The new oral anticoagulants: Reasonable alternatives to warfarin

FACTOR Xa INHIBITORS

Factor Xa is an ideal target for anticoagulants because of its important role in thrombin formation (Figure 1). Selective or direct factor Xa inhibitors significantly reduce the number of strokes and systemic embolic events compared with warfarin in patients with atrial fibrillation. They also may cause fewer major bleeding events than warfarin, although evidence supporting this is less robust.¹⁷ These agents have shown an advantage over enoxaparin for thromboprophylaxis after elective hip or knee replacement surgery and after hip fracture surgery without increasing the rate of bleeding events.¹⁸

Rivaroxaban

Rivaroxaban is an oral direct factor Xa inhibitor. It  reversibly binds to factor Xa with high specificity and inhibits free and clot-bound factor Xa as well as factor Xa in the prothrombinase complex (which catalyzes the conversion of prothrombin to thrombin).¹⁹

Indications. Clinical trials have shown rivaroxaban to have suitable efficacy and safety in several clinical situations.^20–23 It is FDA-approved for:

• Reducing the risk of stroke and systemic embolism in nonvalvular atrial fibrillation
• Preventing deep vein thrombosis after hip or knee replacement surgery
• Treating deep vein thrombosis and pulmonary embolism
• Reducing the risk of recurrence of deep vein thrombosis and pulmonary embolism.

In addition, the European Medicines Agency has approved the use of rivaroxaban together with antiplatelet medications to prevent atherothrombotic events after an acute coronary syndrome with elevated cardiac biomarkers.

Precautions. Rivaroxaban should be taken with food to maximize its absorption. Like dabigatran, it should be avoided or used cautiously in patients with renal failure and liver disease, and it is not recommended for pregnant and nursing women. 

Adverse effects. The most common adverse event is bleeding, although the incidence of major hemorrhage is similar to that with vitamin K antagonists and low-molecular-weight heparins.¹ Other effects include osteoarticular pain, weakness, wound secretion, skin rash, pruritus, abdominal pain, and syncope.

Drug interactions. Inhibitors of the P-glycoprotein transporter or the cytochrome P450 enzymes can alter the metabolism of rivaroxaban, making its levels too high. Rivaroxaban is not recommended for patients receiving systemic treatment with azole-antimycotics (eg, ketoconazole) or protease inhibitors to treat human immunodeficiency virus (HIV) infection (eg, ritonavir), as these drugs are strong inhibitors of both systems and may considerably increase plasma rivaroxaban concentrations.²⁴ Interactions of rivaroxaban with most other inhibitors of the P-glycoprotein transporter or the cytochrome P450 enzymes are considered clinically inconsequential, but caution is still recommended, especially in patients already at risk of bleeding (eg, those taking antiplatelet agents).²⁵  

Strong inducers of the P-glycoprotein transporter and the cytochrome P450 enzymes (eg, rifampicin, phenytoin) can reduce plasma rivaroxaban concentrations and thus decrease its efficacy. Caution is needed if rivaroxaban is taken with these drugs.

Apixaban

Apixaban also selectively and reversibly inhibits free and clot-bound factor Xa, as well as factor Xa in the prothrombinase complex.

Indications. Apixaban has a suitable efficacy and safety profile, and in clinical trials fewer patients died while taking it than those taking warfarin.^26–28 It is FDA-approved for:

• Reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
• Prophylaxis of deep vein thrombosis and pulmonary embolism in patients who have undergone hip or knee replacement
• Treating deep vein thrombosis and pulmonary embolism
• Reducing the risk of recurrent deep vein thrombosis and pulmonary embolism after initial therapy.

Precautions. Apixaban can be used in most patients with renal failure, but at a lower dosage in some circumstances (Table 2). It can be used without dosage adjustment for patients with mild hepatic impairment but should be avoided in those with moderate or advanced liver failure. It is contraindicated in pregnant and nursing women.

Adverse effects. As with other anticoagulants, the most common adverse effect is bleeding, but the incidence is similar to that with vitamin K antagonists and low-molecular-weight heparins.^1,26–28 Other adverse reactions, such as nausea, skin rash, and liver enzyme elevation, are uncommon.

Drug interactions are similar to those of rivaroxaban but are generally less intense. Concomitant use with strong dual inhibitors of the P-glycoprotein transporter or the cytochrome P450 enzymes, especially azole-antimycotics and HIV protease inhibitors, should be avoided, but if used, the apixaban dosage may be halved. Caution is also recommended if using apixaban with dual inducers of the P-glycoprotein transporter and the cytochrome P450 enzymes.²⁹

Edoxaban

Edoxaban, another direct factor Xa inhibitor, has a rapid onset of action. It is taken orally once daily and has antithrombotic efficacy similar to other agents in this group.^1,30

Indications. Edoxaban has been approved by the Japanese Pharmaceuticals and Medical Devices Agency and the FDA for:

• Reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
• Treating deep vein thrombosis and pulmonary embolism after 10 days of initial therapy with a parenteral anticoagulant.

Precautions. Edoxaban should not be used in patients with creatinine clearance above 95 mL/min because patients with this excellent level of renal function may clear the drug too well and therefore have a higher risk of ische­mic stroke than those receiving warfarin.³¹

Adverse effects and drug interactions are similar to those of other factor Xa inhibitors.

Other factor Xa inhibitors

Betrixaban is similar to other factor Xa inhibitors but has some unique pharmacokinetic characteristics, including minimal metabolism through the cytochrome P450 system, limited renal excretion, and a long half-life. This profile may have the advantages of fewer drug interactions and greater flexibility for use in patients with poor renal function, as well as the convenience of once-daily dosing.^4,32 The drug has not yet been approved for clinical use by the FDA or the European Medicines Agency.

Additional oral factor Xa inhibitors, including letaxaban, darexaban, and eribaxaban, are being developed with the aim of overcoming the limitations of available drugs in the group.³³

COAGULATION MONITORING

Given their rapid onset of action, stable pharmacokinetic properties, and few significant drug interactions, the new oral anticoagulants do not generally require coagulation monitoring. However, these drugs may produce alterations in coagulation tests: thrombin inhibitors tend to prolong the activated partial thromboplastin time, and factor Xa inhibitors tend to prolong the prothrombin time. These alterations vary from laboratory to laboratory, depending on the reagents used.^34,35

The new agents have also been reported to cause false-positive results on lupus anticoagulant assays and falsely elevated activated protein C ratio assays, misclassifying patients with the factor V Leiden mutation as normal.^36,37

Anticoagulation from dabigatran therapy can be monitored with the ecarin clotting time test, which yields a dose-dependent prolongation of clotting time.³⁸ Rivaroxaban, apixaban, and edoxaban can be monitored using modified chromogenic anti-Xa assays.²⁵ These tests may help manage overdoses, bleeding events, and emergency perioperative situations, but their usefulness in clinical practice is limited at this time because they are not widely available and they are not validated for this use.