Direct Oral Anticoagulants in the Treatment and Long-Term Prevention of Venous Thrombo-Embolism

Perspective:

The following are 10 points to remember about this clinical update review article:

1. Direct oral anticoagulants (DOACs) specifically target factor IIa or Xa and represent a major step forward in the treatment of acute- and long-term prevention of venous thrombo-embolism (VTE).

2. Conventional anticoagulant treatment of acute deep vein thrombosis (DVT) and pulmonary embolism (PE) consists of an initial course of at least 5 days of parenteral (usually subcutaneous) administration of unfractionated or low-molecular-weight heparin (LMWH) or fondaparinux (acute phase), overlapped and followed by vitamin K antagonist such as warfarin for at least 3 months, a period known as the long-term treatment phase.

3. DOACs represent a major step forward in the treatment and long-term prevention of VTE. They are at least as effective and as safe as conventional therapy (heparins and vitamin K inhibitors) and have practical advantages such as fixed dosing, few food and drug interactions, and no need for laboratory coagulation monitoring.

4. Two important features differentiate DOACs. First, renal impairment has a strong impact on the pharmacokinetic and pharmacodynamic profile of dabigatran, whereas apixaban and edoxaban seem to be less affected by moderate renal insufficiency.

5. Second, DOACs have different metabolisms, especially regarding the implication of cytochrome P450 (CYP) 3A4. While all four DOACs are being eliminated via the P-glycoprotein (P-gp) transporter after absorption, CYP3A4 activity is involved in the rivaroxaban, apixaban, and edoxaban metabolisms, but does not affect significantly the dabigatran pharmacokinetic profile. This important feature is associated with potentially fewer drug–drug interactions with dabigatran.

6. These antithrombotic agents introduce a new paradigm for the day-to-day management of VTE. DOACs should streamline the management of most patients with VTE and will facilitate care in the outpatient setting.

7. However, this simplification of treatment, along with a shift towards outpatient management of VTE, may inappropriately trivialize the importance of VTE and its treatment.

8. Recurrence of VTE as well as bleeding events has serious consequences that should not be overlooked. Data on the extended treatment of VTE showed that DOACs were associated with a favorable safety profile, even when compared with placebo, except for dabigatran at 150 mg twice daily.

9. However, it remains uncertain how to select specific DOACs for particular profiles of patients, and the optimal management of bleeding complications is evolving.

10. Finally, some other issues remain unanswered, such as the effects of DOACs in the setting of cancer, their use in patients with mechanical heart valve, and the availability of a specific reversal agent.

Clinical Topics: Anticoagulation Management, Dyslipidemia, Vascular Medicine, Lipid Metabolism, Novel Agents

Keywords: Cytochrome P-450 Enzyme System, Polysaccharides, Morpholines, Pulmonary Embolism, Heparin, Low-Molecular-Weight, Thiophenes, Warfarin, Thiazoles, P-Glycoproteins, Prothrombin, Pyrazoles, Pyridines, Fibrinolytic Agents, Renal Insufficiency, beta-Alanine, Benzimidazoles, Venous Thrombosis, Embolism, Pyridones


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