New Anticoagulation Targets

Direct Factor Xa inhibitors: a promising approach

Based on preclinical and clinical trial data published to date, direct Factor Xa inhibitors have the potential to advance the field of anticoagulant therapy. Many features of direct Factor Xa inhibition make this a promising approach to the problem of thrombosis.

Factor Xa occupies a critical juncture in the coagulation process

Factor Xa also is an attractive target for the design of new anticoagulants as Factor Xa is positioned at the start of the common pathway of coagulation. As the amount of serine protease is amplified at each step of the cascade, it has been hypothesized that the selective inhibition of coagulation factors above thrombin might be a highly effective antithrombotic strategy.

Sylvia Haas, MD

Professor of Medicine and former Director of the Haemostasis and Thrombosis Research Group at the Institute for Experimental Oncology and Therapy Research, Technical University of Munich, Germany

Factor Xa occupies a critical juncture in the coagulation process. It converts prothrombin (Factor II) to thrombin (Factor IIa). Consistent with the observation that coagulation progresses in an amplified manner, one molecule of Factor Xa catalyses the formation of approximately 1000 molecules of thrombin^{15, 16}
Inhibition of Factor Xa can effectively prevent both platelet-rich arterial thrombi and fibrin-rich venous thrombi⁸⁸

Factor Xa has well-recognised, specific physiologic activity

The only known functions of Factor Xa are to promote coagulation and inflammation. Therefore, in contrast to thrombin inhibition, blocking Factor Xa is less likely to have pleiotropic effects¹⁷
Selective inhibition of Factor Xa can inhibit thrombin generation while allowing existing thrombin to continue its vital functions in normal haemostasis¹⁷

Direct Factor Xa inhibitors: comparison with indirect Factor Xa inhibitors

Indirect Factor Xa inhibitors, such as fondaparinux, require antithrombin as a cofactor and do not inhibit Factor Xa bound to the prothrombinase complex. In contrast, direct Factor Xa inhibitors directly engage the active centre of the Factor Xa molecule and inhibit both free Factor Xa in plasma and Factor Xa attached to the prothrombinase complex¹⁷
Factor Xa activates clotting over a wider concentration range than thrombin, in both in vitro and in vivo systems. Consequently, direct Factor Xa inhibitors may have a wider therapeutic window than thrombin inhibitors. A wider therapeutic window may reduce the need for coagulation monitoring, which would be a major advantage over warfarin¹⁷

Factor Xa inhibitors in development

Direct Factor Xa inhibitors in development have many properties of an ideal anticoagulant, including oral administration, rapid onset of action, and predictable pharmacokinetics and pharmacodynamics.^{17, 89}
A number of small-molecule, orally administered direct Factor Xa inhibitors are currently in development. These include rivaroxaban, apixaban, betrixaban, edoxaban, darexaban, letaxaban and a group of chemical entities that have not yet been named.

At present, the clinical trial program for rivaroxaban is the most advanced.^{17, 89} Rivaroxaban has been approved in September 2008 in the European Union and Canada for the prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery.¹⁵³

EU marketing approval for rivaroxaban was received on Sept 30th 2008 following a review of data from the extensive RECORD clinical programme that included three Phase III trials of rivaroxaban involving nearly 10,000 patients undergoing elective hip or knee replacement surgery (RECORD1, 2 and 3 trials).

Results from these three studies demonstrated the superior efficacy of rivaroxaban, both in head-to-head comparisons with enoxaparin (RECORD1 and 3) as well as when comparing extended-duration (5 weeks) rivaroxaban with short-duration (2 weeks) enoxaparin (RECORD2). In all three trials, rivaroxaban and enoxaparin had comparable safety profiles including low rates of major bleeding.¹⁵³ Additional trials are currently investigating the safety and efficacy of rivaroxaban in VTE treatment, in stroke prevention in atrial fibrillation (AF), in the prevention of deep vein thrombosis (DVT) in the medically ill, and in the management of acute coronary syndrome (ACS).

Apixaban, like rivaroxaban, interrupts the coagulation cascade by blocking the enzymatic activity of Factor Xa. In the ADVANCE-1 study for the prevention of VTE in patients undergoing total knee replacement, apixaban did not meet the prespecified statistical criteria for non-inferiority compared to the North American regimen of 30-mg injections of enoxaparin bid.²²³ In March 2010, results from the Phase III ADVANCE-2 study showed apixaban to be more effective than the European regimen of 40-mg injections of enoxaparin od in reducing the incidence of VTE following total knee replacement surgery.²²² ADVANCE-3 confirmed these findings in patients undergoing hip replacement. Apixaban bid was associated with significantly fewer VTE events when compared with enoxaparin od.²²¹

Betrixaban 40-, 60- and 80-mg doses were compared with warfarin in the Phase II EXPLORE-Xa trial for the prevention of stroke in patients with AF. Results made public in March 2010 revealed that 40 mg of betrixaban reduced the incidence of major and clinically relevant nonmajor bleeds compared to dose-adjusted warfarin. With the higher doses of betrixaban, bleeding rates were similar to those seen with warfarin. Although the study was not powered to examine efficacy, there were no significant differences in stroke rates across the different doses compared with warfarin.¹⁷⁴

Phase II and III studies have also examined edoxaban for stroke prevention in patients with AF and for reducing the risk of recurrent VTE complications of DVT and/or pulmonary embolism (PE).²³⁹ In AF, edoxaban 30 mg and 60 mg daily both were shown to be as safe and effective as warfarin for stroke prophylaxis in patients with AF.²³⁹ However, the risk of bleeding was significantly higher in the 30-mg and 60-mg twice-daily dosing groups compared with warfarin. There were no statistically significant differences in the incidence of stroke.²⁸¹

The efficacy and safety of YM150 are being reviewed in Phase III clinical trials. One Phase II trial (ONYX-2) showed that YM150 was significantly more effective in VTE prophylaxis compared to enoxaparin after elective total hip arthroplasty ― without increasing the risk of major bleeding events.¹⁹¹ In addition to VTE prophylaxis, clinical trials in progress are comparing YM150 with warfarin for the prevention of stroke in AF and for ischaemic vascular events in ACS.²³⁹

Based on findings from these trials, vitamin K antagonists may eventually be replaced as the standard oral anticoagulant for patients at risk for venous or intra-atrial thrombus formation.

Direct thrombin inhibitors

Thrombin has a central role in the coagulation cascade. Produced in small amounts in the initiation phase and large amounts in the propagation phase, thrombin is essential for the amplification of coagulation and fibrin formation.^{15, 88}

Parenteral direct thrombin inhibitors currently available for clinical use ― lepirudin, bivalirudin, and argatroban ― are generally reserved for the treatment of patients with heparin-induced thrombocytopenia. These medications are administered parenterally and require individual dosing based on lab monitoring.⁸⁸ Lepirudin is indicated in both the US and the EU for prophylaxis for thromboembolic complications in patients with thromboembolic disease.^{255, 268} Bivalirudin is indicated in the US for treatment of patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA) and in patients undergoing percutaneous coronary intervention (PCI) and in the EU for patients undergoing PCI or with unstable angina or non-ST-segment elevation myocardial infarction (MI) undergoing urgent or early interventions.^{157, 263} Argatroban is indicated in the US as prophylaxis for or treatment of thrombosis in patients undergoing PCI and is approved for use in some European countries for patients requiring antithrombotic therapy.^{158, 242}

Dabigatran etexilate, an oral direct thrombin inhibitor, was approved for marketing in the European Union in March 2008 for primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery. Administration of both 150 and 220 mg dabigatran etexilate was demonstrated to be as effective and safe as enoxaparin (40 mg) in preventing VTE and all cause mortality in the RE-NOVATE and RE-MODEL trials, respectively.^{88, 132} In 2010, it was also approved in the United States and Canada to prevent stroke and systemic embolism in patients with atrial fibrillation.^{165, 251}

Among patients with AF in the RE-LY (Randomised Evaluation of Long-Term Anticoagulation Therapy) trial, twice-daily dabigatran 150 mg was superior and dabigatran 110 mg twice daily was non-inferior to warfarin in lowering the risk of stroke and systemic embolism, with comparable bleeding rates.¹⁷³ However, both doses of dabigatran were associated with higher rates of MI than was warfarin.¹⁷³ Newly released data that were previously blinded indicate slightly higher bleeding rates than initially reported in 2009; however, these differences were not materially important.¹⁷⁴

Dabigatran etexilate is also being studied as treatment for VTE. The multinational RE-COVER trial, which compared 6 months of dabigatran 150 mg bid with warfarin after parenteral therapy for patients with confirmed DVT or pulmonary embolism, found that dabigatran etexilate was as effective as warfarin, with fewer bleeding events.²¹⁶

There are differences between Factor Xa and thrombin that may cause these clotting factors to be affected differently by drugs that inhibit them. Currently, the only known functions of Factor Xa are promotion of coagulation and inflammation. Thrombin has more diverse actions in the body; in addition to its known effects on coagulation and inflammation, thrombin also activates protein C (which has anticoagulant properties) and promotes cellular proliferation.¹⁷

Ultra-low-molecular-weight heparins

Low-molecular-weight heparin (LMWH) is produced from unfractionated heparin by depolymerisation.²⁰³ Further depolymerisation of LMWHs yields ultra-low-molecular-weight heparin (ULMWH).¹⁹³ Compared with LMWH, ULMWH exhibits an even higher ratio of anti-Factor Xa to anti-Factor IIa activity.¹⁹³ This pharmacodynamic difference has the potential to provide improved antithrombotic efficacy with decreased bleeding risk.

One ULMWH currently in development is semuloparin. Semuloparin, which shows a higher anti-Factor Xa activity than enoxaparin and much lower anti-Factor IIa activity, is under evaluation for prevention of cancer-associated thrombosis and VTE after total knee replacement.^{220, 233}

Factor (TF) VIIa complex

The TF-VIIa complex initiates the coagulation process. Exposure of TF during orthopaedic surgery and in certain patients with cancer may contribute to the high rates of VTE in these groups. TF-VIIa therefore presents a possible target for pharmacologic therapy.⁸⁸

Nematode anticoagulant proteins, which inhibit the TF-VIIa/FXa complex, are currently being explored for VTE prophylaxis in orthopaedic surgery.⁸⁸

Factor IXa

Theoretically, the advantages of Factor IXa inhibition should be similar to those anticipated for Factor Xa inhibition (ie, blocking an early stage of coagulation amplification, effectiveness in both arterial and venous thromboembolic disease).⁸⁸ Since most of Factor Xa is produced by the intrinsic “tenase,” which includes Factor IXa, targeting Factor IXa may be an effective approach to anticoagulation.^{13, 135} Research in this area, however, is not as advanced as research into Factor Xa inhibition. An oral direct Factor IXa inhibitor, TTP889, is currently in clinical trials for VTE prevention in orthopaedic surgery, although the initial study results for this compound were negative.⁸⁸

Aptamers, which are small nucleic acid molecules that directly inhibit specific proteins, are a promising class of compounds for thrombosis prevention and treatment.¹⁸⁶ The availability of antidote control for aptamer anticoagulant activity confers a potential safety benefit for this class of medications.^{186, 217}

Intravenous and subcutaneous formulations of an aptamer-based Factor IXa inhibitor are now in development. One agent in this class, RB006, has a unique mechanism of action. It blocks thrombin generation by preventing association of Factor Xa with the Factor VIIIa/Factor IXa enzyme complex.¹⁸⁶

Factors V and VIII

Activated Factors V and VIII serve as cofactors in the prothrombinase and extrinsic “tenase” complexes, respectively. These factors are the targets of the natural anticoagulant activated protein C, a key element of the physiologic thrombomodulatory system. Inhibition by pharmacologic means of one of these factors could potentially block coagulation propagation.^{6, 135}

Vitamin K antagonists

Tecarfarin is a novel oral vitamin K antagonist with a chemical structure similar to that of warfarin. Initial Phase II trials in patients with arterial thrombosis demonstrated that tecarfarin was as safe and effective as warfarin.¹⁸⁷ However, results of Phase II/III trials did not achieve the primary endpoint of superiority over warfarin, as measured by time in therapeutic range.¹⁵⁹ Further clinical investigation of this compound is under way.

You can find information on current clinical trials of these newer agents at www.clinicaltrials.gov .

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Article references

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Factor Xa: The activated form of Factor X. It catalyses the conversion of prothrombin to thrombin in conjunction with other cofactors.
Prothrombin: Factor II, also called prothrombin, is converted into thrombin as part of the coagulation cascade.
Thrombin: Also called Factor IIa, thrombin performs two functions in the coagulation cascade: activating platelets, and catalysing the conversion of soluble fibrinogen into insoluble fibrin. It is formed from prothrombin by a reaction that is catalysed by Factor Xa.
Pleiotropic: Producing many effects in addition to primary one
Antithrombin: Antithrombin, also known as antithrombin III, is the most important member of a larger family of antithrombins. It is a small protein molecule (a glycoprotein) produced in the liver that binds to a specific pentasaccharide sequence on heparin. This binding to heparin leads to an anticoagulant effect through two different mechanisms: It causes a conformational change in antithrombin that allows antithrombin to bind to and thereby inhibit Factor Xa, which leads to a subsequent decrease in thrombin levels It causes a direct increase of thrombin inhibition as a result of antithrombin binding to the heparin pentasaccharide sequence and thrombin binding to an adjacent segment of heparin at the same time.
Coagulation monitoring: Coagulation monitoring is practice of checking a specific coagulation parameter in order to adjust the dose. A precise adjustment of the drug intake allows the patient to stay within a defined therapeutic range, which is measured by prothrombin time or International Normalized Ratio (INR).
Fondaparinux: An indirect Factor Xa inhibitor comprising a synthetic pentasaccharide sequence matching the part of the heparin molecule that binds to antithrombin. It is administered by subcutaneous injection.
Prothrombinase complex: The prothrombinase complex consisting of the coagulation factors Xa and Va, phospholipid and calcium catalyzes the conversion of prothrombin (Factor II) to thrombin (Factor IIa).
Rivaroxaban: Oral, direct Factor Xa inhibitor.
Venous thromboembolism: A condition in which a blood clot (thrombus) forms in a vein, which in some cases then breaks free and enters the circulation as an embolus, finally lodging in and completely obstructing a blood vessel, e.g., in lungs causing a PE. The term encompasses both DVT and PE.
Acute coronary syndrome: This is an umbrella term used to cover any group of clinical symptoms compatible with acute myocardial ischaemia (chest pain due to insufficient blood supply to the heart muscle that results from coronary artery disease). Acute coronary syndrome covers the spectrum of clinical conditions ranging from unstable angina to STEMI and NSTEMI.
Enoxaparin: A low-molecular-weight heparin currently regarded as the standard of care for VTE prevention in orthopaedic surgery. Enoxaparin is administered by subcutaneous injection and is associated with a low risk of heparin-induced thrombocytopaenia.
Coagulation cascade: Series of reactions by which a small stimulus is amplified to produce rapid coagulation.
Warfarin: A vitamin K antagonist. Most commonly used oral anticoagulant in chronic prevention or treatment of VTE.
Prophylaxis: The prevention of a disease or pathological condition.
Vitamin K antagonists: Vitamin K antagonists block the regeneration of the reduced form of vitamin K.
Fibrin: The primary end product of the coagulation cascade. Fibrin links itself into strands to form a net. This net traps blood cells and tightens itself through cross-linkages, resulting in a dense blood clot.
Angina: Heart condition characterised by intermittent chest pain. Angina usually results from coronary artery disease and may further be classified as stable or unstable angina. Stable angina refers to the more common understanding of angina related to myocardial ischemia. Unstable angina may occur unpredictably at rest which may be a serious indicator of an impending heart attack.
Myocardial infarction: Destruction of heart tissue due to reduced blood flow to the heart. Also known as a heart attack. It usually results from coronary artery disease and is more severe than angina.
Parenteral: Not through the alimentary canal but rather by injection through another route.
Dabigatran: The active form of the prodrug dabigatran etexilate, an oral direct thrombin inhibitor.
Heparin: An anticoagulant that exerts its activity by binding to antithrombin and greatly increasing its activity. The principal coagulation factors inhibited by heparin are Factors IIa and Xa. It is administered by intravenous or subcutaneous injection.
Low-molecular-weight heparin: An anticoagulant derived from unfractionated heparin (UFH), containing only the low-molecular-weight molecules of heparin. It binds to antithrombin, greatly increasing its activity. It inhibits coagulation Factor Xa and, to a lesser extent, Factor IIa. LMWHs are administered by subcutaneous injection.
Intravenous: Administration of liquid substances directly into the venous part of the bloodstream.
Subcutaneous: Below the skin.
Vitamin K: An essential cofactor in the carboxylation of glutamic residues on the procoagulant forms of Factors II, VII, IX, and X. This ultimately leads to increased formation of thrombin and fibrin.