Hematology

Anticoagulants other than heparin and warfarin

Anticoagulants other than heparin and warfarin
Author
Lawrence LK Leung, MD
Section Editor
Pier Mannuccio Mannucci, MD
Deputy Editor
Stephen A Landaw, MD, PhD
Last literature review version 19.3: Fri Sep 30 00:00:00 GMT 2011 | This topic last updated: Tue Oct 25 00:00:00 GMT 2011 (More)

INTRODUCTION — Traditional anticoagulants in clinical use for the prevention or treatment of thromboembolic disease are heparin and its analogues and warfarin. However, they have two major limitations: a narrow therapeutic window of adequate anticoagulation without bleeding, and a highly variable dose-response relation among individuals that requires monitoring by laboratory testing. (See “Therapeutic use of heparin and low molecular weight heparin” and “Therapeutic use of warfarin” and “Therapeutic use of fondaparinux”.)

The variability of unfractionated heparin is due in part to differences in bioavailability of subcutaneous heparin and to competitive occupation of binding sites (or in part to the significant nonspecific binding of heparin), by plasma proteins (other than antithrombin and coagulation factors), by proteins secreted by platelets (platelet factor 4), and by endothelial cells [1,2]. Furthermore, some of the heparin-binding proteins are acute phase reactants, the concentrations of which are increased in sick patients.

Another limitation to heparin is a reduced ability to inactivate thrombin that is bound to fibrin and factor Xa that is bound to activated platelets within a thrombus [3]. As a result, a thrombus may continue to grow during heparin therapy or clotting may be reactivated after heparin has been discontinued.

These limitations have provided the impetus for the development of other antithrombotic agents [4-12]. The major examples of these newer anticoagulants are the factor Xa inhibitors and the direct thrombin inhibitors; some of these newer agents are orally active. The direct thrombin inhibitors, in contrast to heparin, can inactivate fibrin-bound thrombin [3].

These anticoagulants will be reviewed here [13]. Efficacy of those agents that are available clinically are discussed in detail separately in the discussions of the individual thromboembolic disorders. Newer approaches to antiplatelet therapy via inhibition of platelet function by the glycoprotein IIb/IIIa antagonists are also discussed separately. (See “Clinical trials of platelet glycoprotein IIb/IIIa receptor inhibitors in coronary heart disease: Intravenous agents”.)

OVERVIEW OF HEMOSTASIS — Before beginning this review, it is useful to briefly summarize the major steps in normal hemostasis and the importance of thrombin as an anticoagulant target.

The three components of hemostasis, platelet activation, clotting cascade, and fibrinolysis, while often discussed separately, are closely related to each other in vivo. (See “Overview of hemostasis”.) As an example, the assembly of the two key clotting factor complexes, prothrombinase (factor Xa as the protease, factor Va as a cofactor, and prothrombin as the substrate) and tenase (factor IXa, factor VIII, and factor X), takes place on the activated platelet surface (figure 1). The cell surface-bound enzyme complexes markedly accelerate generation of the active enzymes, and protect the active enzymes from inhibition by their plasma protease inhibitors [14-16]. As a result, thrombin generation in vivo is in close proximity to activated platelets.

Another illustration of the integration of the components of hemostasis is that arterial platelet-rich thrombi are relatively resistant to lysis. One potential reason is that platelets contain a large amount of plasminogen activator inhibitor-1 (PAI-1), the physiologic inhibitor of tissue-type plasminogen activator (tPA) [17,18]. PAI-1 is released from activated platelets at the thrombus, contributing to its resistance to lysis by tPA or urokinase.

Because of these interactions, the division of the antithrombotic agents into the three categories: anticoagulants, antiplatelet agents, and thrombolytic agents, is quite arbitrary. This should be kept in mind when we approach antithrombotic therapies from the anticoagulant, antiplatelet, and thrombolytic standpoints.

Clotting cascade — A simplified depiction of the clotting cascade is shown in the figure (figure 2). Tissue factor (TF) is the physiologic initiator of clotting at a vascular wound. It is an absolute cofactor for factor VIIa (FVIIa), and the TF-FVIIa complex activates factor X, either directly or indirectly via activation of factor IX [19]. Factor Xa, in the presence of the cofactor factor Va and anionic phospholipid supplied by the activated cell surface, forms the prothrombinase complex, which activates prothrombin to thrombin.

Factor XI plays a less important role in this scheme, functioning as a tertiary pathway of factor X activation. Thrombin feedback activates factor XI; factor XIa then activates factor IX, which leads to further thrombin formation after the clot has been formed [20,21]. This lesser role is consistent with the clinical observation that bleeding complications are much less likely in patients with factor XI [22] deficiency compared with those with factor V or factor IX deficiency.

One possible mechanism by which bleeding occurs in factor XI deficiency is increased fibrinolysis due to diminished activation of thrombin-activatable fibrinolysis inhibitor (TAFI) [23,24]. The relatively high concentration of thrombin required within the clot for activation of TAFI appears to come from thrombin-mediated factor XI activation after the clot has been formed [23].

Thrombin as an anticoagulant target — Thrombin is the final enzyme of the clotting cascade, and therefore the target of most of the current clinical anticoagulants. The structure of thrombin has been defined by X-ray crystallography. There is a deep groove on one side of the molecule, and the active site of the enzyme is buried deep within this groove. Access to the active site is protected by the surrounding structures, some of which protrude into the opening and shield the active site. Restricted access gives rise to some of the specificity of the enzyme [25,26]. Residues important in thrombin-activatable fibrinolysis inhibitor (TAFI) activation are located above the active site cleft, whereas residues involved in protein C activation are located below the active site cleft [27].

In addition to the active site, there are two important positively charged patches at opposite poles on the thrombin molecule that represent sites for binding to macromolecular ligands: exosite I and exosite II [25,26,28].

 

  • Exosite I is a major docking site, by which thrombin interacts with many of its physiologically relevant substrates, such as the thrombin receptor, fibrinogen, factor V, protein C, and thrombomodulin [27].
  • Exosite II lies mostly on the back of the molecule and is spatially distinct from exosite I. Exosite II interacts with heparin and endogenous heparan sulfate.

 

One class of thrombin inhibitors, the direct thrombin inhibitors, directly interacts with and inhibits the active site of thrombin and exosite I [29]. There are also indirect thrombin inhibitors: heparin interacts with exosite II and antithrombin (AT) to inhibit thrombin; low molecular weight heparin and fondaparinux interact with AT to inhibit factor Xa; and the heparinoid danaparoid has an anticoagulant effect that is partially mediated by inhibition of thrombin via a combination of AT (heparin cofactor I) and heparin cofactor II (see below).

Heparin and antithrombin — Antithrombin (AT) neutralizes most of the enzymes in the clotting cascade, especially thrombin, factor Xa, and factor IXa, by forming equimolar, irreversible complexes [30]. AT has two active functional sites, the reactive center, Arg393-Ser394, which binds to the active site of thrombin, and the heparin binding site located at the amino terminus of the molecule [30]. The binding to heparin is mediated by a unique pentasaccharide sequence that is randomly distributed along the heparin chains [31,32].

By itself, inhibition of thrombin and factor Xa by AT is relatively slow from the viewpoint of hemostasis, taking several minutes to reach completion. However, binding of heparin to the heparin binding site on AT produces a change in the three-dimensional tertiary structure of AT which accelerates the inactivating process by 1000- to 4000-fold [30,31,33]. AT makes contact with a few key residues around the active site of thrombin, but has no major direct interaction with exosite I, with or without heparin [34,35].

The heparin-induced inactivation of thrombin requires the formation of a ternary complex in which heparin binds to both AT and to its binding site on thrombin, exosite II (figure 3) [36]. This complex forms only on pentasaccharide-containing chains at least 18 saccharide units long; this is true of most chains of unfractionated heparin, is less common in low molecular weight heparins, and does not occur with the heparin pentasaccharide fondaparinux (see below) [31,37]. There is no heparin-binding exosite on factor Xa; as a result, heparin interacts with factor Xa indirectly via AT.

DANAPAROID — Danaparoid is a low molecular weight heparinoid, consisting of a mixture of heparan sulfate (83 percent), dermatan sulfate, and chondroitin sulfate [38,39]. Its anticoagulant effect is mediated by inhibition of thrombin via a combination of AT (heparin cofactor I) and heparin cofactor II, plus some undefined endothelial cellular mechanism. As a result of shortage in drug substance in the United States, the manufacturer (Organon) has decided to discontinue providing this medication.

DIRECT THROMBIN INHIBITORS — Recombinant hirudin, argatroban, and bivalirudin are examples of direct thrombin inhibitors (figure 2). Part of the rationale for the clinical use of these drugs is, as mentioned above, the inability of the heparin-AT complex to inactivate clot-bound thrombin [3]. This may be due to the large size of the complex and to masking of the binding site(s) for heparin and AT on the thrombin molecule following the attachment of thrombin to fibrin or arterial wall matrix [40]. Such clot-bound thrombin acts as an important thrombogenic stimulus, such as at a site of coronary thrombosis, particularly following clot disruption by thrombolytic agents. In comparison, the direct thrombin inhibitors, which are AT-independent, inhibit clot-bound thrombin because their sites for binding thrombin are not masked by fibrin [3,7,41,42]. Direct thrombin inhibition can also overcome some of the other limitations of standard heparin therapy. (See “Therapeutic use of heparin and low molecular weight heparin”, section on ‘Limitations’.)

The absence of binding to PF4 is important clinically since antibodies responsible for HIT are provoked by the complex of heparin and platelet factor 4 (PF4) on the platelet surface. Thus, it might be expected that a direct thrombin inhibitor can be used to treat HIT and, in fact, both lepirudin and argatroban have been approved for this purpose. (See “Heparin-induced thrombocytopenia”.)

As will be discussed below, the direct thrombin inhibitors have been studied in a number of different clinical settings, including treatment and prophylaxis of DVT, prevention of embolic stroke in patients with atrial fibrillation, and in the acute management of patients with unstable angina or myocardial infarction [43].

Hirudin — Hirudin is a 65-amino-acid protein originally extracted from the salivary gland of the medicinal leech (Hirudo medicinalis). A number of hirudin analogs are commercially available (lepirudin, bivalirudin, desirudin) [44].

Hirudin binds to thrombin via direct interaction with the active site, and the carboxyl tail of hirudin also binds to the exosite I, giving rise to very high binding affinity [45]. The anticoagulant activity of hirudin is monitored by the aPTT. Its potential disadvantages are cost and the lack of an effective antidote. Subjects receiving desirudin appear to develop antihirudin antibodies at a rate similar to that seen in patients with heparin-induced thrombocytopenia who received lepirudin [46]. Anaphylactoid reactions have been reported with this and other hirudin analogs. It has been suggested that patients previously treated with hirudin or its analogs, including desirudin itself, should not receive desirudin [47].

Lepirudin — Lepirudin is a recombinant hirudin approved for the treatment of heparin-induced thrombocytopenia (HIT) [48,49]. The efficacy of lepirudin was demonstrated in a prospective series of 82 patients with confirmed HIT: 56 with thrombosis, 18 without thrombosis, and 8 undergoing cardiopulmonary bypass surgery [48]. The administration of lepirudin (0.1 to 0.4 mg/kg bolus followed by 0.1 to 0.15 mg/kg per hour infusion) was associated with a rapid increase in platelet count in 89 percent of patients, indicating the absence of crossreactivity with heparin-induced antibodies. The incidence of the combined endpoints (death, amputation, and new thromboembolic events) was significantly lower than in historical controls (25 versus 52 percent at day 35). The rate of bleeding was similar in the two groups.

Adequate anticoagulant levels were documented by prolongation of the activated partial thromboplastin time (aPTT) 1.5 to 3.0-fold above baseline. Caution should be used in patients with renal insufficiency since the drug is cleared by the kidney and its anticoagulant effect is not easily reversed.

Approximately 40 to 70 percent of patients treated with lepirudin for more than five days develop antihirudin antibodies [50,51]. These are not neutralizing antibodies and may actually enhance drug potency, perhaps by delaying its clearance from the circulation [52]. As a result, the aPTT needs to be monitored on a regular basis in such patients.

Bivalirudin — Bivalirudin (hirulog) is a direct thrombin inhibitor frequently used for anticoagulation in the setting of invasive cardiology, particularly percutaneous coronary intervention (PCI). It undergoes predominant non-organ elimination (proteolysis), and has a short half-life of approximately 25 minutes [53]. Its affinity for thrombin is intermediate between that of lepirudin and argatroban, explaining why it interferes with functional clotting assays to an extent intermediate between that achieved by these two other agents.

Bivalirudin has been approved by the United States Food and Drug Administration (FDA) for use in patients with unstable angina in patients undergoing percutaneous coronary intervention. (See “Antithrombotic therapy for intracoronary stent implantation: Clinical trials”, section on ‘Direct thrombin inhibitors and fondaparinux’ and “Anticoagulant therapy in unstable angina and acute non-ST elevation myocardial infarction”.)

Bivalirudin may also be of benefit in ST elevation myocardial infarction, but its role is less well defined. (See “Anticoagulant therapy in acute ST elevation myocardial infarction”, section on ‘Direct thrombin inhibitors’.)

Argatroban — Argatroban is another direct thrombin inhibitor [54]. It is a small molecule that, in contrast to hirudin, interacts with the active site of thrombin but does not make contact with exosites I or II. It has a short in vivo plasma half-life, and is monitored by the aPTT, although dose-dependent changes are also seen in the prothrombin time [55]. Dosing precautions are recommended in patients with hepatic dysfunction; dose adjustment is apparently not required in the presence of renal impairment [56].

A multi-institutional phase III prospective trial of argatroban in HIT, as compared with historical controls, has been completed; as a result of these and other studies, the drug was approved in June 2000 by the FDA for prophylaxis or treatment of thrombosis in heparin induced thrombocytopenia. Use of this agent in HIT is discussed separately. (See “Heparin-induced thrombocytopenia”, section on ‘Argatroban’.)

Argatroban has also been evaluated as an adjunct to thrombolysis in patients with acute myocardial infarction [57]. Although coronary patency (TIMI III flow) was achieved more often with argatroban than heparin, there was no difference between the two groups in the composite endpoints of death, recurrent infarction, cardiogenic shock or heart failure, revascularization, or recurrent ischemia at 30 days. (See “Anticoagulant therapy in acute ST elevation myocardial infarction”, section on ‘Direct thrombin inhibitors’.)

Orally active agents — There are a number of small molecule, direct thrombin inhibitors under development, some of which are orally active.

Dabigatran — Dabigatran etexilate (Pradaxa) is an orally active direct thrombin inhibitor that has been employed for prevention and treatment of venous and arterial thromboembolic disorders in various clinical settings (eg, prevention of VTE after total knee or total hip arthroplasty, treatment of acute VTE, prevention of stroke in atrial fibrillation) [58-64]. Dabigatran etexilate, the prodrug, is converted to the active compound dabigatran by non-specific esterases, which then binds directly to thrombin with high affinity and specificity [65].

SEE MORE:  Hematologic manifestations of HIV infection: Thrombocytopenia and coagulation abnormalities

Pharmacokinetics and dosing — Dabigatran has a half-life of approximately 12 to 14 hours in adult volunteers with normal renal function, which requires twice daily dosing. Maximum anticoagulant effects are achieved within two to three hours of ingestion [66]. Renal excretion of unchanged drug is the predominant elimination pathway, with about 80 percent of an intravenous dose being excreted unchanged in the urine [67,68]. Drug clearance is longer in older adults and those with reduced renal function; its half-life may be >24 hours in those with a creatinine clearance <30 mL/min [69]. Dose reductions have been suggested for some indications in the older adult (variously defined as >75 or >80 years of age) and in those with moderate or severe renal impairment. In the Canadian, UK and European Medicines Agency labeling, dabigatran is contraindicated for use in patients with a creatinine clearance <30 mL/min (severe impairment) [70-72].

Drug interactions — Dabigatran does not interact with the cytochrome P450 system. However, it is a substrate for the efflux transporter P-glycoprotein, and drug interactions may alter its efficacy. Its use in those taking certain P-glycoprotein inducers or inhibitors and those agents that alter dabigatran bioavailability (eg, rifampin, quinidine, ketoconazole, verapamil, amiodarone, clarithromycin), has been considered contraindicated in some labeling (eg, systemic ketoconazole in the Canadian and UK labeling, and quinidine in the European Medicines Agency labeling) [70-73]. In other labeling, concurrent use of these agents should either be avoided, administration separated by at least two hours, or the dose of dabigatran should be appropriately modified [70-72,74]. Dabigatran drug interactions and management suggestions, along with contraindicated combinations according to the prescribing information in various countries, are described in the table (table 1). In case of questions, the official prescribing information for dabigatran should be consulted along with the Lexi-Interact drug interactions program provided by UpToDate.

Drug stability — Due to the potential for product breakdown from moisture and loss of potency, dabigatran capsules should only be dispensed and stored in the original bottle or blister package (MedWatch Safety Alert for Dabigatran). Patients should not store or place this agent in any other container, such as pill boxes or pill organizers. Once the bottle is opened, the pills inside must be used within 60 days.

Coagulation testing — Because of its predictable pharmacokinetics, routine monitoring of coagulation is not recommended for patients taking dabigatran. While the ecarin clotting time, which is not generally available, is the best method to assess bleeding risk in patients taking dabigatran, the dilute thrombin time and aPTT are the most accessible qualitative methods for determining the presence or absence of an anticoagulant effect of this agent [66,69,75-77].

Efficacy in various conditions — A meta-analysis of available efficacy and safety data from three trials has concluded that dabigatran, at the recommended dose of 220 mg once daily, was non-inferior to enoxaparin (40 mg/day) for VTE prophylaxis after total knee or total hip arthroplasty, with a similar toxicity profile [78].

The RE-COVER study was a randomized, double-blind, noninferiority trial involving 2539 patients with acute VTE, which compared 6 months of treatment with either dabigatran (150 mg by mouth twice per day) or dose-adjusted warfarin, after initial parenteral anticoagulation. Results included the following [63]:

 

  • The primary outcome (recurrent symptomatic, objectively confirmed VTE and related deaths) was reached in 2.4 versus 2.1 percent of patients treated with dabigatran or warfarin, respectively. Hazard ratio for dabigatran of 1.10 (95% CI 0.65-1.84).
  • Major bleeding episodes occurred in 1.6 and 1.9 percent of those treated with dabigatran or warfarin, respectively, while episodes of any bleeding were noted in 16.1 and 21.9 percent, respectively.

 

It was concluded that a fixed dose of dabigatran was as effective as warfarin for the treatment of acute VTE, with a safety profile similar to that of warfarin, without requiring laboratory monitoring. Dabigatran has not yet been approved by the United States FDA for this indication, although it has been approved for use in patients with nonvalvular atrial fibrillation. Its cost-effectiveness versus warfarin is likely to depend upon the retail pricing of dabigatran [79], which is currently estimated to cost approximately eight US dollars per day [80]

Results of the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, which evaluated the efficacy and safety of dabigatran (at two different doses) relative to warfarin for patients with nonvalvular atrial fibrillation, are discussed separately. (See “Antithrombotic therapy to prevent embolization in nonvalvular atrial fibrillation”, section on ‘Dabigatran’.)

Reversal of dabigatran activity — There is no specific antidote for dabigatran [81]. Suggestions for reversing its anticoagulant effect have included the following [66,67,69] (see ‘Emergency treatment of bleeding’ below):

 

  • Drug discontinuation is usually sufficient to control bleeding in most clinical settings, since its half-life is relatively short (12 to 14 hours) in subjects with normal renal function.
  • Dabigatran is about one-third protein bound. It can be dialyzed in patients with renal impairment, with about 60 percent being removed after two to three hours of dialysis; charcoal hemofiltration has been suggested.
  • Use of activated charcoal may remove unabsorbed drug from the gastrointestinal tract.
  • Where there is life-threatening bleeding, the use of prothrombin complex concentrates (PCC) has been suggested, although in one study in 12 normal volunteers the use of PCC did not reverse dabigatran-associated prolongations in the aPTT, ecarin clotting time, or thrombin time [76].

 

A monoclonal antibody capable of rapidly and completely inhibiting dabigatran’s anticoagulant activity in vitro and in vivo in a mouse bleeding model has been developed [82]. It is currently under further development for use in clinical settings.

FACTOR XA INHIBITORS

In addition to the direct and indirect thrombin inhibitors, there are a number of indirect factor Xa inhibitors that are being developed (figure 2), such as the tick or leech anticoagulant proteins and their derivatives, and synthetic analogs of the heparin pentasaccharide required for binding to antithrombin [7,29,83-86].

There are also a number of orally active direct factor Xa inhibitors under clinical development. In general, as a class of new anticoagulants, and similar to the direct thrombin inhibitors, they all have rapid onset of action, with peak anticoagulant effect achieved within two to four hours, thus potentially obviating the need for a parenteral anticoagulant (eg, heparin or LMW heparin) in the initial treatment of VTE.

These agents are also designed to have relatively stable pharmacodynamic profiles such that routine monitoring is not required, making them theoretically superior to warfarin for long-term use. If indicated, anti-Xa activity can be measured using an aPTT assay similar to that employed for monitoring of LMW heparin. However, the cost of these new factor Xa inhibitors will likely be substantially higher than that of warfarin [87].

Idraparinux — The synthetic heparin pentasaccharide fondaparinux catalyzes factor Xa inactivation by AT without inhibiting thrombin (figure 3). Idraparinux is a longer acting analogue of fondaparinux, able to be given only once per week. Because of the concern about excessive bleeding following use of this agent, the development of idraparinux has been halted and focus has turned to a biotinylated version, SSR 126517, which is discussed below. (See “Therapeutic use of fondaparinux”, section on ‘Longer-acting analogues’.)

Idrabiotaparinux — Idrabiotaparinux (SSR 126517) is a biotinylated version of idraparinux. The rationale for this modification is that, if indicated, avidin can be infused intravenously, which will bind to the biotinylated idraparinux, causing it to be removed from the circulation. This neutralizes its anti-Xa activity, serving as an antidote and improving the benefit-to-risk profile of idraparinux [88,89]. Phase III trials of this agent in DVT and PE are underway [90,91].

Ultra low molecular weight heparin — AVE5026 is a hemisynthetic, ultra low molecular weight heparin, obtained by highly selective and controlled depolymerization of heparin, resulting in a structure strongly enriched in specific antithrombin-binding oligosaccharides [92]. It has an average molecular weight of 2000 to 3000 Da, as compared with other LMW heparins, which have a mean molecular weight of 4000 to 5000 Da. (See “Therapeutic use of heparin and low molecular weight heparin”, section on ‘Use of LMW heparin’.)

AVE5026 appears to have nearly pure anti-factor Xa activity [92]. It is currently in clinical trials [93].

Rivaroxaban — Rivaroxaban (BAY 59-7939, Xarelto) is an orally available direct factor Xa inhibitor with a bioavailability of 80 percent and peak plasma concentrations occurring 2.5 to 4 hours after oral administration. Dose-finding studies in patients undergoing orthopedic procedures suggested that an oral dose of 10 mg/day was suitable for investigation in phase III trials for the prevention of VTE [94-98]. Similarly, a dose of 20 to 40 mg/day was deemed suitable for phase III trials investigating the treatment of VTE [99].

In vitro studies have shown that rivaroxaban did not cause platelet activation or aggregation in the presence of HIT antibodies [100]. Furthermore, it did not cause the release of, or interact with, platelet factor 4, suggesting the potential use of this agent in patients with heparin-induced thrombocytopenia (HIT).

Efficacy — A number of randomized, double-blind phase III studies for the prevention of VTE in patients undergoing hip or total knee arthroplasty have compared this prophylactic dose of rivaroxaban beginning after surgery with enoxaparin 40 mg/day subcutaneously (ie, the European regimen) starting on the evening before surgery [64,101-103]. The primary efficacy outcome was the composite of any DVT, nonfatal PE, or death from any cause within 13 to 17 days (total knee arthroplasty) or 36 days (hip arthroplasty) following surgery. The primary safety outcome was major bleeding. Results from two representative studies include the following [101,102]. (See “Prevention of venous thromboembolic disease in surgical patients”, section on ‘Rivaroxaban’.)

 

  • For hip arthroplasty, the primary efficacy outcome occurred in 1.1 and 3.7 percent of those in the rivaroxaban and enoxaparin groups, respectively (absolute risk reduction 2.6 percent; 95% CI 1.5-3.7). Major bleeding occurred in 0.3 and 0.1 percent, respectively (p = 0.18).
  • For patients undergoing total knee arthroplasty, the primary efficacy outcome occurred in 9.6 and 18.9 percent of those in the rivaroxaban and enoxaparin groups, respectively (absolute risk reduction 9.2 percent; 95% CI 5.9-12.4). Major bleeding occurred in 0.6 and 0.5 percent, respectively.

 

An additional randomized, double-blind phase III study for the prevention of VTE in 3148 patients undergoing total knee arthroplasty compared the same oral prophylactic dose of rivaroxaban (10 mg once daily beginning 6 to 8 hours after surgery and continuing for a total of 10 to 14 days) with a different dose schedule for enoxaparin (30 mg subcutaneously every 12 hours for 10 to 14 days starting 12 to 24 hours after surgery; the North American regimen). The primary efficacy and safety outcomes were similar to the above study. Results included [104]:

 

  • In the modified intention-to-treat population, the primary efficacy outcome occurred in 6.9 and 10.1 percent of those in the rivaroxaban and enoxaparin groups, respectively (absolute risk reduction 3.2 percent; 95% CI 0.71-5.67; relative risk reduction 31 percent; 95% CI 7.5-49).
  • Major bleeding was not significantly different between the two treatment arms and occurred in 0.7 and 0.3 percent, respectively.

 

An open-label, randomized, non-inferiority study compared the use of oral rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin followed by a vitamin K antagonist for 3, 6, or 12 months in 3449 patients with acute, symptomatic DVT (initial treatment study). A parallel double-blind, randomized study compared rivaroxaban (20 mg daily) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for VTE (continued treatment study). The primary efficacy outcome for both studies was recurrent VTE. Results included the following [105]:

 

  • Rivaroxaban had non-inferior efficacy versus enoxaparin/vitamin K antagonist with respect to recurrent VTE (2.1 versus 3.0 percent; HR 0.68; 95% CI 0.44-1.04).
  • In the continued-treatment study, rivaroxaban had superior efficacy versus placebo with respect to recurrent VTE (1.3 versus 7.1 percent; HR 0.18; 95% CI 0.09-0.39).
  • The principal safety outcome in the initial treatment study, major bleeding or clinically relevant nonmajor bleeding, occurred in 8.1 percent of the patients in each group. In the continued treatment study, four patients in the rivaroxaban group (0.7 percent) and no patients in the placebo group had nonfatal major bleeding.

 

Phase III trials are ongoing to determine the efficacy and safety of rivaroxaban in reducing major ischemic outcomes in patients with acute coronary syndromes [106], for the prevention of stroke or systemic embolization in nonvalvular atrial fibrillation (the ROCKET AF Study) [107], as well as its ability to prevent VTE in a diverse population of medically ill patients (the MAGELLAN Study) [108]. (See “Antithrombotic therapy to prevent embolization in nonvalvular atrial fibrillation”, section on ‘Rivaroxaban’.)

Dosing and safety issues — Rivaroxaban has been approved in the United States, European Union (EU), and Canada for the prevention of venous thromboembolism in adults undergoing elective hip or knee replacement surgery, at a fixed oral dose of 10 mg/day beginning after hemostasis has been established. This dose does not require laboratory monitoring or adjustment. Monitoring can be accomplished through the prothrombin time (PT), the activated partial thromboplastin time (aPTT), or measurement of anti-Xa activity, although in one study their alterations poorly reflected the circulating concentrations as determined by functional approaches (eg, thrombin generation) [75]. The aPTT may be the more reliable test [109,110].

The use of rivaroxaban is not recommended for those with a creatinine clearance <30 mL/min, and is considered contraindicated in those with a creatinine clearance <15 mL/min, as well as in those with significant hepatic impairment (Child-Pugh Class B and C with coagulopathy).

Rivaroxaban interacts with drugs that are potent inhibitors of both CYP-3A4 and P-glycoprotein efflux transporter (eg, systemic ketoconazole, itraconazole, voriconazole, posaconazole or ritonavir), and concurrent use is contraindicated by Canadian product information [70]. Drugs that inhibit either CYP-3A4 or P-glycoprotein, as opposed to both, do not seem to significantly alter rivaroxaban [111]. Potent inducers of CYP-3A4 (eg, rifamycins, carbamazepine, St. John’s wort) may reduce rivaroxaban’s effects [73,111]. Rivaroxaban drug interactions and management suggestions, as well as contraindicated combinations according to the prescribing information in various countries, are described in the table (table 1).

In the event of hemorrhage, standard measures should be employed, as there is no specific antidote for rivaroxaban [81]. Suggestions for reversing its anticoagulant effect have included the following (see ‘Emergency treatment of bleeding’ below):

 

  • Drug discontinuation is usually sufficient to control bleeding in most clinical settings, since its half-life is relatively short (5 to 9 hours) in subjects with normal renal function.
  • Rivaroxaban is over 90 percent protein bound. Accordingly, it cannot be dialyzed; charcoal hemofiltration has been suggested.
  • Use of activated charcoal may remove unabsorbed drug from the gastrointestinal tract.
  • Where there is life-threatening bleeding, the use of prothrombin complex concentrates (PCC) has been suggested, although experience in such patients is limited. However, in one study in 12 normal, non-bleeding volunteers, PCC was able to reverse rivaroxaban-associated prolongation in the PT and to normalize the endogenous thrombin potential [76].
SEE MORE:  Low molecular weight heparin for venous thromboembolic disease

 

Due to potential reproductive toxicity, rivaroxaban is contraindicated in pregnancy.

Apixaban — In a double-blind randomized study comparing apixaban to enoxaparin for thromboprophylaxis after knee replacement, apixaban did not meet the prespecified criteria for noninferiority, but its use was associated with lower rates of clinically relevant bleeding and it had a similar adverse event profile to enoxaparin [112]. Other phase II and III trials have shown that apixaban compared favorably to both enoxaparin and warfarin as VTE prophylaxis in total knee replacement surgery [64,113,114] and that thromboprophylaxis with apixaban, as compared with enoxaparin, was associated with significantly lower rates of venous thromboembolism without increased bleeding in patients undergoing total hip replacement [115]. Apixaban (Eliquis) has subsequently been approved in Europe for use after hip/knee surgery.

A randomized, dose-ranging study compared three different schedules of apixaban (oral daily doses of 5 mg twice daily, 10 mg twice daily, or 20 mg once daily) or LMW heparin followed by a vitamin K antagonist (VKA), all given for a total of 84 to 91 days, in 520 patients with symptomatic DVT. Results included [116]:

 

  • The primary efficacy end-point, a composite of symptomatic recurrent VTE and asymptomatic deterioration of bilateral compression ultrasound or perfusion lung scan obtained at the end of treatment, occurred in 4.7 and 4.2 percent of those treated with apixaban and LMW heparin/VKA, respectively.
  • The primary safety end-point, a composite of major and clinically relevant, non-major bleeding was noted in 7.3 and 7.9 percent of those treated with apixaban and LMW heparin/VKA, respectively.
  • There was no evidence for a dose-response relationship with apixaban for either the efficacy or safety end-points. Routine liver function testing revealed no evidence of liver toxicity.

 

In a phase II double-blind, placebo-controlled, dose-ranging study, there was a dose-related increase in bleeding and a trend toward a reduction in ischemic events with the addition of apixaban to antiplatelet agents (aspirin, clopidogrel) in patients with recent acute coronary syndrome [117].

The use of apixaban in patients with atrial fibrillation is discussed separately. (See “Antithrombotic therapy to prevent embolization in nonvalvular atrial fibrillation”, section on ‘Apixaban’.)

Pharmacokinetic and safety issues — There is little in the way of information concerning the safety of this agent. The following information is known [118,119]:

 

  • No antidote is available
  • Apixaban is approximately 87 percent protein bound. It is not expected to be dialyzable
  • Renal excretion of the unchanged drug is 25 percent
  • Its half-life is 8 to 15 hours
  • Apixaban has minimal impact on the PT, INR, or aPTT at therapeutic concentrations, but factor Xa inhibition seems appropriately sensitive to detect its presence [120].

 

ANTICOAGULANTS IN DEVELOPMENT

Tissue factor and factor VII as potential targets — The recombinant form of tissue factor pathway inhibitor (TFPI), the physiologic inhibitor of the TF/FVIIa complex, is being tested, and there are also specific TF/FVIIa and factor VIIa inhibitors (eg, nematode anticoagulant protein) undergoing development [121-124].

Factor V and factor VIII as combined targets — All of the above anticoagulants target the active enzymes in the clotting cascade. An alternative method is to simultaneously target the two cofactors in the cascade, factor Va and factor VIIIa. There is a potential advantage in this approach. Inhibition of the cofactors dampens the clotting cascade but does not completely block the generation of thrombin as might occur with a thrombin inhibitor if present in excess. This problem may account for the relatively narrow therapeutic window observed for hirudin.

One way of targeting both factor Va and factor VIIIa is to use recombinant activated protein C, which has been approved for treatment of advanced sepsis. Activated protein C, in association with protein S on phospholipid surfaces, proteolytically inactivates factors Va and VIIIa, thereby inactivating prothrombinase. (See “Overview of hemostasis”.)

Other possibilities include a protein C activator such as soluble recombinant thrombomodulin which, when bound to thrombin, converts protein C to activated protein C.

Factor VIII inhibitor — TB-402 is a human IgG4 monoclonal antibody that is a partial inhibitor of factor VIII. As a result of its long half-life (approximately three weeks), this agent may provide a prolonged antithrombotic effect after a single dose. This was demonstrated in a randomized phase II trial in patients following total knee replacement, in which a single postoperative intravenous injection of TB-402 was found to be as effective and safe as 10 days of the LMW heparin enoxaparin (40 mg/day for at least 10 days) in preventing postoperative VTE [125].

Selective inhibition of the procoagulant properties of thrombin — Use of the above noted activated protein C approaches is based upon the premise that thrombin’s procoagulant and anticoagulant properties can be dissociated and exploited. All of the active site inhibitors of thrombin inhibit both types of activities, and an ideal thrombin inhibitor may be one that will selectively inhibit its procoagulant properties while retaining thrombin’s ability to activate protein C, thereby exploiting this powerful natural anticoagulant pathway [126].

Two experimental approaches to selective procoagulant inhibition are the creation of thrombin mutants and of molecules which act like thrombomodulin. A thrombin mutant (E229K) has been identified in which glutamic acid in position 229 in wild-type thrombin is replaced by lysine [127]. This protein has less than 1 percent of the procoagulant properties of wild-type thrombin, while retaining approximately 50 percent of its protein C activation capability [128]. As a result, it functions as an anticoagulant. It does not consume fibrinogen, clotting factors, or platelets, and, even at the peak of its anticoagulation effect, it does not prolong the bleeding time in contrast to hirudin or the platelet glycoprotein IIb/IIIa antagonists.

A small molecule has been identified that suppresses fibrinogen clotting and enhances protein C activation by thrombin, thereby functioning in part like a soluble thrombomodulin [129]. This change in substrate specificity appears to be mediated by an alteration in thrombin’s substrate recognition site, a mechanism seemingly different from the allosteric changes induced by thrombomodulin.

Recombinant soluble thrombomodulin (ART-123) — The recombinant form of the extracellular domain of thrombomodulin has a long plasma half-life of two to three days after a subcutaneous injection, such that it can be given once every five to six days with maintenance of anticoagulant activity [130]. In a phase II trial, ART-123 was shown to be efficacious for VTE prophylaxis following total hip replacement surgery [131].

Factor IXa inhibitor — REG1 consists of RB006, an injectable RNA aptamer that specifically binds and inhibits factor IXa, and RB007, the complementary oligonucleotide that neutralizes its anti-IXa activity if and when needed. Whether selective factor IXa inhibition produces an appropriate anticoagulant effect when combined with platelet-directed therapy in patients with stable coronary artery disease is the subject of ongoing trials [132,133].

Factor XIIa inhibitor — The selective factor XIIa inhibitor rHA-Infestin-4 (recombinant human albumin fused to the factor XIIa inhibitor Infestin-4) is highly active in human plasma and profoundly protects mice and rats from pathologic thrombus formation while not affecting hemostasis [134]. This agent is being considered for the prevention and treatment of acute ischemic cardiovascular and cerebrovascular events in humans.

EMERGENCY TREATMENT OF BLEEDING — The use of any anticoagulant is associated with an increased risk of bleeding. Unlike heparin and warfarin, the actions of which can be reversed using protamine and vitamin K, respectively, most of these newer anticoagulants do not have reversing agents or antidotes [81,135-137].

The treatment of bleeding episodes in patients taking these newer agents is problematical, as there is little in the way of evidence to guide the management of these patients. A number of general measures have been suggested [66,137]:

 

  • Rapid and continuous assessment of the patient’s condition, including establishment of an effective airway, stable hemodynamic status, and optimal body temperature, blood pH, and electrolyte balance, including calcium.
  • Assessment of the patient’s coagulation status (eg, activity of the coagulation cascade (eg, aPTT, thrombin time), hemoglobin level, platelet count)
  • Address mechanical causes of bleeding that may require invasive approaches (eg, endoscopy, radiologic interventions, surgery)
  • Withdraw all of the anticoagulant from the patient’s bedside and withdraw any remaining material from intravenous lines.
  • Consider the use of prohemostatic agents (eg, antifibrinolytic agents, desmopressin, recombinant factor VIIa [138]) and appropriate doses of an antidote, if available.
  • Consider modalities that may specifically remove the anticoagulant (eg, hemodialysis, hemoperfusion, plasmapheresis)

 

SUMMARY AND RECOMMENDATIONS — A number of anticoagulants other than the heparins and vitamin K antagonists are either currently available or in clinical trials. Some of these are orally active.

Mechanisms of action — The mechanisms of action of the anticoagulants discussed here include:

 

  • Direct inhibition of thrombin (eg, ximelagatran, dabigatran)
  • Inhibition of Factor Xa (eg, idraparinux, rivaroxaban)
  • Inhibition of other coagulation factors (eg, tissue factor, factor VIIa, factor V, factor VIII, factor IXa)

 

Anticoagulant-associated bleeding — The treatment of bleeding episodes in patients taking these newer agents is problematical, as most do not have antidotes. General guidelines for the supportive care of bleeding patients taking these agents are provided in the text. (See ‘Emergency treatment of bleeding’ above.)

General guidelines for use of these agents — In addition to the lack of effective antidotes, there is insufficient evidence at this time for long-term safety, and use in patients with hepatic or renal impairment to guide the clinician in the effective use of many of these newer agents, although it is likely that some of them will eventually replace warfarin for long term anticoagulation.

REFERENCES

  1. Hirsh J, Bauer KA, Donati MB, et al. Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:141S.
  2. Eitzman DT, Chi L, Saggin L, et al. Heparin neutralization by platelet-rich thrombi. Role of platelet factor 4. Circulation 1994; 89:1523.
  3. Weitz JI, Hudoba M, Massel D, et al. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990; 86:385.
  4. Hyers TM. Management of venous thromboembolism: past, present, and future. Arch Intern Med 2003; 163:759.
  5. Hirsh J, O’Donnell M, Weitz JI. New anticoagulants. Blood 2005; 105:453.
  6. Weitz JI, Hirsh J, Samama MM, American College of Chest Physicians. New antithrombotic drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:234S.
  7. Turpie AG. New oral anticoagulants in atrial fibrillation. Eur Heart J 2008; 29:155.
  8. Pipeline review: Last of the primary care blockbusters? New antithrombotics line up to unseat warfarin, heparins, plavix. Pharmaceuticals Approvals Monthly. F-D-C Reports 2008; 13:3.
  9. Becker RC. Next-generation antithrombin therapies. J Invasive Cardiol 2009; 21:179.
  10. Franchini M, Mannucci PM. A new era for anticoagulants. Eur J Intern Med 2009; 20:562.
  11. Mannucci PM, Franchini M. Old and new anticoagulant drugs: a minireview. Ann Med 2011; 43:116.
  12. Franchini M, Mannucci PM. New anticoagulants in internal medicine: an update. Eur J Intern Med 2010; 21:466.
  13. Bates SM, Weitz JI. The status of new anticoagulants. Br J Haematol 2006; 134:3.
  14. Tracy PB, Eide LL, Mann KG. Human prothrombinase complex assembly and function on isolated peripheral blood cell populations. J Biol Chem 1985; 260:2119.
  15. Mann KG, Nesheim ME, Church WR, et al. Surface-dependent reactions of the vitamin K-dependent enzyme complexes. Blood 1990; 76:1.
  16. Mann KG. Biochemistry and physiology of blood coagulation. Thromb Haemost 1999; 82:165.
  17. Fay WP, Eitzman DT, Shapiro AD, et al. Platelets inhibit fibrinolysis in vitro by both plasminogen activator inhibitor-1-dependent and -independent mechanisms. Blood 1994; 83:351.
  18. Stringer HA, van Swieten P, Heijnen HF, et al. Plasminogen activator inhibitor-1 released from activated platelets plays a key role in thrombolysis resistance. Studies with thrombi generated in the Chandler loop. Arterioscler Thromb 1994; 14:1452.
  19. Banner DW. The factor VIIa/tissue factor complex. Thromb Haemost 1997; 78:512.
  20. Naito K, Fujikawa K. Activation of human blood coagulation factor XI independent of factor XII. Factor XI is activated by thrombin and factor XIa in the presence of negatively charged surfaces. J Biol Chem 1991; 266:7353.
  21. von dem Borne PA, Meijers JC, Bouma BN. Feedback activation of factor XI by thrombin in plasma results in additional formation of thrombin that protects fibrin clots from fibrinolysis. Blood 1995; 86:3035.
  22. Asakai R, Chung DW, Davie EW, Seligsohn U. Factor XI deficiency in Ashkenazi Jews in Israel. N Engl J Med 1991; 325:153.
  23. Von dem Borne PA, Bajzar L, Meijers JC, et al. Thrombin-mediated activation of factor XI results in a thrombin-activatable fibrinolysis inhibitor-dependent inhibition of fibrinolysis. J Clin Invest 1997; 99:2323.
  24. Minnema MC, Friederich PW, Levi M, et al. Enhancement of rabbit jugular vein thrombolysis by neutralization of factor XI. In vivo evidence for a role of factor XI as an anti-fibrinolytic factor. J Clin Invest 1998; 101:10.
  25. Rydel TJ, Ravichandran KG, Tulinsky A, et al. The structure of a complex of recombinant hirudin and human alpha-thrombin. Science 1990; 249:277.
  26. Grütter MG, Priestle JP, Rahuel J, et al. Crystal structure of the thrombin-hirudin complex: a novel mode of serine protease inhibition. EMBO J 1990; 9:2361.
  27. Hall SW, Nagashima M, Zhao L, et al. Thrombin interacts with thrombomodulin, protein C, and thrombin-activatable fibrinolysis inhibitor via specific and distinct domains. J Biol Chem 1999; 274:25510.
  28. Sheehan JP, Sadler JE. Molecular mapping of the heparin-binding exosite of thrombin. Proc Natl Acad Sci U S A 1994; 91:5518.
  29. Hirsh J, Weitz JI. New antithrombotic agents. Lancet 1999; 353:1431.
  30. Perry DJ. Antithrombin and its inherited deficiencies. Blood Rev 1994; 8:37.
  31. Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997; 337:688.
  32. Choay J, Petitou M, Lormeau JC, et al. Structure-activity relationship in heparin: a synthetic pentasaccharide with high affinity for antithrombin III and eliciting high anti-factor Xa activity. Biochem Biophys Res Commun 1983; 116:492.
  33. Marcum JA, McKenney JB, Rosenberg RD. Acceleration of thrombin-antithrombin complex formation in rat hindquarters via heparinlike molecules bound to the endothelium. J Clin Invest 1984; 74:341.
  34. Myles T, Church FC, Whinna HC, et al. Role of thrombin anion-binding exosite-I in the formation of thrombin-serpin complexes. J Biol Chem 1998; 273:31203.
  35. Tsiang M, Jain AK, Gibbs CS. Functional requirements for inhibition of thrombin by antithrombin III in the presence and absence of heparin. J Biol Chem 1997; 272:12024.
  36. Danielsson A, Raub E, Lindahl U, Björk I. Role of ternary complexes, in which heparin binds both antithrombin and proteinase, in the acceleration of the reactions between antithrombin and thrombin or factor Xa. J Biol Chem 1986; 261:15467.
  37. Jordan RE, Oosta GM, Gardner WT, Rosenberg RD. The kinetics of hemostatic enzyme-antithrombin interactions in the presence of low molecular weight heparin. J Biol Chem 1980; 255:10081.
  38. Danhof M, de Boer A, Magnani HN, Stiekema JC. Pharmacokinetic considerations on Orgaran (Org 10172) therapy. Haemostasis 1992; 22:73.
  39. Nurmohamed MT, Fareed J, Hoppensteadt D, et al. Pharmacological and clinical studies with Lomoparan, a low molecular weight glycosaminoglycan. Semin Thromb Hemost 1991; 17 Suppl 2:205.
  40. Becker DL, Fredenburgh JC, Stafford AR, Weitz JI. Exosites 1 and 2 are essential for protection of fibrin-bound thrombin from heparin-catalyzed inhibition by antithrombin and heparin cofactor II. J Biol Chem 1999; 274:6226.
  41. Berry CN, Girardot C, Lecoffre C, Lunven C. Effects of the synthetic thrombin inhibitor argatroban on fibrin- or clot-incorporated thrombin: comparison with heparin and recombinant Hirudin. Thromb Haemost 1994; 72:381.
  42. Lefkovits J, Topol EJ. Direct thrombin inhibitors in cardiovascular medicine. Circulation 1994; 90:1522.
  43. Di Nisio M, Middeldorp S, Büller HR. Direct thrombin inhibitors. N Engl J Med 2005; 353:1028.
  44. Greinacher A, Warkentin TE. The direct thrombin inhibitor hirudin. Thromb Haemost 2008; 99:819.
  45. Tsuda Y, Szewczuk Z, Wang J, et al. Interactions of hirudin-based inhibitor with thrombin: critical role of the IleH59 side chain of the inhibitor. Biochemistry 1995; 34:8708.
  46. Greinacher A, Eichler P, Albrecht D, et al. Antihirudin antibodies following low-dose subcutaneous treatment with desirudin for thrombosis prophylaxis after hip-replacement surgery: incidence and clinical relevance. Blood 2003; 101:2617.
  47. Desirudin (Iprivask) for DVT prevention. Med Lett Drugs Ther 2010; 52:85.
  48. Greinacher A, Völpel H, Janssens U, et al. Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia: a prospective study. Circulation 1999; 99:73.
  49. Schiele F, Vuillemenot A, Kramarz P, et al. Use of recombinant hirudin as antithrombotic treatment in patients with heparin-induced thrombocytopenia. Am J Hematol 1995; 50:20.
  50. Eichler P, Friesen HJ, Lubenow N, et al. Antihirudin antibodies in patients with heparin-induced thrombocytopenia treated with lepirudin: incidence, effects on aPTT, and clinical relevance. Blood 2000; 96:2373.
  51. Huhle G, Hoffmann U, Song X, et al. Immunologic response to recombinant hirudin in HIT type II patients during long-term treatment. Br J Haematol 1999; 106:195.
  52. Fischer KG, Liebe V, Hudek R, et al. Anti-hirudin antibodies alter pharmacokinetics and pharmacodynamics of recombinant hirudin. Thromb Haemost 2003; 89:973.
  53. Warkentin TE, Greinacher A, Koster A. Bivalirudin. Thromb Haemost 2008; 99:830.
  54. Clarke RJ, Mayo G, FitzGerald GA, Fitzgerald DJ. Combined administration of aspirin and a specific thrombin inhibitor in man. Circulation 1991; 83:1510.
  55. Sheth SB, DiCicco RA, Hursting MJ, et al. Interpreting the International Normalized Ratio (INR) in individuals receiving argatroban and warfarin. Thromb Haemost 2001; 85:435.
  56. Swan SK, Hursting MJ. The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction. Pharmacotherapy 2000; 20:318.
  57. Jang IK, Brown DF, Giugliano RP, et al. A multicenter, randomized study of argatroban versus heparin as adjunct to tissue plasminogen activator (TPA) in acute myocardial infarction: myocardial infarction with novastan and TPA (MINT) study. J Am Coll Cardiol 1999; 33:1879.
  58. Ezekowitz MD, Reilly PA, Nehmiz G, et al. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study). Am J Cardiol 2007; 100:1419.
  59. Eriksson BI, Dahl OE, Büller 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.
  60. Eriksson BI, Dahl OE, Rosencher N, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 2007; 370:949.
  61. RE-MOBILIZE Writing Committee, Ginsberg JS, Davidson BL, et al. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty 2009; 24:1.
  62. Eriksson BI, Friedman RJ. Dabigatran etexilate: pivotal trials for venous thromboembolism prophylaxis after hip or knee arthroplasty. Clin Appl Thromb Hemost 2009; 15 Suppl 1:25S.
  63. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361:2342.
  64. Garcia D, Libby E, Crowther MA. The new oral anticoagulants. Blood 2010; 115:15.
  65. Hauel NH, Nar H, Priepke H, et al. Structure-based design of novel potent nonpeptide thrombin inhibitors. J Med Chem 2002; 45:1757.
  66. van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate–a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103:1116.
  67. Stangier J, Rathgen K, Stähle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet 2010; 49:259.
  68. Blech S, Ebner T, Ludwig-Schwellinger E, et al. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 2008; 36:386.
  69. Hankey GJ, Eikelboom JW. Dabigatran etexilate: a new oral thrombin inhibitor. Circulation 2011; 123:1436.
  70. file://webprod.hc-sc.gc.ca/dpd-bdpp/info.do?lang=eng&code=84384 (Accessed on March 23, 2011).
  71. file://www.medicines.org.uk/EMC/medicine/20759/SPC/Pradaxa+75+mg+hard+capsules/ (Accessed on March 23, 2011).
  72. file://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000829/WC500041059.pdf (Accessed on March 23, 2011).
  73. Eikelboom JW, Weitz JI. New oral anticoagulants for thromboprophylaxis in patients having hip or knee arthroplasty. BMJ 2011; 342:c7270.
  74. Pradaxa (dabigatran etexilate meslylate) US FDA licensed product information available at: file://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=32032&CFID=15739879&CFTOKEN=2704dc395f28ebb2-626B0B78-AEB9-9D1F-6E6BFC1657FE6434&jsessionid=ca30b497042b2e670797.
  75. Freyburger G, Macouillard G, Labrouche S, Sztark F. Coagulation parameters in patients receiving dabigatran etexilate or rivaroxaban: two observational studies in patients undergoing total hip or total knee replacement. Thromb Res 2011; 127:457.
  76. Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011; 124:1573.
  77. Lindahl TL, Baghaei F, Blixter IF, et al. Effects of the oral, direct thrombin inhibitor dabigatran on five common coagulation assays. Thromb Haemost 2011; 105:371.
  78. Wolowacz SE, Roskell NS, Plumb JM, et al. Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty. A meta-analysis. Thromb Haemost 2009; 101:77.
  79. Freeman JV, Zhu RP, Owens DK, et al. Cost-effectiveness of dabigatran compared with warfarin for stroke prevention in atrial fibrillation. Ann Intern Med 2011; 154:1.
  80. Freeman JV, Turakhia MP. Dabigatran compared with warfarin for stroke prevention in atrial fibrillation. Ann Intern Med 2011; 154:570.
  81. Levi M, Eerenberg E, Kamphuisen PW. Bleeding risk and reversal strategies for old and new anticoagulants and antiplatelet agents. J Thromb Haemost 2011; 9:1705.
  82. Van Ryn J, Litzenburger T, Waterman A, et al. An antibody selective to dabigatran safely neutralizes both dabigatran-induced anticoagulant and bleeding activity in in vitro and in vivo models (abstract P-MO-166 from the 2011 meeting of the ISTH). J Thromb Haemost 2011; 9:Suppl 2.
  83. Herbert JM, Hérault JP, Bernat A, et al. Biochemical and pharmacological properties of SANORG 34006, a potent and long-acting synthetic pentasaccharide. Blood 1998; 91:4197.
  84. Petitou M, Hérault JP, Bernat A, et al. Synthesis of thrombin-inhibiting heparin mimetics without side effects. Nature 1999; 398:417.
  85. Rosenberg RD. Redesigning heparin. N Engl J Med 2001; 344:673.
  86. Cohen M, Bhatt DL, Alexander JH, et al. Randomized, double-blind, dose-ranging study of otamixaban, a novel, parenteral, short-acting direct factor Xa inhibitor, in percutaneous coronary intervention: the SEPIA-PCI trial. Circulation 2007; 115:2642.
  87. Gross PL, Weitz JI. New anticoagulants for treatment of venous thromboembolism. Arterioscler Thromb Vasc Biol 2008; 28:380.
  88. Spyropoulos AC. Investigational treatments of venous thromboembolism. Expert Opin Investig Drugs 2007; 16:431.
  89. Paty I, Trellu M, Destors JM, et al. Reversibility of the anti-FXa activity of idrabiotaparinux (biotinylated idraparinux) by intravenous avidin infusion. J Thromb Haemost 2010; 8:722.
  90. Buller HR, Destors JM, Gallus AS, et al. Idrabiotaparinux, a biotinylated long-acting anticoagulant, in the treatment of deep venous thrombosis (EQUINOX study): Safety, efficacy, and reversibility by avidin (abstract). Blood 2008; 112:18.
  91. Equinox Investigators. Efficacy and safety of once weekly subcutaneous idrabiotaparinux in the treatment of patients with symptomatic deep venous thrombosis. J Thromb Haemost 2011; 9:92.
  92. Viskov C, Just M, Laux V, et al. Description of the chemical and pharmacological characteristics of a new hemisynthetic ultra-low-molecular-weight heparin, AVE5026. J Thromb Haemost 2009; 7:1143.
  93. Lassen MR, Dahl OE, Mismetti P, et al. AVE5026, a new hemisynthetic ultra-low-molecular-weight heparin for the prevention of venous thromboembolism in patients after total knee replacement surgery–TREK: a dose-ranging study. J Thromb Haemost 2009; 7:566.
  94. Turpie AG, Fisher WD, Bauer KA, et al. BAY 59-7939: an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study. J Thromb Haemost 2005; 3:2479.
  95. Eriksson BI, Borris L, Dahl OE, et al. Oral, direct Factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost 2006; 4:121.
  96. Eriksson BI, Borris LC, Dahl OE, et al. A once-daily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement. Circulation 2006; 114:2374.
  97. Fisher WD, Eriksson BI, Bauer KA, et al. Rivaroxaban for thromboprophylaxis after orthopaedic surgery: pooled analysis of two studies. Thromb Haemost 2007; 97:931.
  98. Agnelli G, Gallus A, Goldhaber SZ, et al. Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59-7939): the ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59-7939 in Patients With Acute Symptomatic Deep-Vein Thrombosis) study. Circulation 2007; 116:180.
  99. Buller HR, Lensing AW, Prins MH, et al. A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the Einstein-DVT Dose-Ranging Study. Blood 2008; 112:2242.
  100. Walenga JM, Prechel M, Jeske WP, et al. Rivaroxaban–an oral, direct Factor Xa inhibitor–has potential for the management of patients with heparin-induced thrombocytopenia. Br J Haematol 2008; 143:92.
  101. Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008; 358:2765.
  102. Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008; 358:2776.
  103. Kakkar AK, Brenner B, Dahl OE, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet 2008; 372:31.
  104. Turpie AG, Lassen MR, Davidson BL, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet 2009; 373:1673.
  105. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363:2499.
  106. Mega JL, Braunwald E, Mohanavelu S, et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet 2009; 374:29.
  107. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365:883.
  108. Cohen AT, Spiro TE, Büller HR, et al. Extended-duration rivaroxaban thromboprophylaxis in acutely ill medical patients: MAGELLAN study protocol. J Thromb Thrombolysis 2011; 31:407.
  109. Hillarp A, Baghaei F, Fagerberg Blixter I, et al. Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays. J Thromb Haemost 2011; 9:133.
  110. Barrett YC, Wang Z, Frost C, Shenker A. Clinical laboratory measurement of direct factor Xa inhibitors: anti-Xa assay is preferable to prothrombin time assay. Thromb Haemost 2010; 104:1263.
  111. Nutescu E, Chuatrisorn I, Hellenbart E. Drug and dietary interactions of warfarin and novel oral anticoagulants: an update. J Thromb Thrombolysis 2011; 31:326.
  112. Lassen MR, Raskob GE, Gallus A, et al. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med 2009; 361:594.
  113. Lassen MR, Davidson BL, Gallus A, et al. The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement. J Thromb Haemost 2007; 5:2368.
  114. Lassen MR, Raskob GE, Gallus A, et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet 2010; 375:807.
  115. Lassen MR, Gallus A, Raskob GE, et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010; 363:2487.
  116. Botticelli Investigators, Writing Committe, Buller H, Deitchman D, et al. Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis. The Botticelli DVT dose-ranging study. J Thromb Haemost 2008; 6:1313.
  117. APPRAISE Steering Committee and Investigators, Alexander JH, Becker RC, et al. Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial. Circulation 2009; 119:2877.
  118. Gross PL, Weitz JI. New antithrombotic drugs. Clin Pharmacol Ther 2009; 86:139.
  119. Wittkowsky AK. New oral anticoagulants: a practical guide for clinicians. J Thromb Thrombolysis 2010; 29:182.
  120. Wong PC, Crain EJ, Xin B, et al. Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies. J Thromb Haemost 2008; 6:820.
  121. Stassens P, Bergum PW, Gansemans Y, et al. Anticoagulant repertoire of the hookworm Ancylostoma caninum. Proc Natl Acad Sci U S A 1996; 93:2149.
  122. Presta L, Sims P, Meng YG, et al. Generation of a humanized, high affinity anti-tissue factor antibody for use as a novel antithrombotic therapeutic. Thromb Haemost 2001; 85:379.
  123. Lee A, Agnelli G, Büller H, et al. Dose-response study of recombinant factor VIIa/tissue factor inhibitor recombinant nematode anticoagulant protein c2 in prevention of postoperative venous thromboembolism in patients undergoing total knee replacement. Circulation 2001; 104:74.
  124. Giugliano RP, Wiviott SD, Stone PH, et al. Recombinant nematode anticoagulant protein c2 in patients with non-ST-segment elevation acute coronary syndrome: the ANTHEM-TIMI-32 trial. J Am Coll Cardiol 2007; 49:2398.
  125. Verhamme P, Tangelder M, Verhaeghe R, et al. Single intravenous administration of TB-402 for the prophylaxis of venous thromboembolism after total knee replacement: a dose-escalating, randomized, controlled trial. J Thromb Haemost 2011; 9:664.
  126. Hall SW, Gibbs CS, Leung LL. Strategies for development of novel antithrombotics: modulating thrombin’s procoagulant and anticoagulant properties. Cell Mol Life Sci 1997; 53:731.
  127. Tsiang M, Paborsky LR, Li WX, et al. Protein engineering thrombin for optimal specificity and potency of anticoagulant activity in vivo. Biochemistry 1996; 35:16449.
  128. Leung LL, Hall SW. Dissociation of thrombin’s substrate interactions using site-directed mutagenesis. Trends Cardiovasc Med 2000; 10:89.
  129. Berg DT, Wiley MR, Grinnell BW. Enhanced protein C activation and inhibition of fibrinogen cleavage by a thrombin modulator. Science 1996; 273:1389.
  130. Moll S, Lindley C, Pescatore S, et al. Phase I study of a novel recombinant human soluble thrombomodulin, ART-123. J Thromb Haemost 2004; 2:1745.
  131. Kearon C, Comp P, Douketis J, et al. Dose-response study of recombinant human soluble thrombomodulin (ART-123) in the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost 2005; 3:962.
  132. Chan MY, Cohen MG, Dyke CK, et al. Phase 1b randomized study of antidote-controlled modulation of factor IXa activity in patients with stable coronary artery disease. Circulation 2008; 117:2865.
  133. Cohen MG, Purdy DA, Rossi JS, et al. First clinical application of an actively reversible direct factor IXa inhibitor as an anticoagulation strategy in patients undergoing percutaneous coronary intervention. Circulation 2010; 122:614.
  134. Hagedorn I, Schmidbauer S, Pleines I, et al. Factor XIIa inhibitor recombinant human albumin Infestin-4 abolishes occlusive arterial thrombus formation without affecting bleeding. Circulation 2010; 121:1510.
  135. Kessler CM. Current and future challenges of antithrombotic agents and anticoagulants: Strategies for reversal of hemorrhagic complications. Semin Hematol 2004; 41:44.
  136. Warkentin TE, Crowther MA. Reversing anticoagulants both old and new. Can J Anaesth 2002; 49:S11.
  137. Crowther MA, Warkentin TE. Bleeding risk and the management of bleeding complications in patients undergoing anticoagulant therapy: focus on new anticoagulant agents. Blood 2008; 111:4871.
  138. Vavra KA, Lutz MF, Smythe MA. Recombinant factor VIIa to manage major bleeding from newer parenteral anticoagulants. Ann Pharmacother 2010; 44:718.
SEE MORE:  Pathogenesis of the antiphospholipid syndrome