Direct Thrombin Inhibitors

Home , Bivalirudin, Clopidogrel, Dermatan sulfate, Heparin, Hirudin, Lepirudin

The new england journal of medicine

review article

drug therapy Direct Thrombin Inhibitors

Marcello Di Nisio, M.D., Saskia Middeldorp, M.D., and Harry R. Büller, M.D.

From the Department of Vascular Medi- irect thrombin inhibitors (dtis) are a new class of anticoag- cine, Academic Medical Center, Amster- ulants that bind directly to thrombin and block its interaction with its sub- dam (M.D., S.M., H.R.B.); and the Depart- d ment of Medicine and Aging, School of strates. Some DTIs — such as recombinant hirudins, bivalirudin, and ximel- Medicine and Aging Research Center, Gab- agatran, either alone or in combination with melagatran — have undergone extensive riele D’Annunzio University Foundation, evaluation in phase 3 trials for the prevention and treatment of arterial and venous Chieti–Pescara, Italy (M.D.). Address re- print requests to Dr. Di Nisio at the Aca- thrombosis. The evidence concerning the clinical applicability of other DTIs, such as demic Medical Center, Department of Vas- argatroban and dabigatran, is limited to phase 2 studies. Four parenteral DTIs have cular Medicine F4-138, Meibergdreef 9, been approved by the Food and Drug Administration (FDA) in North America: hirudin 1105 AZ, Amsterdam, the Netherlands, or at [email protected]. and argatroban for the treatment of heparin-induced thrombocytopenia, bivalirudin as an alternative to heparin in percutaneous coronary intervention, and desirudin as pro- N Engl J Med 2005;353:1028-40. phylaxis against venous thromboembolism in hip replacement. This review discusses Copyright © 2005 Massachusetts Medical Society. 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 en- dothelium. The interaction of tissue factor with plasma factor VII activates the coagulation cascade, producing thrombin by stepwise activation of a series of proenzymes (Fig. 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.

differences from heparins Thrombin-inhibiting drugs can block the action of thrombin by binding to three do- mains: the active site or catalytic site and two exosites (Fig. 2). Located next to the active site, exosite 1 acts as a dock for substrates such as fibrin, thereby orienting the appro- priate 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 (Fig. 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.2-4 Thus, heparins have a reduced capacity for the inhibition of fibrin-bound thrombin, which ap-

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drug therapy

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.) pears to be detrimental, because active thrombin site functions of thrombin.8 Therefore, in contrast further triggers thrombus growth. to the hirudins, bivalirudin produces only a transient Since DTIs act independently of antithrombin, inhibition of thrombin. they can inhibit thrombin bound to fibrin or fi- By interacting only with the active site, univalent brin degradation products.3-5 Bivalent DTIs block DTIs inactivate fibrin-bound thrombin.9,10 Argat- thrombin at both the active site and exosite 1, where- roban and melagatran (like bivalirudin) dissociate as univalent DTIs bind only to the active site. The from thrombin, leaving a small amount of free, en- group of bivalent DTIs includes hirudin and bival- zymatically active thrombin available for hemostatic irudin, whereas argatroban, melagatran (and its interactions.11,12 oral precursor, ximelagatran), and dabigatran are By reducing the thrombin-mediated activation of univalent DTIs. Native hirudin and recombinant platelets, DTIs also have an antiplatelet effect.13,14 hirudins (lepirudin and desirudin) form an irrevers- Since DTIs do not bind to plasma proteins, these ible 1:1 stoichiometric complex with thrombin.6 In agents should produce a more predictable response a similar way, bivalirudin, a synthetic hirudin, binds than does unfractionated heparin and should be to the active site and exosite 1,7 but once bound, it more effective than low-molecular-weight heparins is cleaved by thrombin, thereby restoring the active- because they inhibit fibrin-bound thrombin.

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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.

12,15 pharmacokinetics renal function. Although excessive anticoag- and pharmacodynamics ulation with hirudin in patients with renal insuffi- ciency can be managed with high-volume hemo- The routes of administration, plasma half-lives, and filtration with hirudin-permeable hemodialysis main sites of clearance of the various DTIs are list- membranes,15 the available data remain scarce. ed in Table 1. DTIs with a predominant renal clear- Studies in animals suggest that excessive plasma ance such as hirudin, melagatran, and dabigatran concentrations of melagatran can be managed by are likely to accumulate in patients with impaired either hemodialysis or the administration of acti-

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drug therapy

Table 1. Main Properties and Pharmacokinetic Characteristics of Direct Thrombin Inhibitors.

Ximelagatran Recombinant Bivalirudin Argatroban and Melagatran Characteristic Hirudins* (Hirulog) (Novastan) (Exanta) Dabigatran Route of Intravenous, subcu- Intravenous Intravenous Intravenous, subcuta- Oral administration taneous neous (melagatran), oral (ximelagatran) Plasma half-life Intravenous, 60 min; 25 min 45 min Intravenous and sub- 12 hr subcutaneous, cutaneous, 2–3 hr; 120 min oral, 3–5 hr Main site of clearance Kidney Kidney, liver, Liver Kidney Kidney other sites

* Recombinant hirudins include lepirudin (Refludan) and desirudin (Iprivask). vated prothrombin complex concentrates.12 Since peared to be due mainly to a significant reduction patients with severe renal impairment have been in myocardial infarction, without a significant ef- excluded from the clinical trials, the safety of DTIs fect on death. The analysis by agent revealed that that are predominantly cleared by the kidneys re- benefits were similar for hirudin and bivalirudin, mains to be established. whereas a nonsignificant, small increase in the risk Bivalirudin is only partially excreted by the kid- of death or myocardial infarction was observed with neys, as hepatic metabolism and proteolysis at oth- univalent DTIs. Serious bleeding occurred less fre- er sites also contribute to its metabolism.16 How- quently among patients receiving DTIs than among ever, the half-life of bivalirudin is prolonged with those receiving heparin, but there was substantial severe renal impairment, and dose adjustments are heterogeneity for this outcome. Serious bleeding needed.17 occurred more frequently with hirudin than with Argatroban is predominantly cleared by hepatic heparin but less often with bivalirudin and univa- metabolism and requires dose adjustments in pa- lent inhibitors. The data on univalent DTIs should tients with hepatic dysfunction.18 The use of aspirin be interpreted with caution owing to the rather does not appear to influence the plasma concentra- small number of events and the fact that these re- tions of DTIs.19,20 sults are derived from dose-finding studies, with all dosage groups combined. studies in arterial thrombosis In 2001, the data from another randomized clinical trial in acute coronary syndromes became avail- acute coronary syndromes with or without able.24 In this study, patients with myocardial in- percutaneous coronary intervention farction characterized by ST-segment elevation were Patients with acute coronary syndromes (acute my- randomly assigned to receive either bivalirudin or ocardial infarction, either with or without ST-seg- unfractionated heparin combined with streptoki- ment elevation, and unstable angina) remain at risk nase.24 No difference was observed in the primary for recurrent myocardial ischemia, despite treat- outcome of 30-day mortality between the two treatment with aspirin, clopidogrel, and heparin.21,22 ment groups, although a benefit of bivalirudin was The role of DTIs in the management of acute coro- observed for the secondary outcome of reinfarction nary syndromes was reviewed by the Direct Throm- within 96 hours. In contrast to the results of the bin Inhibitor Trialists’ Collaborative Group in a meta-analysis, rates of serious bleeding were not meta-analysis of data on individual patients.23 Elev- lower with bivalirudin. en randomized trials were pooled, providing a total Some aspects regarding the role of DTIs in acute of 35,970 patients who were assigned to receive ei- coronary syndromes require comment. In the trials ther DTIs or unfractionated heparin from 24 hours reviewed in the meta-analysis23 and in the Hirulog up to 7 days and then were followed for at least 30 and Early Reperfusion or Occlusion 2 (HERO-2) days. As compared with heparin, DTIs reduced the study,24 DTIs have been compared with unfraction- incidence of the composite outcome of death and ated heparin. However, several analyses have sug- myocardial infarction both at the end of treatment gested that low-molecular-weight heparin may be and at 30 days (Table 2). The difference in risk ap- superior to unfractionated heparin in patients with

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The new england journal of medicine (percentage) unfractionated heparin, 2.3 unfractionated heparin, 0.5 unfractionated heparin, 4.1 gatran, 2; placebo, 1 warfarin, 2.4 warfarin, 4.3 Serious Bleeding Combined DTIs, 1.9; Combined Bivalirudin, 0.7; Bivalirudin, 2.4; ximela- Combined Ximelagatran, 1.7; Ximelagatran, 3.2; Major unfractionated heparin, 8.2 unfractionated heparin, 10.9 unfractionated heparin, 10.0 gatran, 12.7; placebo, 16.3 warfarin, 3.3 warfarin, 1.9 Percentage of Efficacy Outcome Combined DTIs, 7.4; Combined Bivalirudin, 10.8; Bivalirudin, 9.2; ximela- Combined Ximelagatran, 2.3; Ximelagatran, 2.6; Patients with a t Percutaneous Coronary Intervention) t Percutaneous Coronary Percutaneous Coronary Intervention Linking Angi- Percutaneous Coronary th Recent Myocardial Damage, and SPORTIF Stroke Pre- Outcomes Major Efficacy infarction at 30 days infarction, urgent repeat revascularization, or serious bleeding nonfatal myocardial infarction, or severe recurrent ischemia embolism embolism Death or myocardial Death at 30 days Death, myocardial Death from any cause, All strokes or systemic All strokes or systemic Control Treatment heparin heparin for 48 hr heparin plus GPIIb/IIIa inhibitors for 12–18 hr daily for 6 mo mean of 17 mo mean of 20 mo Unfractionated Unfractionated Unfractionated Placebo twice for a Warfarin for a Warfarin gatroban, efegatran fol- kg intravenously, lowed by 0.5 mg/kg/ hr for 12 and then 0.25 mg/kg/hr for 36 hr intravenous bolus, followed by 1.75 mg/ kg/hr for duration of procedure 36 mg, 48 or 60 mg twice daily for 6 mo twice daily for a mean of 17 mo twice daily for a mean of 20 mo Hirudin, bivalirudin, ar- Bivalirudin at 0.25 mg/ Bivalirudin at 0.75 mg/kg Ximelagatran at 24 mg, Ximelagatran at 36 mg Ximelagatran at 36 mg 6,010 1,883 3,407 3,922 No. of Patients DTI Regimen 35,970 17,073 with or without percutaneous coronary intervention elevation vention without ST elevation Acute coronary syndromes Myocardial infarction with ST Percutaneous coronary inter- Myocardial infarction with or Nonvalvular atrial fibrillation Nonvalvular atrial fibrillation study 27 25 28 23 26 24 Clinical Studies Comparing Direct Thrombin Inhibitors with Control Therapy in Patients with Coronary Syndromes (with or withou Therapy in Patients with Coronary Direct Thrombin Inhibitors with Control Clinical Studies Comparing coronary artery disease Collaborative Trialists’ Group coronary artery disease or Atrial Fibrillation.* Table 2. Table StudyShort-term treatment of Direct Thrombin Inhibitor HERO-2 Diagnosis or Treatment REPLACE-2 Long-term treatment of ESTEEM Atrial fibrillation SPORTIF III SPORTIF V vention Using an Oral Thrombin Inhibitor in Atrial Fibrillation. omax to Reduced Clinical Events 2, ESTEEM Efficacy and Safety of the Oral Direct Thrombin Inhibitor Ximelagatran in Patients wi omax to Reduced Clinical Events * HERO-2 Hirulog and Early Reperfusion or Occlusion 2, REPLACE-2 Randomized Evaluation in DTI denotes direct thrombin inhibitor,

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drug therapy unstable angina and myocardial infarction.29-31 the two groups. However, the use of bivalirudin was Moreover, aggressive antiplatelet therapy has be- associated with a lower rate of serious bleeding. come the standard treatment in acute coronary syn- GPIIb/IIIa inhibitors were used in only 7.2 percent dromes, and the role of DTIs has not been estab- of the bivalirudin recipients, which may have con- lished in the setting of the combined use of aspirin tributed to the lower costs associated with this ap- and clopidogrel, as well as glycoprotein IIb/IIIa proach.34 The composite outcome remained not (GPIIb/IIIa) inhibitors. significantly different at six months35 and was not Therefore, hirudin is an unattractive alternative affected by concomitant clopidogrel treatment.36 for the treatment of patients with acute coronary A subanalysis of this trial confirmed the similar ef- syndromes, given the lack of a clear efficacy bene- ficacy and the lower incidence of bleeding for bival- fit, the observed increase in bleeding, and the high- irudin, regardless of renal function.37 er cost as compared with unfractionated heparin. In In summary, bivalirudin appears to be safer than a similar manner, bivalirudin does not appear to be heparin in patients undergoing percutaneous cor- more efficacious or safer than unfractionated hep- onary intervention, provided that GPIIb/IIIa inhibi- arin and cannot be recommended in this setting. tors are administered if complications occur during the procedure. percutaneous coronary intervention The meta-analysis mentioned above23 suggested long-term treatment of acute coronary that the prespecified subgroup of patients under- syndromes going percutaneous coronary intervention had no In patients with acute coronary syndromes, long- significant efficacy benefit, but the incidence of se- term treatment with aspirin leads to a reduction in rious bleeding was less with hirudin and bivaliru- the relative risk of recurrent ischemic events of ap- din than with unfractionated heparin. proximately 23 percent.21,22 The addition of vita- Bivalirudin was compared with heparin during min K antagonists further reduces cardiovascular coronary angioplasty for unstable or postinfarction complications, but at the expense of more bleed- angina. Initial results suggested that there was a ing.21,22 Long-term treatment with low-molecular- benefit,32 a finding that was supported in a longer- weight heparin does not offer an additional benefit term follow-up using an intention-to-treat analy- over aspirin alone.21,22,38 The role of DTIs for long- sis.33 The combined outcome of death, myocardial term secondary prophylaxis in patients also receiv- infarction, and revascularization at 7 and 90 days ing aspirin was investigated in the Efficacy and occurred less frequently with bivalirudin, mainly Safety of the Oral Direct Thrombin Inhibitor Ximel- owing to an effect on the need for revascularization. agatran in Patients with Recent Myocardial Damage At 90 days, serious bleeding was significantly re- (ESTEEM) trial.26 Ximelagatran in four oral doses duced in the bivalirudin group (3.7 percent vs. 9.3 was compared with placebo in patients with myo- percent).33 cardial infarction. Ximelagatran significantly re- The meta-analysis23 pooled data from trials that duced the incidence of the combined outcome of were conducted before the introduction of newer all-cause mortality, nonfatal myocardial infarction, therapies such as intracoronary stenting and the and severe recurrent ischemia during the six-month use of GPIIb/IIIa inhibitors. In the Randomized treatment period as compared with placebo, with- Evaluation in Percutaneous Coronary Intervention out a dose–response effect. The use of ximelagatran Linking Angiomax to Reduced Clinical Events 2 was not associated with a rate of serious bleeding (REPLACE-2) study, patients undergoing urgent or higher than that of aspirin alone, but the total risk of elective percutaneous coronary intervention were bleeding was higher and dose-related. Elevation of randomly assigned to receive unfractionated hepa- alanine aminotransferase of more than three times rin plus GPIIb/IIIa inhibitors or to receive bivaliru- the upper limit of normal occurred in 11 percent of din to which GPIIb/IIIa inhibitors were added only the patients treated with ximelagatran and in 2 per- if complications occurred during the procedure.25 cent of those receiving placebo. Aspirin was prescribed to all patients, and the use In summary, the investigation of the role of ximel- of clopidogrel was encouraged. The composite ef- agatran in the long-term treatment of acute coro- ficacy and safety outcome of death, myocardial in- nary syndromes is limited to one phase 2 trial that farction, urgent repeat revascularization, and seri- was promising with respect to efficacy but identified ous bleeding was not significantly different between possible hepatic toxicity as an important concern.

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Thus, at present, ximelagatran should not be con- sirudin, melagatran, and ximelagatran have been sidered for long-term treatment after acute coro- studied in phase 3 trials in patients undergoing hip nary syndromes. or knee surgery (Table 3). Recently, a pilot study investigated the role of the combination of melagatran atrial fibrillation and ximelagatran in elective abdominal surgery.53 The most serious clinical complication of atrial fibrillation is ischemic stroke.39 Although aspirin is ximelagatran the treatment of choice for low-risk patients, vita- Oral ximelagatran has been investigated either alone min K antagonists are preferred for high-risk pa- or in combination with subcutaneous melagatran tients since there is a 36 percent reduction in the rel- for the prevention of venous thromboembolism af- ative risk of stroke as compared with aspirin.39 ter orthopedic surgery. In a double-blind, random- Ximelagatran was compared with dose-adjusted ized trial among patients undergoing total hip re- warfarin for the prevention of all strokes and sys- placement, the efficacy and safety of initiating oral temic embolism in patients with nonvalvular atrial ximelagatran after surgery, as compared with enox- fibrillation and at least one additional risk factor aparin, were evaluated.43 The rates of both overall in the trials called Stroke Prevention Using an venous thromboembolism and proximal deep ve- Oral Thrombin Inhibitor in Atrial Fibrillation III nous thrombosis (with or without pulmonary em- (SPORTIF III) and SPORTIF V.27,28 These two stud- bolism) were significantly higher in patients receiv- ies had an identical design, except that the SPORTIF ing ximelagatran than they were among those III trial was open-label, whereas the SPORTIF V trial treated with enoxaparin; the incidence of episodes was double-blinded. Ximelagatran was observed to of serious bleeding was similar. be as effective as warfarin with respect to the pri- Warfarin (with the use of a target international mary efficacy outcome of stroke or systemic embo- normalized ratio of 2.5) has been the control treat- lism. Furthermore, ximelagatran conferred a signif- ment in two phase 3 trials among patients under- icantly lower risk of serious bleeding in the pooled going total knee replacement.44,45 Both treatments analysis. Ximelagatran was associated with a sig- were started postoperatively. In the first study, the nificant increase in the proportion of patients with incidence of overall venous thromboembolism and alanine aminotransferase levels at least three times proximal deep venous thrombosis (with or without the upper limit of normal as compared with warfarin symptomatic pulmonary embolism) was not sig- (6.1 percent vs. 0.8 percent). nificantly lower in patients receiving ximelagat- On the basis of the SPORTIF trials, ximelagatran; the incidence of serious bleeding was similar ran might be a convenient alternative for vitamin K in the two groups.44 In the second trial, two doses antagonists in patients who have atrial fibrillation of ximelagatran were compared with warfarin in plus at least one additional risk factor. However, the order to demonstrate superiority of the higher ximel- safety of this management strategy remains to be agatran dose.45 A dose of 36 mg of ximelagatran determined. reduced the rate of overall deep venous thrombosis as compared with both 24 mg of ximelagatran and other indications warfarin. Serious bleeding occurred with a similar Recently, data have become available from phase 2 frequency in all groups. Elevations of alanine amino- studies on the efficacy and safety of argatroban in transferase that were more than three times the up- acute stroke40 and bivalirudin in coronary artery per limit of normal were observed less frequently bypass surgery.41 However, these studies included with both doses of ximelagatran than with warfarin small numbers of patients and will not be discussed at the end of treatment, though the levels had nor- further. malized in the warfarin group four to six weeks lat- er, whereas persistent increases in levels of alanine prevention of venous aminotransferase were observed in some patients in thromboembolism the ximelagatran groups (0.6 percent and 0.1 percent in the high- and low-dose groups, respectively). Despite prophylaxis, the rate of symptomatic venous thromboembolism in patients undergoing serious melagatran–ximelagatran orthopedic surgery remains as high as 1.5 to 10 per- The efficacy of the use of subcutaneous melagatran cent in the three months following surgery.42 De- followed by oral ximelagatran was tested in two

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drug therapy (percentage) Serious Bleeding aparin, 0.9 0.9 ximelagatran (24 mg), 0.8; warfarin, 0.7 1.4; enoxaparin, 1.7 dabigatran (150 mg), 4.1; dabigatran (225 mg), 3.8; dabigatran (300 mg), 4.7; enoxaparin, 2.0 3.3; enoxaparin, 1.2 2.0 aparin–warfarin, 2.2 1.3 Ximelagatran, 0.8; enox- Ximelagatran, 1.7; warfarin, Ximelagatran (36 mg), 0.8; Melagatran–ximelagatran, Dabigatran (50 mg), 0.3; Melagatran–ximelagatran, Desirudin, 1.9; enoxaparin, No cases of serious bleeding Ximelagatran, 1.3; enox- Ximelagatran, 1.1; placebo, lism. lmonary embolism cannot be ruled out. in Inhibitor in Venous Thromboembolism. in Inhibitor Venous rombin Inhibition in Orthopedic Surgery III, Results for Efficacy aparin, 1.2 25.7 ximelagatran (24 mg), 24.9; warfarin, 27.6 31.0; enoxaparin, 27.3 dabigatran (150 mg), 17.4; dabigatran (225 mg), 13.1; dabigatran (300 mg), 16.6; enoxaparin, 24.0 2.3; enoxaparin, 6.3 25.5 heparin, 23 aparin–warfarin, 2.0 12.6 Outcomes (percentage) Ximelagatran, 3.6; enox- Ximelagatran, 19.2; warfarin, Ximelagatran (36 mg), 20.3; Melagatran–ximelagatran, Dabigatran (50 mg), 28.5; Melagatran–ximelagatran, Desirudin, 18.4; enoxaparin, Desirudin, 7; unfractionated Ximelagatran, 2.1; enox- Ximelagatran, 2.8; placebo, throm- Outcomes thrombosis with or without pulmonary embolism boembolism boembolism or death embolism† boembolism boembolism‡ thrombosis thrombosis thromboembolism thromboembolism Primary Efficacy Proximal deep venous Overall venous Overall venous throm- venous thrombo- Total Overall venous throm- Serious venous throm- Overall deep venous Overall deep venous recurrent venous Total Recurrent venous Control 7–12 days 12 days 12 days 8–11 days 6–10 days 8–11 days 8–12 days heparin for 8–11 days warfarin 18 mo Treatment Enoxaparin for for 7– Warfarin for 7– Warfarin Enoxaparin for Enoxaparin for Enoxaparin for Enoxaparin for Unfractionated Enoxaparin– Placebo for DTI Regimen daily for 7–12 days daily for 7–12 days mg twice daily for 7–12 days 3 mg, followed by ximelagatran at 24 mg twice daily for 8–11 days 225 mg twice daily or 300 once daily for 6–10 days 2 mg/hr before surgery and followed 3 mg/hr after surgery, by ximelagatran at 24 mg twice daily for 8–11 days ously twice daily for 8–12 days ously twice daily for 8–11 days daily for 6 mo daily for 18 mo Ximelagatran at 24 mg twice Ximelagatran at 24 mg twice Ximelagatran at 36 mg and 24 Melagatran subcutaneously at Dabigatran at 50 mg, 150 or Melagatran subcutaneously at Desirudin at 15 mg subcutane- Desirudin at 15 mg subcutane- Ximelagatran at 36 mg twice Ximelagatran at 24 mg twice 680 445 1851 1838 1973 1233 2788 2835 2079 2489 No. of Patients Diagnosis ment ment ment ment or total knee replacement ment or total knee replacement ment or total knee replacement ment ment thrombosis embolism or Treatment Total hip replace- Total knee replace- Total knee replace- Total hip replace- Total hip replace- Total hip replace- Total hip replace- Total hip replace- Total Acute deep venous thrombo- Venous 49 50 46 43 44 52 * 47 48 45 51 Clinical Studies Comparing Direct Thrombin Inhibitors with Control Therapy for Prophylaxis and Treatment of Venous Thromboembo of Venous Therapy for Prophylaxis and Treatment Direct Thrombin Inhibitors with Control Clinical Studies Comparing Table 3. Table Study Postoperative initiation of prophylaxis et al. Colwell et al. Francis A EXULT METHRO III BISTRO II Preoperative initiation of prophylaxis EXPRESS Eriksson et al. Eriksson et al. Initial treatment THRIVE Long-term secondary prophylaxis THRIVE III BISTRO II Boehringer Ingelheim Study in Thrombosis II, EXPRESS Expanded Prophylaxis Evaluation Surgery Study, and THRIVE Thromb BISTRO II Boehringer Ingelheim Study in Thrombosis II, EXPRESS Surgery Study, Expanded Prophylaxis Evaluation * A Exanta (Ximelagatran) Used to Lessen Thrombosis A, METHRO III Melagatran for Th EXULT DTI denotes direct thrombin inhibitor, † venous thromboembolism includes deep thrombosis, fatal or nonfatal pulmonary embolism, and unexplained death. Total ‡ Serious venous thromboembolism includes proximal deep thrombosis, symptomatic pulmonary embolism, and death in which pu

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phase 3 trials among patients undergoing total hip administration of ximelagatran alone or combined or total knee replacement.46,48 In the Melagatran with subcutaneous melagatran postoperatively ap- for Thrombin Inhibition in Orthopedic Surgery III pears to be less effective than low-molecular-weight (METHRO III) study, postoperative initiation of mel- heparin but more effective than warfarin, with simi- agatran followed by ximelagatran was compared lar bleeding risks. In the administration of preoper- with preoperative initiation of enoxaparin.46 Both ative prophylaxis, both desirudin and the combina- groups in the study were associated with similar tion of melagatran and ximelagatran were observed rates of venous thromboembolism and of serious to be more effective than either unfractionated or bleeding. In the Expanded Prophylaxis Evaluation low-molecular-weight heparin.48-50 However, the Surgery Study (EXPRESS), the administration of reduction in thromboembolic events with either melagatran before surgery followed by ximelagatran ximelagatran or melagatran was offset by more was compared with preoperative administration bleeding episodes. of enoxaparin.48 The rates of venous thromboem- Current data, taken together, suggest no impor- bolism were significantly lower with the melagat- tant advantages to using most DTIs as compared ran–ximelagatran regimen, but both serious and with the routine use of low-molecular-weight hep- minor bleeding were observed more frequently. arin for prophylaxis of venous thromboembolism. The one exception appears to be desirudin, which desirudin can be recommended for prophylaxis among pa- Two phase 3 trials have evaluated preoperative ad- tients undergoing hip replacement. ministration of desirudin among patients under- 49,50 going hip replacement. In one study, desirudin treatment of established was compared with preoperative administration of venous thromboembolism enoxaparin.49 The incidence of overall and proximal deep venous thrombosis was lower in patients initial treatment treated with desirudin, with a similar risk of seri- Phase 2 studies with recombinant hirudin and mel- ous bleeding in the two groups. In the other study, agatran have consistently suggested a similar effi- preoperative administration of desirudin was com- cacy and safety of DTIs as compared with standard pared with preoperative administration of unfrac- treatment with low-molecular-weight heparin plus tionated heparin.50 Desirudin reduced the incidence vitamin K antagonists for the initial treatment of of overall and proximal deep venous thrombosis. venous thromboembolism.54,55 In the phase 3 Serious bleeding episodes were similar in the two Thrombin Inhibitor in Venous Thromboembolism groups. (THRIVE) study, patients with deep venous thrombosis were randomly assigned to receive either six dabigatran months of oral ximelagatran or initial treatment The Boehringer Ingelheim Study in Thrombosis II with subcutaneous enoxaparin combined with war- (BISTRO II) trial, a phase 2 study, compared oral farin.51 Ximelagatran was as effective as the combi- dabigatran with enoxaparin in the prevention of ve- nation therapy, and rates of bleeding complications nous thromboembolism after orthopedic surgery.47 were similar. However, alanine aminotransferase Dabigatran was started 1 to 4 hours after surgery, levels increased to more than three times the upper whereas enoxaparin was initiated 12 hours before limit of normal in 9.6 percent of the patients receiv- surgery. The highest doses of dabigatran were as- ing ximelagatran and in 2.0 percent of those treated sociated with a significantly lower incidence of with the combination of enoxaparin and warfarin. venous thromboembolism than was enoxaparin. Thus, oral ximelagatran was as effective for the However, the risk of serious bleeding with dabigat- treatment of venous thromboembolism without the ran increased in a dose-dependent manner. need for monitoring, but there was concern about safety, given increases in hepatic enzymes. perioperative timing The timing for the initiation of thromboprophylax- long-term secondary prophylaxis is relative to surgery might be more important with After six months of treatment with vitamin K an- the administration of DTIs than with low-molecu- tagonists, patients with venous thromboembolism lar-weight heparin, although, to our knowledge, have a 5 to 7 percent risk of recurrence in the first a direct comparison has not been performed.42 The year after discontinuation.56 Therefore, long-term

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drug therapy treatment has been recommended for patients at and thrombosis who were treated with argatroban, high risk for recurrence. Extended prophylaxis with the rates of new thrombotic episodes were 13 and ximelagatran was compared with placebo for 18 19 percent, as compared with approximately 35 months in patients with thromboembolism who percent in historical controls, with bleeding rates of had been treated with vitamin K antagonists for at 6 and 11 percent.60,61 least 6 months.52 Ximelagatran significantly re- Antihirudin antibodies develop in 40 to 74 per- duced the rate of recurrent venous thromboembo- cent of patients receiving lepirudin after four days lism without a significant increase in the incidence or more of treatment.59,63,64 Of note, fatal anaphy- of either serious or minor bleeding. However, ximel- laxis has been described with lepirudin, particularly agatran was associated with a significantly in- in patients who are treated again within three creased rate of elevated alanine aminotransferase months of a previous exposure to this agent.65 In levels (6.4 percent vs. 1.2 percent). Thus, there is contrast, argatroban does not appear to be immu- concern about hepatic toxicity with long-term use nogenic.66 Thus, lepirudin and argatroban appear of ximelagatran. to be effective in patients with heparin-induced thrombocytopenia, but drawbacks are an enhanced heparin-induced risk of bleeding and immunogenicity of lepirudin. thrombocytopenia remaining issues Heparin-induced thrombocytopenia is an adverse drug reaction mediated by the immune system, with direct thrombin inhibitors clinical manifestations initiated by antibodies di- and liver function rected against platelet factor 4, which becomes an No available data report about hepatic dysfunction antigenic target when bound to heparin. This anti- with the use of recombinant hirudins, bivalirudin, body–platelet factor 4–heparin complex is able to or argatroban. The pharmacokinetic and pharma- activate platelets and may cause venous and arterial codynamic properties of ximelagatran and melagat- thrombosis. Although the immediate discontinua- ran do not appear to be influenced in the presence tion of heparin is mandatory in this condition, the of mild-to-moderate impairment of liver function,67 strategy is insufficient, given the high cumulative and short-term exposure to ximelagatran (about 12 risk of thrombosis during 30-day administration days) does not appear to increase the risk of hepa- of the drug — up to 53 percent without antithrom- totoxicity.68 However, data on longer-term use of botic treatment.57 Thus, for patients with suspected ximelagatran and melagatran indicate that alanine or confirmed heparin-induced thrombocytopenia, aminotransferase levels can become elevated after the use of alternative anticoagulants is recommend- one to six months in 6 to 10 percent of patients. Al- ed.57 The use of DTIs for this condition is theoreti- though increases that have been reported so far are cally supported by the intense thrombin activity ob- usually asymptomatic and reversible, even if the served in these patients.57-59 medication is continued, the few cases of fatal hep- Two DTIs, lepirudin and argatroban, are ap- atotoxicity observed with prolonged administration proved in the United States for heparin-induced of ximelagatran have led the FDA to deny approval thrombocytopenia. The data about the efficacy and of ximelagatran in the United States,69 and only safety of lepirudin and argatroban come from pro- short-term use of ximelagatran has been approved spective cohort studies that used historical con- in Europe.70 The mechanisms of these liver-enzyme trols.59-61 In patients with proven heparin-induced abnormalities are still unknown. thrombocytopenia who were treated with lepirudin, a thrombotic event occurred in approximately 4 per- monitoring activity cent of patients, as compared with 15 percent in The best method to monitor therapy with DTIs has historical controls, but the administration of lepi- not been clearly established.71-76 The usefulness of rudin was associated with a higher rate of serious the activated partial-thromboplastin time seems bleeding (14 percent vs. 8 percent).59 Similar results limited by its poor linearity and reproducibility, es- were reported for patients with heparin-induced pecially when heparin or a vitamin K antagonist is thrombocytopenia with thromboembolic compli- coadministered.71-73,77-79 The ecarin clotting time cations.62 In two series of patients with a clinical better reflects the actual plasma concentration of diagnosis of heparin-induced thrombocytopenia DTIs, but this test is not widely available.74-77,80-82

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Recombinant hirudins and argatroban can be ly shown superior efficacy combined with a similar monitored with the use of the activated partial- safety in comparison with the present standard thromboplastin time and bivalirudin with the acti- treatment with heparin and antiplatelet agents. For vated clotting time. In patients with heparin-induced patients with unstable angina who are undergoing immune thrombocytopenia, antihirudin antibodies a percutaneous coronary intervention, bivalirudin form complexes with lepirudin that may reduce the may be superior to heparin plus GPIIb/IIIa inhibi- renal clearance of the drug.63 This phenomenon tors administered in case of intraprocedural com- often results in a need to reduce and monitor the plications. No DTIs have been convincingly dem- dose to maintain the lepirudin anticoagulant effect onstrated to be efficacious and safe for long-term within the therapeutic range, especially in patients treatment after acute coronary syndromes. In con- with impaired renal function.57 trast, the efficacy data of ximelagatran in atrial fi- Since there is no antidote for rapidly reversing brillation are promising, but concern with regard the effect of DTIs, monitoring these drugs is impor- to hepatic toxicity with long-term use must be re- tant for patients who have a high risk of bleeding. solved. When thromboprophylaxis is initiated after However, given the short half-life of most DTIs, the serious orthopedic surgery, ximelagatran-contain- major anticoagulant effects of DTIs should have dis- ing regimens are less effective than is treatment appeared by 12 to 24 hours after the last dose. Pre- with low-molecular-weight heparin, but such regi- liminary data suggest that recombinant factor VIIa mens are superior to warfarin therapy and have a has a limited capacity to reverse the anticoagulant similar safety profile. Preoperative initiation of de- effects of melagatran.83 sirudin is an alternative to the standard approach, but preoperative initiation of melagatran plus ximel- conclusions agatran increases the risk of bleeding. Dr. Büller reports having received consulting fees from Astra- Despite many well-performed clinical trials, there Zeneca. We are indebted to Dr. Ron J.G. Peters, Department of Cardiolo- are few clinical indications for DTIs. For acute cor- gy, Academic Medical Center, Amsterdam, for critical review of the onary syndromes, none of the DTIs have consistent- manuscript.

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