New Oral Direct Thrombin Inhibitors and Factor Xa Anticoagulants

By: Neal Shah

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Anticlotting agents are staples in the prevention and treatment of thrombotic disorders, such as deep vein thrombosis, stroke, pulmonary embolism, myocardial infarction, and atrial fibrillation.¹  Intravenous medications, such as unfractionated heparin (UFH), low molecular weight heparin (LMWH), and direct thrombin inhibitors (DTI), are commonly used in, both, inpatient and outpatient settings.  UFH and DTI require activated partial thromboplastin (aPTT) time as a monitoring tool for bleeding, due to the inhibition of the factor Xa and IIa pathways.  LMWH are more selective to Xa than IIa, and do not absolutely require aPTT monitoring.  A new class of selective Xa inhibitors, pioneered by fondaparinux, also does not require aPTT monitoring.¹  Fondaparinux acts at the step prior to IIa inhibitors: it inhibits factor Xa, which prevents activation of IIa from II (where DTIs act).  Oral therapy was mainly limited to using warfarin or the antiplatelet agent, aspirin.  Warfarin is a Vitamin K antagonist (VKA) that inhibits the activation of coagulating factors II, VII, IX, and X, as well as proteins C and S.  To exert its effects safely, it requires an International Normalized Ratio (INR) between 2 and 3 (or 2.5 to 3.5 for mechanical valve replacement).  An INR above three may indicate an elevated risk of bleeding or hemorrhaging.  UFH and warfarin have an advantage over LMWH, DTIs, and fondaparinux – unlike the latter, which have no real “antidote,” UFH and warfarin are reversible by protamine and Vitamin K, respectively.^1,2

The U.S. Food and Drug Administration (FDA) approved a new, oral, reversible DTI in October 2010, known as dabigatran.  It is indicated for the reduction of stroke risk in non-valvular atrial fibrillation.³  Dabigatran has reliable pharmacokinetics, touting no need for therapeutic monitoring, a rapid onset, and no real drug interactions—a stark contrast to warfarin.⁴  Unfortunately, dabigatran also comes with downsides, as it must be adjusted for impaired renal function, has a higher dyspepsia and GI bleeding rate than warfarin, and is dosed twice a day.⁵  There have been many cost-effective analyses between warfarin and dabigatran.  In one study, the CHADS₂ criteria was used as the basis for initiation of anticoagulant therapy.⁶  In patients with atrial fibrillation, the rates of stroke and intracranial bleeding with dabigatran therapy was comparatively lower than with warfarin.⁶  In the RE-COVER trial, dabigatran was noninferior to warfarin (in regards to safety issues), but did have more adverse reactions leading to discontinuations.⁷

In July 2011, rivaroxaban became the first, oral, selective, reversible factor Xa inhibitor.  It was approved by the FDA for the reduction of blood clots, DVT, and PE following knee or hip replacement surgery.⁸  The FDA also approved its indication for the reduction of stroke risk in patients with non-valvular atrial fibrillation (similar to dabigatran).⁹  Rivaroxaban does not require monitoring and is also renally eliminated  like dabigatran.  Alas, it has multiple cytochrome 3A4 drug interactions – inhibition of 3A4 can increase the anticoagulant effects of rivaroxaban.¹⁰  Johnson & Johnson (J&J), which manufactures rivaroxaban, funded the ROCKET-AF trial comparing rivaroxaban to warfarin.  In this head-to-head trial, rivaroxaban was noninferior to warfarin for the prevention of stroke or embolism.  There was also a reduction in intracranial hemorrhage and fatal bleeding compared to warfarin.¹¹  Rivaroxaban can potentially be another great alternative to warfarin, especially since its pharmacokinetics are easier to predict and it is dosed once per day (unlike dabigatran).

Apixaban is another oral, reversible factor Xa inhibitor – it has not obtained FDA approval in the United States, yet.  According to meta-analysis, it seems to have similar efficacy to rivaroxaban.  Apixaban may be an effective alternative in high-risk patients and those intolerant to aspirin.  It is also metabolized via 3A4 (like rivaroxaban), but since less of the drug is eliminated renally (25% apixaban vs. 66% rivaroxaban), it may be preferable in patients with decreased renal function.¹³

SOURCES:

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3. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm230241.htm accessed December 21, 2011.
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