The new oral anticoagulants: Reasonable alternatives to warfarin

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ABSTRACTDabigatran (a direct thrombin inhibitor) and rivaroxaban, apixaban, and edoxaban (direct activated factor X inhibitors) are increasingly being used in clinical practice. Compared with vitamin K antagonists, they are more convenient, do not require laboratory monitoring, have limited drug and food interactions, and have fixed dosages suitable for most patients. But the shortcomings of these agents can jeopardize their efficacy and increase the risk of bleeding. Their future role in preventing and treating thromboembolic disease will depend on building clinical experience, but current evidence indicates that they are reasonable alternatives to vitamin K antagonists.


  • The new oral anticoagulants have favorable pharmacologic properties and similar efficacy and safety as vitamin K antagonists.
  • The new agents are indicated for preventing stroke and systemic embolism in patients with nonvalvular atrial fibrillation and preventing and treating deep vein thrombosis and pulmonary embolism (the indications regarding venous thromboembolism differ somewhat among agents).
  • Except for dabigatran, lack of an antidote in case of bleeding or emergency surgery is a major drawback.
  • Be cautious when using these drugs in patients with renal or liver disease and in those taking an inhibitor or inducer of the P-glycoprotein transporter or the cytochrome P450 enzymes.



For decades, vitamin K antagonists such as warfarin, acenocoumarol, phenindione, and phenprocoumon have been the only available oral anticoagulants. These drugs have similar pharmacologic profiles and share significant drawbacks in clinical use: a narrow therapeutic window, food and drug interactions, and the need for repeated blood testing to ensure the desired international normalized ratio.

Such problems have fostered research in the field of coagulation, and new oral agents that selectively target coagulation factors have become available. At least three such products are already available in most countries: dabigatran (a thrombin or factor IIa inhibitor) and rivaroxaban and apixaban (factor Xa inhibitors).1,2 Other factor Xa inhibitors, including edoxaban3 (available in the United States and Japan) and betrixaban,4 may also soon become available worldwide.

The new oral anticoagulants are more effective than vitamin K antagonists in preventing several thromboembolic conditions, have fewer drug interactions, and likely have fewer side effects.5 Indications for these new agents are expected to expand as new clinical trial results become available.6,7

This review summarizes the clinically relevant characteristics of the new oral anticoagulants (Table 1) and provides guidance on their usage (Table 2).



Characteristics of thrombin inhibitors and factor Xa inhibitors

Dabigatran etexilate is a prodrug that is rapidly and completely converted by esterases in the plasma and liver into its active metabolite, dabigatran. It competitively and reversibly binds to freely circulating and clot-bound thrombin, thereby blocking thrombin’s pro­coagulant properties (Figure 1).

Approved indications for and doses of the new oral anticoagulants

Clinical trials have shown dabigatran to be similar to warfarin and enoxaparin in efficacy and safety in preventing and treating thromboembolic disease.8–10

Indications. Dabigatran is approved by the US Food and Drug Administration (FDA) for:

  • Preventing stroke and systemic embolism in patients with nonvalvular atrial fibrillation
  • Treating deep vein thrombosis and pulmonary embolism in patients who have been treated with a parenteral anticoagulant for 5 to 10 days
  • Preventing recurrence of deep vein thrombosis and pulmonary embolism in patients who have previously been treated with other medications.
Selected steps in the blood coagulation pathway
Figure 1. Selected steps in the blood coagulation pathway. Sites of action of thrombin inhibitors and factor Xa inhibitors are denoted by blue slashes.

Precautions. Dabigatran should not be used, or should be used only in a reduced dosage, in patients with renal failure. It can be used in patients with moderate liver impairment but should be avoided in patients with advanced liver disease (cirrhosis), especially if they have coagulopathy. Its use in pregnant and nursing women is not recommended.

Adverse effects. Bleeding, including gastrointestinal and intracranial hemorrhage, is the most important adverse effect,11 but the incidence is similar to that with vitamin K antagonists and low-molecular-weight heparins.1,12 Dyspepsia is common and may be severe enough to require stopping treatment.13 Other possible effects are pain or burning in the throat, skin rash, and syncope. The risk of acute coronary syndrome is slightly increased but is outweighed by the benefit of ischemic stroke prevention.14,15

Drug interactions. Normally, permeability (P)-glycoprotein intestinal transporter extrudes substrate drugs back into the gut lumen after initial absorption, thereby interfering with drug bioavailability. Strong P-glycoprotein inhibitors (eg, ketoconazole, cyclosporine, tacrolimus, dronedarone, amiodarone, verapamil, clarithromycin) increase the plasma concentration of dabigatran. Despite that, giving these drugs with dabigatran is generally safe except in patients with renal failure (and especially with ketoconazole and dronedarone). To reduce interaction with verapamil, dabigatran should be taken at least 2 hours before this drug.

Potent P-glycoprotein transporter inducers such as rifampicin, carbamazepine, and phenytoin reduce the plasma concentration of dabigatran, and concomitant use of dabigatran with these drugs should be avoided.1

Another selective thrombin inhibitor

Ximelagatran was extensively investigated and approved in several countries in 2006. However, it was withdrawn after reports of severe hepatotoxicity.16 No other selective thrombin inhibitors are currently in an advanced stage of development.

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