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Disadvantages of VKA and requirements for novel anticoagulants

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Vitamin K antagonists have been in wide use for over 70 years. Warfarin, the most commonly used vitamin K antagonist, has been shown to be highly effective in treating and preventing thrombosis. Despite this, warfarin has many disadvantages, which has led to the development of a new class of oral anticoagulants targeted to specific coagulation factors designated as target-specific oral anticoagulants (TSOAs). TSOAs include the thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban, apixaban). This chapter reviews the disadvantages of warfarin and evaluates both the advantages and disadvantages of the new oral anticoagulants.

Introduction

The vitamin K antagonists have been in wide use since the 1940's with warfarin being the most commonly used vitamin K antagonist. Warfarin is highly effective in treating and preventing thrombosis, but despite its prolific use, warfarin has many disadvantages. These include a narrow therapeutic index, delayed onset and offset of effect, limitations secondary to genetics, multiple drug interactions, interactions with dietary vitamin K intake, and requirements for monitoring and high quality dose management. With these various limitations there has been a recent focus on the need for new oral anticoagulants, and a new class of target-specific oral anticoagulants has been developed. The advantages of these new oral anticoagulants compared to warfarin include a rapid onset of therapeutic effect, fewer drug interactions, fixed dose response relationships without the requirement for monitoring, and cost-effectiveness. However, there also are notable disadvantages of these novel drugs, which include reliance on renal elimination, the absence of a reversal agent, gastrointestinal bleeding, and compliance issues.

Section snippets

Disadvantages of vitamin K antagonists

Warfarin has no intrinsic activity but acts as an indirect anticoagulant with multiple targets [1]. Warfarin acts by inhibiting microsomal vitamin K epoxide reductase, which normally converts vitamin K 2,3-epoxide, an inactive metabolite of vitamin K, to reduced active vitamin K. Vitamin K is necessary for the post-translational carboxylation of glutamate residues for synthesis of coagulation factors II, VII, IX, and X. Thus, by inhibiting the inter-conversion of vitamin K to its active form

Target-specific oral anticoagulants

The new target-specific oral anticoagulants (TSOAs) achieve anticoagulant effect by directly antagonizing a specific activated coagulation factor. These drugs differ in many ways from warfarin with their rapid onset of action, short half-life, less drug interactions, no dietary interaction, and fixed dose response without the need for monitoring. A comparison of the pharmacokinetics of warfarin and the TSOAs can be seen in Table 1.

Efficacy and safety

The factor IIa and Xa inhibitors have undergone extensive study in clinical trials with positive results for efficacy and safety compared to standard therapy for stroke prevention in atrial fibrillation and the prevention of primary and secondary venous thromboembolism. A summary of the results from these trials can be seen in Tables 2 and 3. In the RE-LY trial dabigatran etexilate 150 mg twice a day showed a significant reduction in stroke and systemic embolism, and the dose of 110 mg twice a

Disadvantages of target specific oral anticoagulants

With the well-deserved focus on the advantages of the target-specific oral anticoagulants there are disadvantages that should be noted prior to the replacement of vitamin K antagonists. The familiarity with warfarin and relative comfort in reversing over-anticoagulation makes it still the primary choice for many clinicians, more than half a century since its first use.

Summary

Warfarin continues to be one of the most commonly prescribed anticoagulants in the world. By no means is warfarin the ideal anticoagulant with its multiple disadvantages. This is an exciting time in the field of anticoagulation with the introduction of target-specific oral anticoagulants. These agents have many advantages over the VKAs, but these advantages may also be disadvantages depending on the specific patient. More real-world clinical experience is necessary to see if the new oral

Conflict of Interest

None.

Practice Points

  • Warfarin is under prescribed to many patients because of its many disadvantages and need for labor intensive management

  • Because of a delayed onset, warfarin requires initial bridging therapy with a rapidly acting parenteral anticoagulant

  • A notable advantage of target-specific oral anticoagulants is their rapid onset and offset of action

  • Unlike warfarin, target-specific oral anticoagulants do not require routine monitoring

  • Drug interactions with target-specific oral

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