Rivaroxaban: A Fixed-dose Regimen for Anticoagulation

Abstract & Commentary

By Jeffrey T. Jensen, MD, MPH, Editor, Leon Speroff, Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.

Synopsis: Rivaroxaban, a novel oral factor Xa inhibitor, provided a highly effective simple, fixed-dose regimen for treatment of acute deep vein thromboembolism without the need for laboratory monitoring and reduced the risk of recurrent clot during continued treatment.

Source: The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499-2510.

This paper presents two parallel studies that evaluate the safety and efficacy of oral rivaroxaban in the treatment of acute deep venous thrombosis (DVT) and in continuing prophylaxis for recurrence. The authors compared oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol) for 3, 6, or 12 months in patients with acute, symptomatic DVT in an open-label, randomized, event-driven, non-inferiority study. They also studied patients who had completed 6-12 months of initial treatment for DVT (either from the acute phase study or from usual care) in a double-blind, randomized, event-driven superiority study comparing rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months. The primary efficacy outcome for both studies was recurrent venous thromboembolism. The principal safety outcome was major bleeding (or clinically relevant non-major bleeding) in the initial treatment study and major bleeding in the continued treatment study.

In the acute protocol, 1731 patients were given rivaroxaban and 1718 were treated with enoxaparin plus a vitamin K antagonist. The number of recurrent DVTs in rivaroxaban-treated subjects (36 events [2.1%]) was statistically non-inferior to that observed in the enoxaparin-vitamin K antagonist group (51 events, [3.0%]; hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.44-1.04). Safety was similar with identical numbers of bleeding events (8.1%) in each group. In the continued treatment study, 602 patients received rivaroxaban and 594 placebo. The rivaroxaban-treated subjects had significantly fewer recurrent DVTs (8 events [1.3%] vs 42 [7.1%] with placebo; HR, 0.18; 95% CI, 0.09-0.39). While significantly more of the rivaroxaban-treated subjects experienced clinically relevant non-major bleeding, only four experienced non-fatal major bleeding vs none in the placebo group (P = 0.11). The authors concluded that rivaroxaban offers a simple, single-drug approach that simplifies the care of patients requiring anticoagulation for DVT.

Commentary

One pleasure of working in a university environment is collaboration and contact with colleagues from other specialties. My favorite hematologist has an office just down the hallway from me, and when he becomes excited about a new medication I listen. Rivaroxaban is a factor Xa inhibitor. In addition to the present study investigating acute and chronic venous thromboembolism, the clinical trial development program has included randomized trials of DVT prevention following elective orthopedic procedures, DVT prevention in hospitalized medically ill patients, and stroke prevention in patients with atrial fibrillation.1-3

Obstetrician gynecologists deal with pregnant women and women using hormonal contraception and menopausal hormonal therapies. Since estrogen increases the risk of both DVT and arterial thromboembolism, these conditions are important concerns for our practice.

One of the medications that most physicians love to hate is warfarin. The major headache in dealing with patients on warfarin is the need for frequent blood monitoring and dose adjustment. The major advantage of rivaroxaban is that it is dosed orally in a fixed dose that does not require blood monitoring for adjustment. It also is unnecessary to switch drugs after initial treatment. For acute treatment, the drug is dosed twice per day. For longer-term prophylaxis, once daily treatment is all that's required. The current study adds to a body of literature demonstrating that rivaroxaban may improve the risk-benefit ratio of both short- and long-term anticoagulation therapy for a variety of conditions. During the acute phase of treatment, there were similar numbers of recurrent DVTs reported among patients treated with rivaroxaban and conventional therapy. Since it is no surprise that any anticoagulation therapy would reduce recurrent DVTs during prolonged treatment, the powerful reduction in risk of recurrent clot with rivaroxaban therapy is less important than the impressive safety data. The risk of non-fatal major bleeding was less than 1%. While minor bleeding (primarily mucosal bleeding) was higher with treatment, few subjects discontinued because of this.

This important new drug is likely to change our practice in a manner similar to the introduction of low molecular weight heparin. By eliminating the cost and complexity of monitoring anticoagulation therapy, more gynecologists will feel comfortable prescribing this medication. While not yet approved by the FDA, rivaroxaban (Xarelto®) will likely join dabigatran (Pradaxa®) as an oral alternative to warfarin. Dabigatran was approved by the FDA in October 2010 to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. An 18,000-person, randomized, non-inferiority trial called RE-LY (Randomized Evaluation of Long-term anticoagulation therapY) found that a 150 mg dose of dabigatran twice daily was more effective in preventing strokes in high-risk patients than warfarin, while a lower dose (110 mg) was comparable, but with a lower bleeding risk than warfarin (the risk is similar with the approved dose of 150 mg twice daily).4 This drug is not approved for DVT prophylaxis or treatment, but is being used off-label by some hematologists as it does not require blood monitoring.

All this is good news for women. It is also good for news for health care providers.

References

  1. ROCKET AF study investigators. Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation. Am Heart J 2010;159:340-347.e1.
  2. Mega JL, et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46). Lancet 2009;374:29-38.
  3. Turpie AG, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4). Lancet 2009;373:1673-1680.
  4. Camm AJ. The RE-LY study: Randomized Evaluation of Long-term anticoagulant therapY: Dabigatran vs. warfarin. Eur Heart J 2009;30:2554-2555.