CHAPTER 2-11: ANTICOAGULANTS, NEWER

INTRODUCTION

The newer target-specific oral anticoagulant medications dabigatran, rivaroxaban, apixaban, and edoxaban have become increasingly popular alternatives to the vitamin K antagonist, warfarin (see Warfarin and Superwarfarins), the former mainstay of oral anticoagulation for prevention and treatment of venous thrombus events and stroke risk reduction in atrial fibrillation. These newer drugs inhibit a single target-specific step in coagulation rather than blocking multiple vitamin K–dependent blood factors as done by warfarin.

MECHANISM OF TOXICITY

1. Dabigatran is a competitive, direct inhibitor of both bound and free thrombin.

2. The factor Xa inhibitors rivaroxaban, apixaban, and edoxaban affect both free and bound factor Xa.

3. All of these agents also cause some small degree of indirect inhibition of platelet aggregation due to the decreased thrombin activity.

4. The resulting anticoagulation is both the intended benefit of these drugs and also the mechanism of toxicity in the event of adverse bleeding, ranging from minor to life-threatening hemorrhage.

5. Overdose during pregnancy. FDA pregnancy categories B (apixaban) and C (dabigatran, edoxaban, and rivaroxaban). There is insufficient information regarding overdose in pregnancy for these agents.

6. Pharmacokinetics.

   1. These agents have a more rapid onset of action and shorter half-lives than warfarin (see Table II–6).

   2. They also have the advantage of far fewer food–drug and drug–drug interactions compared to warfarin, although drug concentrations of all these drugs may be increased in the presence of p-glycoprotein (p-gp) inhibitors.

   3. Apixaban and rivaroxaban are highly protein bound, 87% and 92–95% respectively, whereas dabigatran protein binding is much less at 35%.

   4. Decline in renal function may lead to increased drug concentrations, especially with use of dabigatran.

   5. Dabigatran etexilate is a prodrug which is hydrolyzed to form its active moiety; its bioavailability is significantly increased (from 3–7% to 75%) when the pellets are ingested without the capsule shell.

TOXIC DOSE

1. Acute ingestion. Impaired coagulation can occur with any ingestion; however, this does not imply that bleeding will occur. Systemic absorption of rivaroxaban is thought to be self-limited with no further increase in plasma levels with oral doses above 50 mg. Apixaban has been shown to be well tolerated at doses up to 50 mg PO daily for 3–7 days without clinically significant events.

2. Chronic. The majority of reported clinically significant bleeding has occurred with chronic ingestion.

CLINICAL PRESENTATION

1. Bleeding has ranged from minor to life-threatening hemorrhage, including bleeding gums, ecchymoses, hematemesis, hemoptysis, hematochezia, melena, hematuria, menorrhagia, ...