Pharmacology Update

Rivaroxaban Tablets (Xarelto™)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship to this field of study.

The first orally administered factor XA inhibitor has been approved by the FDA for the prevention of deep vein thrombosis (DVT). Rivaroxaban was developed by Bayer and is marketed in this country by Janssen Pharmaceuticals as Xarelto.

Indications

Rivaroxaban is indicated for the prophylaxis of DVT in patients undergoing knee or hip replacement surgery (arthroplasty).1

Dosage

The recommended dose is 10 mg taken orally once daily starting at least 6 to 10 hours after surgery once hemostasis has been established.1 The duration of therapy is 35 days for patients undergoing hip replacement surgery and 12 days for knee replacement surgery. Rivaroxaban may be taken without regard to meals.

Rivaroxaban is supplied as 10 mg film-coated tablets.

Potential Advantages

Rivaroxaban, a once-a-day oral medication, is more effective than subcutaneous enoxaparin at reducing the risk of venous thromboembolic events (VTE).

Potential Disadvantages

Concomitant use of drugs that are both p-glycoprotein and strong CYP3A4 inducers should be avoided.1 Examples are carbamazepine, phenytoin, rifampin, and St. John's wort. Rivaroxaban should be avoided in patients with moderate or severe hepatic impairment, hepatic disease associated with coagulopathy, or severe renal impairment.1

Comments

Rivaroxaban is the first factor Xa inhibitor to be approved. Its efficacy and safety were compared to enoxaparin in 9011 subjects in three comparative trials (RECORD 1, 2, and 3).1-4 Subjects undergoing total hip or knee arthroplasty were randomized to rivaroxaban 10 mg once daily or enoxparin 40 mg subcutaneously once daily. Rivaroxaban was started 6-10 hours after wound closure and enoxaparin was started 12 hours preoperatively. In RECORD 1, subjects who were scheduled to undergo elective hip arthroplasty received prophylaxis (rivaroxaban or enoxaparin) for 33-34 days.2 In RECORD 2, subjects undergoing total hip arthroplasty received rivaroxaban for an extended duration (31-39 day) compared to short-term enoxaparin (10-14 days).3 In RECORD 3, subjects undergoing total knee arthroplasty received rivaroxaban or enoxaparin for 10-14 days.4 The efficacy endpoint was total VTE events. This composite endpoint includes proximal or distal DVT, non-fatal PE, or all-cause mortality. The main secondary efficacy outcome was major VTE (proximal DVT, nonfatal PE, or VTE-related death). The rates for total VTE events were 1.1% for rivaroxaban vs 3.9% for enoxaparin in RECORD 1, and 2% vs 8.4% for RECORD 2. These represent a significant relative-risk reduction of 71% (95% confidence interval [CI]: 50, 83,) and 76% (95% CI: 59, 86), respectively. A larger relative-risk reduction was observed with major VTE (91% and 87%, respectively). In patients with total knee arthroplasty (n = 2432), the VTE rates were 9.7% for rivaroxaban compared to 18.8% for enoxaparin. This represented a significant relative-risk reduction of 48% (95% CI: 34, 60). Overall, bleeding events were similar between rivaroxaban and enoxaparin and were not statistically different (5.8% vs 5.6%). The rate of severe bleeding events was also similar (0.3% vs 0.2%). A systematic review that included the above studies and three other studies showed a risk ratio of 0.38 (95% CI, 0.25, 0.59).5 Rivaroxaban (10 mg daily for 10 -14 days) was also found to be more effective than enoxaparin (30 mg twice daily for 10-14 days) for the prophylaxis of VTE after total knee arthroplasty (event rate of 6.9% vs 10.1%).6 The results of a phase III trial of rivaroxaban compared warfarin in the prevention of stroke and non-CNS embolism in patients with atrial fibrillation were presented last November.7 This could lead to FDA approval for this indication in the near future.

Clinical Implications

Rivaroxaban, an Xa inhibitor, appears to be more effective than enoxaparin for the prophylaxis of VTE in patients undergoing total hip or knee arthroplasty. Oral administration in postopertative patients represents a major advantage over previous therapies. Rivaroxaban represents an important advance and may eventually be approved for other indications as well, including stroke and non-CNS embolism prophylaxis for patients with atrial fibrillation.

References

1. Xarelto Prescribing Information. Titusville, NJ: Janssen Pharmaceuticals; July 2011.

2. Eriksson BL, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008;358:2765-2775.

3. Kakkar AK, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty. Lancet 2008;372:31-39.

4. Lassen MR, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008;358:2776-2786.

5. Turun S, et al. A systematic review of rivaroxaban versus enoxaparin in the prevention of venous thromboembolism after hip or knee replacement. Thrombosis Research 2011;127:525-534.

6. Turpie AG, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4). Lancet 2009;373:1673-1680.

7. Califf R, et al. American Heart Association Scientific Session, Chicago, IL. November 15, 2010.