Single Coagulation Factor Inhibitors

While older, traditional anticoagulant drugs affect multiple factors in the coagulation pathway, many of the newer drugs selectively inhibit a single coagulation factor.

Fondaparinux is a synthetic indirect inhibitor of Factor Xa. Its structure is based on the natural pentasaccharide contained within heparin and low-molecular-weight heparins (LMWHs). It potentiates the rate of neutralisation of Factor Xa by antithrombin. Unlike heparin, fondaparinux does not inactivate thrombin. In addition, fondaparinux does not inhibit Factor Xa bound in the prothrombinase complex and therefore does not completely inhibit Factor Xa. Long-term use is limited by the requirement of subcutaneous injection.^{17, 105}

Bleeding is the most common adverse event with fondaparinux, with major bleeding occurring at about the same rate as seen with patients treated with LMWHs. Unlike the heparins, however, protamine cannot be used to reverse the effect of fondaparinux when bleeding is excessive.¹⁰⁵

In the final steps of the coagulation cascade, thrombin converts fibrinogen to fibrin. Fibrin-bound thrombin remains active and continues to promote thrombus expansion. The heparin-antithrombin complex does not inactivate fibrin-bound thrombin. In contrast, direct thrombin inhibitors do not require antithrombin and can inactivate the clot-bound thrombin.¹⁰⁶

Parenteral direct thrombin inhibitors are used during percutaneous coronary interventions (PCIs) and to treat or prevent thrombosis in patients with heparin-induced thrombocytopenia (HIT). Three such medications are currently in clinical use — lepirudin, bivalirudin, and argatroban. These drugs differ with respect to thrombin binding sites, reversibility, pharmacology, and specific indications.¹⁰⁶

Lepirudin was the first direct thrombin inhibitor (DTI) approved for clinical use.⁸⁹ This medication is a recombinant form of hirudin — an anticoagulant originally derived from leech saliva.^{255, 268} Although it is more effective than heparin, lepirudin is associated with an increased risk of bleeding.^{89, 201} Unlike lepirudin, bivalirudin and argatroban bind reversibly to thrombin.^{89, 201} Bivalirudin is “bivalent” since it binds to the fibrinogen-binding region and the catalytic site of thrombin, thereby decreasing platelet-dependent thrombosis.¹⁰⁶ It is approved for anticoagulation during percutaneous coronary intervention (PCI) in the EU and the US, to treat patients with unstable angina or non-ST-segment elevation myocardial infarction for whom urgent or early intervention is planned in the EU, and in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA) in the US. ^{157, 263} Argatroban is used clinically as an alternative anticoagulant in patients with heparin-induced thrombocytopenia type II as general prophylaxis or for treatment of thrombosis and in those undergoing PCI.^{158, 242} The major side effect with both bivalirudin and argatroban is bleeding. Long-term use is limited by the requirement for intravenous administration.^{89, 201}

The first oral direct thrombin inhibitor available for clinical use was ximelagatran. This medication represented a major advance over existing oral anticoagulants (eg, vitamin K antagonists) because it did not require anticoagulant monitoring or dose adjustments. In clinical trials for venous thromboembolism (VTE) prevention and treatment, ximelagatran was either more effective than or comparable to warfarin. However, safety monitoring revealed liver toxicity in 6% of patients. For this reason, use of the drug was discontinued in 2006.⁸⁸

A second direct oral thrombin inhibitor, dabigatran etexilate, 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. Dabigatran etexilate is a small molecule prodrug which does not exhibit any pharmacological activity. After oral administration, dabigatran etexilate is rapidly absorbed and converted to its active principal, dabigatran, by esterase-catalysed hydrolysis in plasma and in the liver.

Dabigatran etexilate was compared to the vitamin K antagonist (VKA) warfarin in a large, multinational trial designed to assess stroke prevention efficacy in patients with atrial fibrillation. The RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy) enrolled over 18,000 patients. They were randomised to receive either open-label warfarin, with dosing adjusted to achieve a target INR of 2 to 3, or 1 of 2 blinded doses of dabigatran (110 mg or 150 mg, twice daily). Patients were followed for a median of 2 years. The primary outcome measure was the incidence of stroke or systemic embolism.¹⁷³

Both doses of dabigatran etexilate were non-inferior to warfarin in preventing stroke or systemic embolism. In patients taking 150 mg of dabigatran etexilate twice daily, the rate of the primary outcome was 1.11%, versus 1.69% in the warfarin group (relative risk, 0.66, P<0.001 for superiority). Rates of major bleeding, the primary safety outcome, were 3.36% per year with warfarin, 3.11% per year with dabigatran etexilate 150 mg twice daily and 2.71% per year with dabigatran 110 mg twice daily.¹⁷³ Both doses of dabigatran etexilate were associated with higher rates of myocardial infarction (MI) than 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

Based on the findings of the RE-LY trial, dabigatran etexilate has been approved for use in the United States to reduce the risk of stroke in patients with nonvalvular atrial fibrillation (AF).²⁵¹ It is the first non-VKA oral antithrombotic medication to be approved for this indication.

Dabigatran etexilate has also been studied for venous thromboembolism prophylaxis among patients undergoing elective total hip replacement (in the RE-NOVATE trial) and total knee replacement (in the RE-MODEL trial). The RE-NOVATE study was a non-inferiority trial of 2 doses of dabigatran etexilate (220 mg and 150 mg) once daily versus enoxaparin in almost 2500 patients.¹⁹⁰ No significant differences were found in the primary outcome of all venous thromboembolic events and all-cause mortality, and rates of major bleeding and other adverse events were also similar.¹⁹⁰ The RE-MODEL trial was similarly designed and examined almost 2200 patients.¹⁸⁹ Total venous thromboembolism rates and all-cause mortality (the primary outcomes) were not significantly different, nor were rates of major bleeding or other adverse events.¹⁸⁹

Based on the findings of these 2 trials, dabigatran etexilate was approved for use in the European Union to prevent VTE after elective total hip or total knee replacement.²⁶⁷ 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}

Dabigatran etexilate 150 mg twice daily also has been compared to warfarin for secondary prevention of VTE in patients with confirmed deep vein thrombosis (DVT) or pulmonary embolism (PE) in the RE-COVER trial, published in the New England Journal of Medicine in 2009. This randomised, double-blind trial included 2564 patients. The results established the non-inferiority of this dose of dabigatran compared to oral VKA therapy (the current standard). After 6 months, recurrent VTE was documented in 2.4% of patients taking dabigatran etexilate and in 2.1% of those in the warfarin group. There was no significant difference between the 2 groups in rates of bleeding. More patients, however, discontinued dabigatran etexilate due to adverse events, including dyspepsia, compared to warfarin (9% versus 6.8%).²⁶¹

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} These agents include rivaroxaban, apixaban, betrixaban, edoxaban and a group of chemical entities that have not yet been named. Factor Xa inhibitors directly engage the active centre of the Factor Xa molecule. These agents inhibit both free Factor Xa in plasma and Factor Xa attached to the prothrombinase complex.¹⁷

Rivaroxaban was the first direct Factor Xa inhibitor to receive approval in the European Union and Canada for VTE prophylaxis in adult patients undergoing total hip or knee replacement surgery. Approval in the European Union was based on 3 Phase III trials of the RECORD programme involving nearly 10,000 patients undergoing elective hip or knee replacement surgery. In all 3 trials, rivaroxaban and enoxaparin had comparable safety profiles, including low rates of major bleeding. At the same time, rivaroxaban was found to be significantly more effective.¹⁶⁷

Rivaroxaban is also being studied for other antithrombotic indications. These trials are investigating rivaroxaban efficacy and safety for stroke prevention in AF, primary prevention of VTE in hospitalised medically ill patients, treatment of DVT and secondary prevention of cardiovascular events in patients with acute coronary syndrome.¹⁵⁶

Results of a large, randomised, double-blind, Phase III trial comparing rivaroxaban to warfarin for prevention of stroke and systemic embolism in patients with AF were reported at the American Heart Association meeting in November 2010. This trial, known as ROCKET-AF, randomized 14,2654 patients to either rivaroxaban, 20 mg once daily or adjusted-dose warfarin. Patients were treated for an average of 19 months. Compared with warfarin, rivaroxaban was associated with a 21% relative risk reduction in stroke and non−central nervous system systemic embolism (1.70% versus 2.15%). Rates of major and non-major clinically relevant bleeding were similar in the 2 groups (14.91% with rivaroxaban versus 14.52% with warfarin).²³⁶ Results from this study, as well as from the RE-LY study with dabigatran etexilate, indicate that these novel oral anticoagulants can deliver improved efficacy and greater convenience for stroke prevention in AF compared to oral VKA therapy, without compromising safety.

Results from the EINSTEIN-DVT and EINSTEIN-Extension studies, both of which involved patients with DVT, were published in the New England Journal of Medicine in December 2010.¹⁶²

EINSTEIN-DVT included 3449 patients with DVT randomised to receive either rivaroxaban 15 mg twice daily for 3 weeks and then 20 mg once daily, or injections of enoxaparin followed by therapy with an oral VKA, for 3, 6 or 12 months. The primary outcome was recurrent VTE. Rivaroxaban demonstrated non-inferior efficacy: 36 events (2.1%) versus 51 events (3.0%) with the standard treatment of enoxaparin-VKA (hazard ratio: 0.68; P<0.001). Major bleeding or clinically relevant non-major bleeding occurred in 8.1% of patients in both groups.¹⁶²

The separate EINSTEIN-Extension study compared rivaroxaban (20 mg once daily) to placebo for an additional 6 to 12 months following an initial course of 6 to 12 months of treatment for VTE. Results indicated rivaroxaban to be superior to placebo, with 8 (1.3%) episodes of recurrent VTE in the treated group versus 42 (7.1%) in the placebo group (hazard ratio: 0.18; P<0.001). Four patients had non-fatal major bleeding with active treatment versus none in the placebo group (P=0.11). The authors observe that rivaroxaban offers a simple, single-drug option with potential to improve the benefit-to-risk ratio of VTE treatment, both for short-term and continued treatment.¹⁶²

Apixaban is another oral direct Factor Xa inhibitor currently being studied for the treatment of a range of thrombotic disorders. Like rivaroxaban, apixaban binds both free Factor Xa and Factor Xa bound within the prothrombinase complex.¹⁵⁶ In ADVANCE-1, which compared apixaban 2.5 mg twice daily with enoxaparin 30 mg twice daily for prevention of DVT following knee replacement surgery, apixaban did not prove non-inferiority for the primary endpoint of DVT, non-fatal PE, or death from any cause (9.0% with apixaban, 8.8% with enoxaparin.) The overall rate of primary events among the patients on enoxaparin in this study, however, was much lower than expected, which influenced the study results. Major and clinically relevant non-major bleeding events were less frequent with apixaban than with enoxaparin (2.9% versus 4.3%, P=0.03).²³³

A second study, ADVANCE-2, also compared apixaban (2.5 mg twice daily) to enoxaparin (40 mg once daily) in patients undergoing knee replacement surgery. In this study, apixaban was superior to enoxaparin with respect to the primary outcome measure, which was a composite of asymptomatic DVT, symptomatic DVT, non-fatal PE, and all-cause death during treatment (15% versus 24%, relative risk 0.62, P<0.0001). Bleeding rates were lower for apixaban, but this difference did not reach statistical significance (3.5% versus 4.8%, P=0.09).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 (1.4% versus 3.9%, relative risk 0.36, P<0.0001). Bleeding rates were similar (4.8% versus 5.0%).²²¹