Oral Direct Factor XA Inhibitors

ORAL DIRECT FACTOR XA INHIBITORS

Oral Xa inhibitors, including rivaroxaban and apixaban, are approved or in advanced stages of development and along with oral thrombin inhibitors (discussed below) are likely to have a major impact on antithrombotic pharmacotherapy. These drugs inhibit factor Xa, in the final common pathway of clotting (see Figure 34–2). These drugs are given as fixed doses and do not require monitoring. They have a rapid onset of action and shorter half-lives than warfarin (approximately 10 hours but half-life may be prolonged in elderly patients or those with renal impairment).

Rivaroxaban is approved for prevention of venous throm-boembolism following hip or knee surgery. The prophylactic dose is 10 mg orally per day. A recent large randomized clinical trial of DVT treatment compared a higher dose of rivaroxaban (15 mg bid for 3 weeks, followed by 20 mg daily) to a standard treatment regimen of enoxaparin followed by warfarin. This trial demon-strated non-inferiority of rivaroxaban in preventing recurrent venous thromboembolism and showed no difference in bleeding risk. Another trial reported non-inferiority of rivaroxaban to war-farin for prevention of stroke in patients with atrial fibrillation.

Apixaban is currently in clinical development. A recent studyof patients undergoing total hip replacement compared apixaban 2.5 mg orally once per day with enoxaparin 40 mg subcutane-ously once per day. This trial demonstrated the apixaban arm had lower rates of venous thromboembolism and similar bleedingrates. Another multicenter study randomized patients with recent myocardial infarction to apixaban 5 mg or placebo. This trial was stopped early because of an increase in bleeding risk without a significant decrease in ischemic events. Another trial comparing apixaban to aspirin for stroke prevention in atrial fibrillation was stopped early because of evidence of increased efficacy in the apixaban arm.

Thus, it appears that the primary target populations for devel-opment of both rivaroxaban and apixaban will be prevention and treatment of patients with venous thromboembolism and stroke prevention in patients with atrial fibrillation. Both of these drugs are excreted in part by the kidneys; therefore, the dosage may need to be reduced in patients with renal impairment. In such patients, use of a hepatically metabolized drug such as warfarin may be a better alternative. No antidotes exist for direct Xa inhibitors.