedure.
Long-Term Treatment of Acute Coronary Syndromes
In patients with acute coronary syndromes, long-term treatment with aspirin leads to a reduction in the relative risk of recurrent ischemic events of approximately 23 percent.21,22 The addition of vitamin K antagonists further reduces cardiovascular complications, but at the expense of more bleeding.21,22 Long-term treatment with low-molecular-weight heparin does not offer an additional benefit over aspirin alone.21,22,38 The role of DTIs for long-term secondary prophylaxis in patients also receiving aspirin was investigated in the Efficacy and Safety of the Oral Direct Thrombin Inhibitor Ximelagatran in Patients with Recent Myocardial Damage (ESTEEM) trial.26 Ximelagatran in four oral doses was compared with placebo in patients with myocardial infarction. Ximelagatran significantly reduced the incidence of the combined outcome of all-cause mortality, nonfatal myocardial infarction, and severe recurrent ischemia during the six-month treatment period as compared with placebo, without a dose–response effect. The use of ximelagatran was not associated with a rate of serious bleeding higher than that of aspirin alone, but the total risk of bleeding was higher and dose-related. Elevation of alanine aminotransferase of more than three times the upper limit of normal occurred in 11 percent of the patients treated with ximelagatran and in 2 percent of those receiving placebo.
In summary, the investigation of the role of ximelagatran in the long-term treatment of acute coronary syndromes is limited to one phase 2 trial that was promising with respect to efficacy but identified possible hepatic toxicity as an important concern. Thus, at present, ximelagatran should not be considered for long-term treatment after acute coronary syndromes.
Atrial Fibrillation
The most serious clinical complication of atrial fibrillation is ischemic stroke.39 Although aspirin is the treatment of choice for low-risk patients, vitamin K antagonists are preferred for high-risk patients since there is a 36 percent reduction in the relative risk of stroke as compared with aspirin.39
Ximelagatran was compared with dose-adjusted warfarin for the prevention of all strokes and systemic embolism in patients with nonvalvular atrial fibrillation and at least one additional risk factor in the trials called Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation III (SPORTIF III) and SPORTIF V.27,28 These two studies had an identical design, except that the SPORTIF III trial was open-label, whereas the SPORTIF V trial was double-blinded. Ximelagatran was observed to be as effective as warfarin with respect to the primary efficacy outcome of stroke or systemic embolism. Furthermore, ximelagatran conferred a significantly lower risk of serious bleeding in the pooled analysis. Ximelagatran was associated with a significant increase in the proportion of patients with alanine aminotransferase levels at least three times the upper limit of normal as compared with warfarin (6.1 percent vs. 0.8 percent).
On the basis of the SPORTIF trials, ximelagatran might be a convenient alternative for vitamin K antagonists in patients who have atrial fibrillation plus at least one additional risk factor. However, the safety of this management strategy remains to be determined.
Other Indications
Recently, data have become available from phase 2 studies on the efficacy and safety of argatroban in acute stroke40 and bivalirudin in coronary artery bypass surgery.41 However, these studies included small numbers of patients and will not be discussed further.
Prevention of Venous Thromboembolism
Despite prophylaxis, the rate of symptomatic venous thromboembolism in patients undergoing serious orthopedic surgery remains as high as 1.5 to 10 percent in the three months following surgery.42 Desirudin, melagatran, and ximelagatran have been studied in phase 3 trials in patients undergoing hip or knee surgery (Table 3). Recently, a pilot study investigated the role of the combination of melagatran and ximelagatran in elective abdominal surgery.53
Table 3. Clinical Studies Comparing Direct Thrombin Inhibitors with Control Therapy for Prophylaxis and Treatment of Venous Thromboembolism.
Ximelagatran
Oral ximelagatran has been investigated either alone or in combination with subcutaneous melagatran for the prevention of venous thromboembolism after orthopedic surgery. In a double-blind, randomized trial among patients undergoing total hip replacement, the efficacy and safety of initiating oral ximelagatran after surgery, as compared with enoxaparin, were evaluated.43 The rates of both overall venous thromboembolism and proximal deep venous thrombosis (with or without pulmonary embolism) were significantly higher in patients receiving ximelagatran than they were among those treated with enoxaparin; the incidence of episodes of serious bleeding was similar.
Warfarin (with the use of a target international normalized ratio of 2.5) has been the control treatment in two phase 3 trials among patients undergoing total knee replacement.44,45 Both treatments were started postoperatively. In the first study, the incidence of overall venous thromboembolism and proximal deep venous thrombosis (with or without symptomatic pulmonary embolism) was not significantly lower in patients receiving ximelagatran; the incidence of serious bleeding was similar in the two groups.44 In the second trial, two doses of ximelagatran were compared with warfarin in order to demonstrate superiority of the higher ximelagatran dose.45 A dose of 36 mg of ximelagatran reduced the rate of overall deep venous thrombosis as compared with both 24 mg of ximelagatran and warfarin. Serious bleeding occurred with a similar frequency in all groups. Elevations of alanine aminotransferase that were more than three times the upper limit of normal were observed less frequently with both doses of ximelagatran than with warfarin at the end of treatment, though the levels had normalized in the warfarin group four to six weeks later, whereas persistent increases in levels of alanine aminotransferase were observed in some patients in the ximelagatran groups (0.6 percent and 0.1 percent in the high- and low-dose groups, respectively).
Melagatran–Ximelagatran
The efficacy of the use of subcutaneous melagatran followed by oral ximelagatran was tested in two phase 3 trials among patients undergoing total hip or total knee replacement.46,48 In the Melagatran for Thrombin Inhibition in Orthopedic Surgery III (METHRO III) study, postoperative initiation of melagatran followed by ximelagatran was compared with preoperative initiation of enoxaparin.46 Both groups in the study were associated with similar rates of venous thromboembolism and of serious bleeding. In the Expanded Prophylaxis Evaluation Surgery Study (EXPRESS), the administration of melagatran before surgery followed by ximelagatran was compared with preoperative administration of enoxaparin.48 The rates of venous thromboembolism were significantly lower with the melagatran–ximelagatran regimen, but both serious and minor bleeding were observed more frequently.
Desirudin
Two phase 3 trials have evaluated preoperative administration of desirudin among patients undergoing hip replacement.49,50 In one study, desirudin was compared with preoperative administration of enoxaparin.49 The incidence of overall and proximal deep venous thrombosis was lower in patients treated with desirudin, with a similar risk of serious bleeding in the two groups. In the other study, preoperative administration of desirudin was compared with preoperative administration of unfractionated heparin.50 Desirudin reduced the incidence of overall and proximal deep venous thrombosis. Serious bleeding episodes were similar in the two groups.
Dabigatran
The Boehringer Ingelheim Study in Thrombosis II (BISTRO II) trial, a phase 2 study, compared oral dabigatran with enoxaparin in the prevention of venous thromboembolism after orthopedic surgery.47 Dabigatran was started 1 to 4 hours after surgery, whereas enoxaparin was initiated 12 hours before surgery. The highest doses of dabigatran were associated with a significantly lower incidence of venous thromboembolism than was enoxaparin. However, the risk of serious bleeding with dabigatran increased in a dose-dependent manner.
Perioperative Timing
The timing for the initiation of thromboprophylaxis relative to surgery might be more important with the administration of DTIs than with low-molecular-weight heparin, although, to our knowledge, a direct comparison has not been performed.42 The administration of ximelagatran alone or combined with subcutaneous melagatran postoperatively appears to be less effective than low-molecular-weight heparin but more effective than warfarin, with similar bleeding risks. In the administration of preoperative prophylaxis, both desirudin and the combination of melagatran and ximelagatran were observed to be more effective than either unfractionated or low-molecular-weight heparin.48,49,50 However, the reduction in thromboembolic events with either ximelagatran or melagatran was offset by more bleeding episodes.
Current data, taken together, suggest no important advantages to using most DTIs as compared with the routine use of low-molecular-weight heparin for prophylaxis of venous thromboembolism. The one exception appears to be desirudin, which can be recommended for prophylaxis among patients undergoing hip replacement.
Treatment of Established Venous Thromboembolism
Initial Treatment
Phase 2 studies with recombinant hirudin and melagatran have consistently suggested a similar efficacy and safety of DTIs as compared with standard treatment with low-molecular-weight heparin plus vitamin K antagonists for the initial treatment of venous thromboembolism.54,55 In the phase 3 Thrombin Inhibitor in Venous Thromboembolism (THRIVE) study, patients with deep venous thrombosis were randomly assigned to receive either six months of oral ximelagatran or initial treatment with subcutaneous enoxaparin combined with warfarin.51 Ximelagatran was as effective as the combination therapy, and rates of bleeding complications were similar. However, alanine aminotransferase levels increased to more than three times the upper limit of normal in 9.6 percent of the patients receiving ximelagatran and in 2.0 percent of those treated with the combination of enoxaparin and warfarin. Thus, oral ximelagatran was as effective for the treatment of venous thromboembolism without the need for monitoring, but there was concern about safety, given increases in hepatic enzymes.
Long-Term Secondary Prophylaxis
After six months of treatment with vitamin K antagonists, patients with venous thromboembolism have a 5 to 7 percent risk of recurrence in the first year after discontinuation.56 Therefore, long-term treatment has been recommended for patients at high risk for recurrence. Extended prophylaxis with ximelagatran was compared with placebo for 18 months in patients with thromboembolism who had been treated with vitamin K antagonists for at least 6 months.52 Ximelagatran significantly reduced the rate of recurrent venous thromboembolism without a significant increase in the incidence of either serious or minor bleeding. However, ximelagatran was associated with a significantly increased rate of elevated alanine aminotransferase levels (6.4 percent vs. 1.2 percent). Thus, there is concern about hepatic toxicity with long-term use of ximelagatran.
Heparin-Induced Thrombocytopenia
Heparin-induced thrombocytopenia is an adverse drug reaction mediated by the immune system, with clinical manifestations initiated by antibodies directed against platelet factor 4, which becomes an antigenic target when bound to heparin. This antibody–platelet factor 4–heparin complex is able to activate platelets and may cause venous and arterial thrombosis. Although the immediate discontinuation of heparin is mandatory in this condition, the strategy is insufficient, given the high cumulative risk of thrombosis during 30-day administration of the drug — up to 53 percent without antithrombotic treatment.57 Thus, for patients with suspected or confirmed heparin-induced thrombocytopenia, the use of alternative anticoagulants is recommended.57 The use of DTIs for this condition is theoretically supported by the intense thrombin activity observed in these patients.57,58,59
Two DTIs, lepirudin and argatroban, are approved in the United States for heparin-induced thrombocytopenia. The data about the efficacy and safety of lepirudin and argatroban come from prospective cohort studies that used historical controls.59,60,61 In patients with proven heparin-induced thrombocytopenia who were treated with lepirudin, a thrombotic event occurred in approximately 4 percent of patients, as compared with 15 percent in historical controls, but the administration of lepirudin was associated with a higher rate of serious bleeding (14 percent vs. 8 percent).59 Similar results were reported for patients with heparin-induced thrombocytopenia with thromboembolic complications.62 In two series of patients with a clinical diagnosis of heparin-induced thrombocytopenia and thrombosis who were treated with argatroban, the rates of new thrombotic episodes were 13 and 19 percent, as compared with approximately 35 percent in historical controls, with bleeding rates of 6 and 11 percent.60,61
Antihirudin antibodies develop in 40 to 74 percent of patients receiving lepirudin after four days or more of treatment.59,63,64 Of note, fatal anaphylaxis has been described with lepirudin, particularly in patients who are treated again within three months of a previous exposure to this agent.65 In contrast, argatroban does not appear to be immunogenic.66 Thus, lepirudin and argatroban appear to be effective in patients with heparin-induced thrombocytopenia, but drawbacks are an enhanced risk of bleeding and immunogenicity of lepirudin.
Remaining Issues
Direct Thrombin Inhibitors and Liver Function
No available data report about hepatic dysfunction with the use of recombinant hirudins, bivalirudin, or argatroban. The pharmacokinetic and pharmacodynamic properties of ximelagatran and melagatran do not appear to be influenced in the presence of mild-to-moderate impairment of liver function,67 and short-term exposure to ximelagatran (about 12 days) does not appear to increase the risk of hepatotoxicity.68 However, data on longer-term use of ximelagatran and melagatran indicate that alanine aminotransferase levels can become elevated after one to six months in 6 to 10 percent of patients. Although increases that have been reported so far are usually asymptomatic and reversible, even if the medication is continued, the few cases of fatal hepatotoxicity observed with prolonged administration of ximelagatran have led the FDA to deny approval of ximelagatran in the United States,69 and only short-term use of ximelagatran has been approved in Europe.70 The mechanisms of these liver-enzyme abnormalities are still unknown.
Monitoring Activity
The best method to monitor therapy with DTIs has not been clearly established.71,72,73,74,75,76 The usefulness of the activated partial-thromboplastin time seems limited by its poor linearity and reproducibility, especially when heparin or a vitamin K antagonist is coadministered.71,72,73,77,78,79 The ecarin clotting time better reflects the actual plasma concentration of DTIs, but this test is not widely available.74,75,76,77,80,81,82
Recombinant hirudins and argatroban can be monitored with the use of the activated partial-thromboplastin time and bivalirudin with the activated clotting time. In patients with heparin-induced immune thrombocytopenia, antihirudin antibodies form complexes with lepirudin that may reduce the renal clearance of the drug.63 This phenomenon often results in a need to reduce and monitor the dose to maintain the lepirudin anticoagulant effect within the therapeutic range, especially in patients with impaired renal function.57
Since there is no antidote for rapidly reversing the effect of DTIs, monitoring these drugs is important for patients who have a high risk of bleeding. However, given the short half-life of most DTIs, the major anticoagulant effects of DTIs should have disappeared by 12 to 24 hours after the last dose. Preliminary data suggest that recombinant factor VIIa has a limited capacity to reverse the anticoagulant effects of melagatran.83
Conclusions
Despite many well-performed clinical trials, there are few clinical indications for DTIs. For acute coronary syndromes, none of the DTIs have consistently shown superior efficacy combined with a similar safety in comparison with the present standard treatment with heparin and antiplatelet agents. For patients with unstable angina who are undergoing a percutaneous coronary intervention, bivalirudin may be superior to heparin plus GPIIb/IIIa inhibitors administered in case of intraprocedural complications. No DTIs have been convincingly demonstrated to be efficacious and safe for long-term treatment after acute coronary syndromes. In contrast, the efficacy data of ximelagatran in atrial fibrillation are promising, but concern with regard to hepatic toxicity with long-term use must be resolved. When thromboprophylaxis is initiated after serious orthopedic surgery, ximelagatran-containing regimens are less effective than is treatment with low-molecular-weight heparin, but such regimens are superior to warfarin therapy and have a similar safety profile. Preoperative initiation of desirudin is an alternative to the standard approach, but preoperative initiation of melagatran plus ximelagatran increases the risk of bleeding.
Dr. Büller reports having received consulting fees from AstraZeneca.
We are indebted to Dr. Ron J.G. Peters, Department of Cardiology, Academic Medical Center, Amsterdam, for critical review of the manuscript.
Source Information
From the Department of Vascular Medicine, Academic Medical Center, Amsterdam (M.D., S.M., H.R.B.); and the Department of Medicine and Aging, School of Medicine and Aging Research Center, Gabriele D'Annunzio University Foundation, Chieti–Pescara, Italy (M.D.).
Address reprint requests to Dr. Di Nisio at the Academic Medical Center, Department of Vascular Medicine F4-138, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands, or at m.dinisio@amc.uva.nl.
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Harrington RA, Becker RC, Ezekowitz M, et al. Antithrombotic therapy for coronary artery disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:Suppl 3:513S-548S.
Menon V, Harrington RA, Hochman JS, et al. Thrombolysis and adjunctive therapy in acute myocardial infarction: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:Suppl 3:549S-575S.
The Direct Thrombin Inhibitor Trialists' Collaborative Group. Direct thrombin inhibitors in acute coronary syndromes: principal results of a meta-analysis based on individual patients' data. Lancet 2002;359:294-302.
White H, Hirulog and Early Reperfusion or Occlusion (HERO)-2 Trial Investigators. Thrombin-specific anticoagulation with bivalirudin versus heparin in patients receiving fibrinolytic therapy for acute myocardial infarction: the HERO-2 randomised trial. Lancet 2001;358:1855-1863.
Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003;289:853-863.
Wallentin L, Wilcox RG, Weaver WD, et al. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial. Lancet 2003;362:789-797.
Olsson SB. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet 2003;362:1691-1698.
Albers GW, Diener HC, Frison L, et al. Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial. JAMA 2005;293:690-698.
Antman EM, Cohen M, Radley D, et al. Assessment of the treatment effect of enoxaparin for unstable angina/non-Q-wave myocardial infarction: TIMI 11B-ESSENCE meta-analysis. Circulation 1999;100:1602-1608.
The Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction. Lancet 2001;358:605-613.
Petersen JL, Mahaffey KW, Hasselblad V, et al. Efficacy and bleeding complications among patients randomized to enoxaparin or unfractionated heparin for antithrombin therapy in non-ST-segment elevation acute coronary syndromes: a systematic overview. JAMA 2004;292:89-96.
Bittl JA, Strony J, Brinker JA, et al. Treatment with bivalirudin (Hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina. N Engl J Med 1995;333:764-769.
Bittl JA, Chaitman BR, Feit F, Kimball W, Topol EJ. Bivalirudin versus heparin during coronary angioplasty for unstable or postinfarction angina: final report reanalysis of the Bivalirudin Angioplasty Study. Am Heart J 2001;142:952-959.
Cohen DJ, Lincoff AM, Lavelle TA, et al. Economic evaluation of bivalirudin with provisional glycoprotein IIb/IIIa inhibition versus heparin with routine glycoprotein IIB/IIIA inhibition for percutaneous coronary intervention: results from the REPLACE-2 trial. J Am Coll Cardiol 2004;44:1792-1800.
Lincoff AM, Kleiman NS, Kereiakes DJ, et al. Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary revascularization: REPLACE-2 randomized trial. JAMA 2004;292:696-703.
Saw J, Lincoff AM, DeSmet W, et al. Lack of clopidogrel pretreatment effect on the relative efficacy of bivalirudin with provisional glycoprotein IIb/IIIa blockade compared to heparin with routine glycoprotein IIb/IIIa blockade: a REPLACE-2 substudy. J Am Coll Cardiol 2004;44:1194-1199.
Chew DP, Lincoff AM, Gurm H, et al. Bivalirudin versus heparin and glycoprotein IIb/IIIa inhibition among patients with renal impairment undergoing percutaneous coronary intervention (a subanalysis of the REPLACE-2 trial). Am J Cardiol 2005;95:581-585.
Eikelboom JW, Anand SS, Malmberg K, Weitz JI, Ginsberg JS, Yusuf S. Unfractionated heparin and low-molecular-weight heparin in acute coronary syndrome without ST elevation: a meta-analysis. Lancet 2000;355:1936-1942.
Singer DE, Albers GW, Dalen JE, Go AS, Halperin JL, Manning WJ. Antithrombotic therapy in atrial fibrillation: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:Suppl 3:429S-456S.
LaMonte MP, Nash ML, Wang DZ, et al. Argatroban anticoagulation in patients with acute ischemic stroke (ARGIS-1): a randomized, placebo-controlled safety study. Stroke 2004;35:1677-1682.
Merry AF, Raudkivi PJ, Middleton NG, et al. Bivalirudin versus heparin and protamine in off-pump coronary artery bypass surgery. Ann Thorac Surg 2004;77:925-931.
Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:Suppl 3:338S-400S.
Colwell CW Jr, Berkowitz SD, Davidson BL, et al. Comparison of ximelagatran, an oral direct thrombin inhibitor, with enoxaparin for the prevention of venous thromboembolism following total hip replacement: a randomized, double-blind study. J Thromb Haemost 2003;1:2119-2130.
Francis CW, Davidson BL, Berkowitz SD, et al. Ximelagatran versus warfarin for the prevention of venous thromboembolism after total knee arthroplasty: a randomized, double-blind trial. Ann Intern Med 2002;137:648-655.
Francis CW, Berkowitz SD, Comp PC, et al. Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. N Engl J Med 2003;349:1703-1712.
Eriksson BI, Agnelli G, Cohen AT, et al. Direct thrombin inhibitor melagatran followed by oral ximelagatran in comparison with enoxaparin for prevention of venous thromboembolism after total hip or knee replacement. Thromb Haemost 2003;89:288-296.
Eriksson BI, Dahl OE, Buller HR, et al. A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial. J Thromb Haemost 2005;3:103-111.
Eriksson BI, Agnelli G, Cohen AT, et al. The direct thrombin inhibitor melagatran followed by oral ximelagatran compared with enoxaparin for the prevention of venous thromboembolism after total hip or knee replacement: the EXPRESS study. J Thromb Haemost 2003;1:2490-2496.
Eriksson BI, Wille-Jorgensen P, Kalebo P, et al. A comparison of recombinant hirudin with a low-molecular-weight heparin to prevent thromboembolic complications after total hip replacement. N Engl J Med 1997;337:1329-1335.
Eriksson BI, Ekman S, Lindbratt S, et al. Prevention of thromboembolism with use of recombinant hirudin: results of a double-blind, multicenter trial comparing the efficacy of desirudin (Revasc) with that of unfractionated heparin in patients having a total hip replacement. J Bone Joint Surg Am 1997;79:326-333.
Fiessinger J-N, Huisman MV, Davidson BL, et al. Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial. JAMA 2005;293:681-689.
Schulman S, Wahlander K, Lundstrom T, Clason SB, Eriksson H. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med 2003;349:1713-1721.
Bergqvist D, Solhaug J-H, Holmdahl L, et al. Pharmacokinetics, preliminary efficacy and safety of subcutaneous melagatran and oral ximelagatran: a multicenter study of thromboprophylaxis in elective abdominal surgery. Clin Drug Invest 2004;24:127-36.
Schiele F, Lindgaerde F, Eriksson H, et al. Subcutaneous recombinant hirudin (HBW 023) versus intravenous sodium heparin in treatment of established acute deep vein thrombosis of the legs: a multicentre prospective dose-ranging randomized trial. Thromb Haemost 1997;77:834-838.
Eriksson H, Eriksson UG, Frison L, et al. Pharmacokinetics and pharmacodynamics of melagatran, a novel synthetic LMW thrombin inhibitor, in patients with acute DVT. Thromb Haemost 1999;81:358-363.
Buller HR, Agnelli G, Hull RD, Hyers TM, Prins MH, Raskob GE. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:Suppl 3:401S-428S.
Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia: recognition, treatment, and prevention: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:Suppl 3:311S-337S.
Boshkov LK, Warkentin TE, Hayward CP, Andrew M, Kelton JG. Heparin-induced thrombocytopenia and thrombosis: clinical and laboratory studies. Br J Haematol 1993;84:322-328.
Lubenow N, Eichler P, Lietz T, Farner B, Greinacher A. Lepirudin for prophylaxis of thrombosis in patients with acute isolated heparin-induced thrombocytopenia: an analysis of 3 prospective studies. Blood 2004;104:3072-3077.
Lewis BE, Wallis DE, Berkowitz SD, et al. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation 2001;103:1838-1843.
Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med 2003;163:1849-1856.
Greinacher A, Eichler P, Lubenow N, Kwasny H, Luz M. Heparin-induced thrombocytopenia with thromboembolic complications: meta-analysis of 2 prospective trials to assess the value of parenteral treatment with lepirudin and its therapeutic aPTT range. Blood 2000;96:846-851.
Eichler P, Friesen H-J, Lubenow N, Jaeger B, Greinacher A. Antihirudin antibodies in patients with heparin-induced thrombocytopenia treated with lepirudin: incidence, effects on aPTT, and clinical relevance. Blood 2000;96:2373-2378.
Huhle G, Hoffmann U, Song X, Wang LC, Heene DL, Harenberg J. Immunologic response to recombinant hirudin in HIT type II patients during long-term treatment. Br J Haematol 1999;106:195-201.
Greinacher A, Lubenow N, Eichler P. Anaphylactic and anaphylactoid reactions associated with lepirudin in patients with heparin-induced thrombocytopenia. Circulation 2003;108:2062-2065.
Walenga JM, Ahmad S, Hoppensteadt D, Iqbal O, Hursting MJ, Lewis BE. Argatroban therapy does not generate antibodies that alter its anticoagulant activity in patients with heparin-induced thrombocytopenia. Thromb Res 2002;105:401-405.
Wahlander K, Eriksson-Lepkowska M, Frison L, Fager G, Eriksson UG. No influence of mild-to-moderate hepatic impairment on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor. Clin Pharmacokinet 2003;42:755-764.
Food and Drug Administration Cardiovascular and Renal Advisory Committee. Integrated Executive Summary of FDA review for NDA 21-686 Exanta (ximelagatran), September 10, 2004. (Accessed August 11, 2005, at http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4069B1_03_FDA-Backgrounder-Execsummaryredacted.pdf.)
AstraZeneca receives action letter from FDA for EXANTA (ximelagatran). Press release from AstraZeneca International, October 11, 2004. (Accessed August 11, 2005, at http://www.astrazeneca.com/pressrelease/3285.aspx.)
Successful outcome of the mutual recognition procedure for EXANTA (ximelagatran) in Europe. Press release from AstraZeneca International, May 4, 2004. (Accessed August 11, 2005, at http://www.astrazeneca.com/pressrelease/1898.aspx.)
Fenyvesi T, Jorg I, Harenberg J. Monitoring of anticoagulant effects of direct thrombin inhibitors. Semin Thromb Hemost 2002;28:361-368.
Moser M, Ruef J, Peter K, et al. Ecarin clotting time but not aPTT correlates with PEG-hirudin plasma activity. J Thromb Thrombolysis 2001;12:165-169.
Nurmohamed MT, Berckmans RJ, Morrien-Salomons WM, et al. Monitoring anticoagulant therapy by activated partial thromboplastin time: hirudin assessment: an evaluation of native blood and plasma assays. Thromb Haemost 1994;72:685-692.
Callas DD, Hoppensteadt D, Iqbal O, Fareed J. Ecarin clotting time (ECT) is a reliable method for the monitoring of hirudins, argatroban, efegatran and related drugs in therapeutic and cardiovascular indications. Ann Hematol 1996;1:A58-A58. abstract.
Callas DD, Fareed J. Comparative anticoagulant effects of various thrombin inhibitors, as determined in the ecarin clotting time method. Thromb Res 1996;83:463-468.
Radziwon P, Breddin HK, Esslinger H-U. Ecarin time is more suitable to monitor PEG-hirudin treatment compared to APTT, TT, ACT, or aIIa-activity. Ann Hematol 1996;1:A57-A57. abstract.
Walenga JM, Hoppensteadt D, Koza M, Pifarre R, Fareed J. Comparative studies on various assays for the laboratory evaluation of r-hirudin. Semin Thromb Hemost 1991;17:103-112.
Marbet GA, Verstraete M, Kienast J, et al. Clinical pharmacology of intravenously administered recombinant desulfatohirudin (CGP 39393) in healthy volunteers. J Cardiovasc Pharmacol 1993;22:364-372.
Schenk JF, Glusa E, Radziwon P, Butti A, Markwardt F, Breddin HK. A recombinant hirudin (IK-HIR02) in healthy volunteers. I. Effects on coagulation parameters and bleeding time. Haemostasis 1996;26:140-9.
Casserly IP, Kereiakes DJ, Gray WA, et al. Point-of-care ecarin clotting time versus activated clotting time in correlation with bivalirudin concentration. Thromb Res 2004;113:115-121.
Faaij RA, van Griensven JMT, Schoenmaker RC, et al. The effect of warfarin on the pharmacokinetics and pharmacodynamics of napsagatran in healthy male volunteers. Eur J Clin Pharmacol 2001;57:25-29.
Cho L, Kottke-Marchant K, Lincoff AM, et al. Correlation of point-of-care ecarin clotting time versus activated clotting time with bivalirudin concentrations. Am J Cardiol 2003;91:1110-1112.
Wolzt M, Levi M, Sarich TC, et al. Effect of recombinant factor VIIa on melagatran-induced inhibition of thrombin generation and platelet activation in healthy volunteers. Thromb Haemost 2004;91:1090-1096.(Marcello Di Nisio, M.D., )
Mechanisms of Action
Coagulation Cascade and Generation of Thrombin
After injury to a vessel wall, tissue factor is exposed on the surface of the damaged endothelium. The interaction of tissue factor with plasma factor VII activates the coagulation cascade, producing thrombin by stepwise activation of a series of proenzymes (Figure 1). Thrombin is central in the clotting process: it converts soluble fibrinogen to fibrin; activates factors V, VIII, and XI, which generates more thrombin; and stimulates platelets. Furthermore, by activating factor XIII, thrombin favors the formation of cross-linked bonds among the fibrin molecules, stabilizing the clot. The coagulation cascade is regulated by natural anticoagulants, such as tissue factor pathway inhibitor, the protein C and protein S system, and antithrombin, all of which help to restrict the formation of the hemostatic plug to the site of injury.
Figure 1. Thrombin Generation.
The activation of coagulation proceeds through a stepwise activation of proteases that eventually results in the fibrin framework. After vascular injury, tissue-factor expression by endothelial cells is a critical step in the initial formation of fibrin, whereas the activation of factors XI, IX, and VIII is important to continue the formation of fibrin. The molecule of thrombin plays a central role within the coagulation cascade. The formation of the clot is highly regulated by natural anticoagulant mechanisms that confine the hemostatic process to the site of the injury to the vessel. Most of these natural anticoagulants are directed against the generation or action of thrombin and include antithrombin and the protein C system. Solid lines denote activation pathways, and dashed lines denote inhibitory pathways.
(This figure has been corrected from the version published on September 8, 2005.)
Differences from Heparins
Thrombin-inhibiting drugs can block the action of thrombin by binding to three domains: the active site or catalytic site and two exosites (Figure 2). Located next to the active site, exosite 1 acts as a dock for substrates such as fibrin, thereby orienting the appropriate peptide bonds in the active site. Exosite 2 serves as the heparin-binding domain.1 Thrombin is inhibited indirectly by low-molecular-weight heparins, because these drugs strongly catalyze the function of antithrombin. A heparin–thrombin–antithrombin complex is formed in which heparin binds simultaneously to exosite 2 in thrombin and to antithrombin. Furthermore, heparin can act as a bridge between thrombin and fibrin by binding both to fibrin and exosite 2 (Figure 2). Because both thrombin exosites are occupied within this fibrin–heparin–thrombin complex, the enzymatic activity of thrombin is relatively protected from inactivation by the heparin–antithrombin complex.2,3,4 Thus, heparins have a reduced capacity for the inhibition of fibrin-bound thrombin, which appears to be detrimental, because active thrombin further triggers thrombus growth.
Figure 2. Mechanism of Action of Direct Thrombin Inhibitors as Compared with Heparin.
In the absence of heparin, the rate of thrombin inactivation by antithrombin is relatively low, but after conformational change induced by heparin, antithrombin irreversibly binds to and inhibits the active site of thrombin. Thus, the anticoagulant activity of heparin originates from its ability to generate a ternary heparin–thrombin–antithrombin complex. The activity of DTIs is independent of the presence of antithrombin and is related to the direct interaction of these drugs with the thrombin molecule. Although bivalent DTIs simultaneously bind the exosite 1 and the active site, the univalent drugs in this class interact only with an active site of the enzyme. In the lower panel, the heparin–antithrombin complex cannot bind fibrin-bound thrombin, whereas given their mechanism of action, DTIs can bind to and inhibit the activity of not only soluble thrombin but also thrombin bound to fibrin, as is the case in a blood clot. An animated version of this figure is available with the full text of the article at www.nejm.org.
Since DTIs act independently of antithrombin, they can inhibit thrombin bound to fibrin or fibrin degradation products.3,4,5 Bivalent DTIs block thrombin at both the active site and exosite 1, whereas univalent DTIs bind only to the active site. The group of bivalent DTIs includes hirudin and bivalirudin, whereas argatroban, melagatran (and its oral precursor, ximelagatran), and dabigatran are univalent DTIs. Native hirudin and recombinant hirudins (lepirudin and desirudin) form an irreversible 1:1 stoichiometric complex with thrombin.6 In a similar way, bivalirudin, a synthetic hirudin, binds to the active site and exosite 1,7 but once bound, it is cleaved by thrombin, thereby restoring the active-site functions of thrombin.8 Therefore, in contrast to the hirudins, bivalirudin produces only a transient inhibition of thrombin.
By interacting only with the active site, univalent DTIs inactivate fibrin-bound thrombin.9,10 Argatroban and melagatran (like bivalirudin) dissociate from thrombin, leaving a small amount of free, enzymatically active thrombin available for hemostatic interactions.11,12
By reducing the thrombin-mediated activation of platelets, DTIs also have an antiplatelet effect.13,14 Since DTIs do not bind to plasma proteins, these agents should produce a more predictable response than does unfractionated heparin and should be more effective than low-molecular-weight heparins because they inhibit fibrin-bound thrombin.
Pharmacokinetics and Pharmacodynamics
The routes of administration, plasma half-lives, and main sites of clearance of the various DTIs are listed in Table 1. DTIs with a predominant renal clearance such as hirudin, melagatran, and dabigatran are likely to accumulate in patients with impaired renal function.12,15 Although excessive anticoagulation with hirudin in patients with renal insufficiency can be managed with high-volume hemofiltration with hirudin-permeable hemodialysis membranes,15 the available data remain scarce. Studies in animals suggest that excessive plasma concentrations of melagatran can be managed by either hemodialysis or the administration of activated prothrombin complex concentrates.12 Since patients with severe renal impairment have been excluded from the clinical trials, the safety of DTIs that are predominantly cleared by the kidneys remains to be established.
Table 1. Main Properties and Pharmacokinetic Characteristics of Direct Thrombin Inhibitors.
Bivalirudin is only partially excreted by the kidneys, as hepatic metabolism and proteolysis at other sites also contribute to its metabolism.16 However, the half-life of bivalirudin is prolonged with severe renal impairment, and dose adjustments are needed.17
Argatroban is predominantly cleared by hepatic metabolism and requires dose adjustments in patients with hepatic dysfunction.18 The use of aspirin does not appear to influence the plasma concentrations of DTIs.19,20
Studies in Arterial Thrombosis
Acute Coronary Syndromes with or without Percutaneous Coronary Intervention
Patients with acute coronary syndromes (acute myocardial infarction, either with or without ST-segment elevation, and unstable angina) remain at risk for recurrent myocardial ischemia, despite treatment with aspirin, clopidogrel, and heparin.21,22 The role of DTIs in the management of acute coronary syndromes was reviewed by the Direct Thrombin Inhibitor Trialists' Collaborative Group in a meta-analysis of data on individual patients.23 Eleven randomized trials were pooled, providing a total of 35,970 patients who were assigned to receive either DTIs or unfractionated heparin from 24 hours up to 7 days and then were followed for at least 30 days. As compared with heparin, DTIs reduced the incidence of the composite outcome of death and myocardial infarction both at the end of treatment and at 30 days (Table 2). The difference in risk appeared to be due mainly to a significant reduction in myocardial infarction, without a significant effect on death. The analysis by agent revealed that benefits were similar for hirudin and bivalirudin, whereas a nonsignificant, small increase in the risk of death or myocardial infarction was observed with univalent DTIs. Serious bleeding occurred less frequently among patients receiving DTIs than among those receiving heparin, but there was substantial heterogeneity for this outcome. Serious bleeding occurred more frequently with hirudin than with heparin but less often with bivalirudin and univalent inhibitors. The data on univalent DTIs should be interpreted with caution owing to the rather small number of events and the fact that these results are derived from dose-finding studies, with all dosage groups combined.
Table 2. Clinical Studies Comparing Direct Thrombin Inhibitors with Control Therapy in Patients with Coronary Syndromes (with or without Percutaneous Coronary Intervention) or Atrial Fibrillation.
In 2001, the data from another randomized clinical trial in acute coronary syndromes became available.24 In this study, patients with myocardial infarction characterized by ST-segment elevation were randomly assigned to receive either bivalirudin or unfractionated heparin combined with streptokinase.24 No difference was observed in the primary outcome of 30-day mortality between the two treatment groups, although a benefit of bivalirudin was observed for the secondary outcome of reinfarction within 96 hours. In contrast to the results of the meta-analysis, rates of serious bleeding were not lower with bivalirudin.
Some aspects regarding the role of DTIs in acute coronary syndromes require comment. In the trials reviewed in the meta-analysis23 and in the Hirulog and Early Reperfusion or Occlusion 2 (HERO-2) study,24 DTIs have been compared with unfractionated heparin. However, several analyses have suggested that low-molecular-weight heparin may be superior to unfractionated heparin in patients with unstable angina and myocardial infarction.29,30,31 Moreover, aggressive antiplatelet therapy has become the standard treatment in acute coronary syndromes, and the role of DTIs has not been established in the setting of the combined use of aspirin and clopidogrel, as well as glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors.
Therefore, hirudin is an unattractive alternative for the treatment of patients with acute coronary syndromes, given the lack of a clear efficacy benefit, the observed increase in bleeding, and the higher cost as compared with unfractionated heparin. In a similar manner, bivalirudin does not appear to be more efficacious or safer than unfractionated heparin and cannot be recommended in this setting.
Percutaneous Coronary Intervention
The meta-analysis mentioned above23 suggested that the prespecified subgroup of patients undergoing percutaneous coronary intervention had no significant efficacy benefit, but the incidence of serious bleeding was less with hirudin and bivalirudin than with unfractionated heparin.
Bivalirudin was compared with heparin during coronary angioplasty for unstable or postinfarction angina. Initial results suggested that there was a benefit,32 a finding that was supported in a longer-term follow-up using an intention-to-treat analysis.33 The combined outcome of death, myocardial infarction, and revascularization at 7 and 90 days occurred less frequently with bivalirudin, mainly owing to an effect on the need for revascularization. At 90 days, serious bleeding was significantly reduced in the bivalirudin group (3.7 percent vs. 9.3 percent).33
The meta-analysis23 pooled data from trials that were conducted before the introduction of newer therapies such as intracoronary stenting and the use of GPIIb/IIIa inhibitors. In the Randomized Evaluation in Percutaneous Coronary Intervention Linking Angiomax to Reduced Clinical Events 2 (REPLACE-2) study, patients undergoing urgent or elective percutaneous coronary intervention were randomly assigned to receive unfractionated heparin plus GPIIb/IIIa inhibitors or to receive bivalirudin to which GPIIb/IIIa inhibitors were added only if complications occurred during the procedure.25 Aspirin was prescribed to all patients, and the use of clopidogrel was encouraged. The composite efficacy and safety outcome of death, myocardial infarction, urgent repeat revascularization, and serious bleeding was not significantly different between the two groups. However, the use of bivalirudin was associated with a lower rate of serious bleeding. GPIIb/IIIa inhibitors were used in only 7.2 percent of the bivalirudin recipients, which may have contributed to the lower costs associated with this approach.34 The composite outcome remained not significantly different at six months35 and was not affected by concomitant clopidogrel treatment.36 A subanalysis of this trial confirmed the similar efficacy and the lower incidence of bleeding for bivalirudin, regardless of renal function.37
In summary, bivalirudin appears to be safer than heparin in patients undergoing percutaneous coronary intervention, provided that GPIIb/IIIa inhibitors are administered if complications occur during the procedure.
Long-Term Treatment of Acute Coronary Syndromes
In patients with acute coronary syndromes, long-term treatment with aspirin leads to a reduction in the relative risk of recurrent ischemic events of approximately 23 percent.21,22 The addition of vitamin K antagonists further reduces cardiovascular complications, but at the expense of more bleeding.21,22 Long-term treatment with low-molecular-weight heparin does not offer an additional benefit over aspirin alone.21,22,38 The role of DTIs for long-term secondary prophylaxis in patients also receiving aspirin was investigated in the Efficacy and Safety of the Oral Direct Thrombin Inhibitor Ximelagatran in Patients with Recent Myocardial Damage (ESTEEM) trial.26 Ximelagatran in four oral doses was compared with placebo in patients with myocardial infarction. Ximelagatran significantly reduced the incidence of the combined outcome of all-cause mortality, nonfatal myocardial infarction, and severe recurrent ischemia during the six-month treatment period as compared with placebo, without a dose–response effect. The use of ximelagatran was not associated with a rate of serious bleeding higher than that of aspirin alone, but the total risk of bleeding was higher and dose-related. Elevation of alanine aminotransferase of more than three times the upper limit of normal occurred in 11 percent of the patients treated with ximelagatran and in 2 percent of those receiving placebo.
In summary, the investigation of the role of ximelagatran in the long-term treatment of acute coronary syndromes is limited to one phase 2 trial that was promising with respect to efficacy but identified possible hepatic toxicity as an important concern. Thus, at present, ximelagatran should not be considered for long-term treatment after acute coronary syndromes.
Atrial Fibrillation
The most serious clinical complication of atrial fibrillation is ischemic stroke.39 Although aspirin is the treatment of choice for low-risk patients, vitamin K antagonists are preferred for high-risk patients since there is a 36 percent reduction in the relative risk of stroke as compared with aspirin.39
Ximelagatran was compared with dose-adjusted warfarin for the prevention of all strokes and systemic embolism in patients with nonvalvular atrial fibrillation and at least one additional risk factor in the trials called Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation III (SPORTIF III) and SPORTIF V.27,28 These two studies had an identical design, except that the SPORTIF III trial was open-label, whereas the SPORTIF V trial was double-blinded. Ximelagatran was observed to be as effective as warfarin with respect to the primary efficacy outcome of stroke or systemic embolism. Furthermore, ximelagatran conferred a significantly lower risk of serious bleeding in the pooled analysis. Ximelagatran was associated with a significant increase in the proportion of patients with alanine aminotransferase levels at least three times the upper limit of normal as compared with warfarin (6.1 percent vs. 0.8 percent).
On the basis of the SPORTIF trials, ximelagatran might be a convenient alternative for vitamin K antagonists in patients who have atrial fibrillation plus at least one additional risk factor. However, the safety of this management strategy remains to be determined.
Other Indications
Recently, data have become available from phase 2 studies on the efficacy and safety of argatroban in acute stroke40 and bivalirudin in coronary artery bypass surgery.41 However, these studies included small numbers of patients and will not be discussed further.
Prevention of Venous Thromboembolism
Despite prophylaxis, the rate of symptomatic venous thromboembolism in patients undergoing serious orthopedic surgery remains as high as 1.5 to 10 percent in the three months following surgery.42 Desirudin, melagatran, and ximelagatran have been studied in phase 3 trials in patients undergoing hip or knee surgery (Table 3). Recently, a pilot study investigated the role of the combination of melagatran and ximelagatran in elective abdominal surgery.53
Table 3. Clinical Studies Comparing Direct Thrombin Inhibitors with Control Therapy for Prophylaxis and Treatment of Venous Thromboembolism.
Ximelagatran
Oral ximelagatran has been investigated either alone or in combination with subcutaneous melagatran for the prevention of venous thromboembolism after orthopedic surgery. In a double-blind, randomized trial among patients undergoing total hip replacement, the efficacy and safety of initiating oral ximelagatran after surgery, as compared with enoxaparin, were evaluated.43 The rates of both overall venous thromboembolism and proximal deep venous thrombosis (with or without pulmonary embolism) were significantly higher in patients receiving ximelagatran than they were among those treated with enoxaparin; the incidence of episodes of serious bleeding was similar.
Warfarin (with the use of a target international normalized ratio of 2.5) has been the control treatment in two phase 3 trials among patients undergoing total knee replacement.44,45 Both treatments were started postoperatively. In the first study, the incidence of overall venous thromboembolism and proximal deep venous thrombosis (with or without symptomatic pulmonary embolism) was not significantly lower in patients receiving ximelagatran; the incidence of serious bleeding was similar in the two groups.44 In the second trial, two doses of ximelagatran were compared with warfarin in order to demonstrate superiority of the higher ximelagatran dose.45 A dose of 36 mg of ximelagatran reduced the rate of overall deep venous thrombosis as compared with both 24 mg of ximelagatran and warfarin. Serious bleeding occurred with a similar frequency in all groups. Elevations of alanine aminotransferase that were more than three times the upper limit of normal were observed less frequently with both doses of ximelagatran than with warfarin at the end of treatment, though the levels had normalized in the warfarin group four to six weeks later, whereas persistent increases in levels of alanine aminotransferase were observed in some patients in the ximelagatran groups (0.6 percent and 0.1 percent in the high- and low-dose groups, respectively).
Melagatran–Ximelagatran
The efficacy of the use of subcutaneous melagatran followed by oral ximelagatran was tested in two phase 3 trials among patients undergoing total hip or total knee replacement.46,48 In the Melagatran for Thrombin Inhibition in Orthopedic Surgery III (METHRO III) study, postoperative initiation of melagatran followed by ximelagatran was compared with preoperative initiation of enoxaparin.46 Both groups in the study were associated with similar rates of venous thromboembolism and of serious bleeding. In the Expanded Prophylaxis Evaluation Surgery Study (EXPRESS), the administration of melagatran before surgery followed by ximelagatran was compared with preoperative administration of enoxaparin.48 The rates of venous thromboembolism were significantly lower with the melagatran–ximelagatran regimen, but both serious and minor bleeding were observed more frequently.
Desirudin
Two phase 3 trials have evaluated preoperative administration of desirudin among patients undergoing hip replacement.49,50 In one study, desirudin was compared with preoperative administration of enoxaparin.49 The incidence of overall and proximal deep venous thrombosis was lower in patients treated with desirudin, with a similar risk of serious bleeding in the two groups. In the other study, preoperative administration of desirudin was compared with preoperative administration of unfractionated heparin.50 Desirudin reduced the incidence of overall and proximal deep venous thrombosis. Serious bleeding episodes were similar in the two groups.
Dabigatran
The Boehringer Ingelheim Study in Thrombosis II (BISTRO II) trial, a phase 2 study, compared oral dabigatran with enoxaparin in the prevention of venous thromboembolism after orthopedic surgery.47 Dabigatran was started 1 to 4 hours after surgery, whereas enoxaparin was initiated 12 hours before surgery. The highest doses of dabigatran were associated with a significantly lower incidence of venous thromboembolism than was enoxaparin. However, the risk of serious bleeding with dabigatran increased in a dose-dependent manner.
Perioperative Timing
The timing for the initiation of thromboprophylaxis relative to surgery might be more important with the administration of DTIs than with low-molecular-weight heparin, although, to our knowledge, a direct comparison has not been performed.42 The administration of ximelagatran alone or combined with subcutaneous melagatran postoperatively appears to be less effective than low-molecular-weight heparin but more effective than warfarin, with similar bleeding risks. In the administration of preoperative prophylaxis, both desirudin and the combination of melagatran and ximelagatran were observed to be more effective than either unfractionated or low-molecular-weight heparin.48,49,50 However, the reduction in thromboembolic events with either ximelagatran or melagatran was offset by more bleeding episodes.
Current data, taken together, suggest no important advantages to using most DTIs as compared with the routine use of low-molecular-weight heparin for prophylaxis of venous thromboembolism. The one exception appears to be desirudin, which can be recommended for prophylaxis among patients undergoing hip replacement.
Treatment of Established Venous Thromboembolism
Initial Treatment
Phase 2 studies with recombinant hirudin and melagatran have consistently suggested a similar efficacy and safety of DTIs as compared with standard treatment with low-molecular-weight heparin plus vitamin K antagonists for the initial treatment of venous thromboembolism.54,55 In the phase 3 Thrombin Inhibitor in Venous Thromboembolism (THRIVE) study, patients with deep venous thrombosis were randomly assigned to receive either six months of oral ximelagatran or initial treatment with subcutaneous enoxaparin combined with warfarin.51 Ximelagatran was as effective as the combination therapy, and rates of bleeding complications were similar. However, alanine aminotransferase levels increased to more than three times the upper limit of normal in 9.6 percent of the patients receiving ximelagatran and in 2.0 percent of those treated with the combination of enoxaparin and warfarin. Thus, oral ximelagatran was as effective for the treatment of venous thromboembolism without the need for monitoring, but there was concern about safety, given increases in hepatic enzymes.
Long-Term Secondary Prophylaxis
After six months of treatment with vitamin K antagonists, patients with venous thromboembolism have a 5 to 7 percent risk of recurrence in the first year after discontinuation.56 Therefore, long-term treatment has been recommended for patients at high risk for recurrence. Extended prophylaxis with ximelagatran was compared with placebo for 18 months in patients with thromboembolism who had been treated with vitamin K antagonists for at least 6 months.52 Ximelagatran significantly reduced the rate of recurrent venous thromboembolism without a significant increase in the incidence of either serious or minor bleeding. However, ximelagatran was associated with a significantly increased rate of elevated alanine aminotransferase levels (6.4 percent vs. 1.2 percent). Thus, there is concern about hepatic toxicity with long-term use of ximelagatran.
Heparin-Induced Thrombocytopenia
Heparin-induced thrombocytopenia is an adverse drug reaction mediated by the immune system, with clinical manifestations initiated by antibodies directed against platelet factor 4, which becomes an antigenic target when bound to heparin. This antibody–platelet factor 4–heparin complex is able to activate platelets and may cause venous and arterial thrombosis. Although the immediate discontinuation of heparin is mandatory in this condition, the strategy is insufficient, given the high cumulative risk of thrombosis during 30-day administration of the drug — up to 53 percent without antithrombotic treatment.57 Thus, for patients with suspected or confirmed heparin-induced thrombocytopenia, the use of alternative anticoagulants is recommended.57 The use of DTIs for this condition is theoretically supported by the intense thrombin activity observed in these patients.57,58,59
Two DTIs, lepirudin and argatroban, are approved in the United States for heparin-induced thrombocytopenia. The data about the efficacy and safety of lepirudin and argatroban come from prospective cohort studies that used historical controls.59,60,61 In patients with proven heparin-induced thrombocytopenia who were treated with lepirudin, a thrombotic event occurred in approximately 4 percent of patients, as compared with 15 percent in historical controls, but the administration of lepirudin was associated with a higher rate of serious bleeding (14 percent vs. 8 percent).59 Similar results were reported for patients with heparin-induced thrombocytopenia with thromboembolic complications.62 In two series of patients with a clinical diagnosis of heparin-induced thrombocytopenia and thrombosis who were treated with argatroban, the rates of new thrombotic episodes were 13 and 19 percent, as compared with approximately 35 percent in historical controls, with bleeding rates of 6 and 11 percent.60,61
Antihirudin antibodies develop in 40 to 74 percent of patients receiving lepirudin after four days or more of treatment.59,63,64 Of note, fatal anaphylaxis has been described with lepirudin, particularly in patients who are treated again within three months of a previous exposure to this agent.65 In contrast, argatroban does not appear to be immunogenic.66 Thus, lepirudin and argatroban appear to be effective in patients with heparin-induced thrombocytopenia, but drawbacks are an enhanced risk of bleeding and immunogenicity of lepirudin.
Remaining Issues
Direct Thrombin Inhibitors and Liver Function
No available data report about hepatic dysfunction with the use of recombinant hirudins, bivalirudin, or argatroban. The pharmacokinetic and pharmacodynamic properties of ximelagatran and melagatran do not appear to be influenced in the presence of mild-to-moderate impairment of liver function,67 and short-term exposure to ximelagatran (about 12 days) does not appear to increase the risk of hepatotoxicity.68 However, data on longer-term use of ximelagatran and melagatran indicate that alanine aminotransferase levels can become elevated after one to six months in 6 to 10 percent of patients. Although increases that have been reported so far are usually asymptomatic and reversible, even if the medication is continued, the few cases of fatal hepatotoxicity observed with prolonged administration of ximelagatran have led the FDA to deny approval of ximelagatran in the United States,69 and only short-term use of ximelagatran has been approved in Europe.70 The mechanisms of these liver-enzyme abnormalities are still unknown.
Monitoring Activity
The best method to monitor therapy with DTIs has not been clearly established.71,72,73,74,75,76 The usefulness of the activated partial-thromboplastin time seems limited by its poor linearity and reproducibility, especially when heparin or a vitamin K antagonist is coadministered.71,72,73,77,78,79 The ecarin clotting time better reflects the actual plasma concentration of DTIs, but this test is not widely available.74,75,76,77,80,81,82
Recombinant hirudins and argatroban can be monitored with the use of the activated partial-thromboplastin time and bivalirudin with the activated clotting time. In patients with heparin-induced immune thrombocytopenia, antihirudin antibodies form complexes with lepirudin that may reduce the renal clearance of the drug.63 This phenomenon often results in a need to reduce and monitor the dose to maintain the lepirudin anticoagulant effect within the therapeutic range, especially in patients with impaired renal function.57
Since there is no antidote for rapidly reversing the effect of DTIs, monitoring these drugs is important for patients who have a high risk of bleeding. However, given the short half-life of most DTIs, the major anticoagulant effects of DTIs should have disappeared by 12 to 24 hours after the last dose. Preliminary data suggest that recombinant factor VIIa has a limited capacity to reverse the anticoagulant effects of melagatran.83
Conclusions
Despite many well-performed clinical trials, there are few clinical indications for DTIs. For acute coronary syndromes, none of the DTIs have consistently shown superior efficacy combined with a similar safety in comparison with the present standard treatment with heparin and antiplatelet agents. For patients with unstable angina who are undergoing a percutaneous coronary intervention, bivalirudin may be superior to heparin plus GPIIb/IIIa inhibitors administered in case of intraprocedural complications. No DTIs have been convincingly demonstrated to be efficacious and safe for long-term treatment after acute coronary syndromes. In contrast, the efficacy data of ximelagatran in atrial fibrillation are promising, but concern with regard to hepatic toxicity with long-term use must be resolved. When thromboprophylaxis is initiated after serious orthopedic surgery, ximelagatran-containing regimens are less effective than is treatment with low-molecular-weight heparin, but such regimens are superior to warfarin therapy and have a similar safety profile. Preoperative initiation of desirudin is an alternative to the standard approach, but preoperative initiation of melagatran plus ximelagatran increases the risk of bleeding.
Dr. Büller reports having received consulting fees from AstraZeneca.
We are indebted to Dr. Ron J.G. Peters, Department of Cardiology, Academic Medical Center, Amsterdam, for critical review of the manuscript.
Source Information
From the Department of Vascular Medicine, Academic Medical Center, Amsterdam (M.D., S.M., H.R.B.); and the Department of Medicine and Aging, School of Medicine and Aging Research Center, Gabriele D'Annunzio University Foundation, Chieti–Pescara, Italy (M.D.).
Address reprint requests to Dr. Di Nisio at the Academic Medical Center, Department of Vascular Medicine F4-138, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands, or at m.dinisio@amc.uva.nl.
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