Xarelto®:
Newly Approved for the Treatment of Pulmonary Embolism

Xarelto® is an oral, direct Factor Xa inhibitor that is now approved for the treatment of pulmonary embolism (PE). This follows the approval of Xarelto® in 2011 for the treatment of deep vein thrombosis (DVT) and the prevention of recurrent DVT and PE. Xarelto® is currently the only oral single-drug solution approved in these indications. The approvals were based on the results of three pivotal studies in the treatment of venous thromboembolism (VTE): EINSTEIN DVT1 and EINSTEIN PE,2 which evaluated Xarelto® for acute treatment, and EINSTEIN EXT,1 which evaluated the benefit versus risk of long-term treatment with Xarelto® - figure 1. Positive results from all three studies were reported in two New England Journal of Medicine publications.1,2

The EINSTEIN investigators concluded that ’Our findings in this study involving patients with pulmonary embolism, along with those of our previous evaluation involving patients with deep-vein thrombosis, support the use of rivaroxaban as a single oral agent for patients with venous thromboembolism.’

Single-drug Xarelto®: Revolutionizing the Treatment of DVT and PE

The unique single-drug approach with Xarelto® provides substantial benefits for patients and physicians by simplifying the treatment of VTE, and is a simple and highly effective alternative to the complex dual-drug approach with subcutaneous low molecular weight heparin followed by a dose adjusted vitamin K antagonist (VKA).►

Xarelto®: Newly Approved for the Treatment of Pulmonary Embolism

Xarelto® has the benefits of:

  • Fast onset of action equivalent to that of enoxaparin, with effective anticoagulation achieved within 2–4 hours3 - figure 2
  • No need for routine coagulation monitoring, dose adjustments or adherence to dietary restrictions (unlike VKAs)
Xarelto® has previously demonstrated superior efficacy to enoxaparin for the prevention of VTE after elective hip or knee replacement surgery4–7 and is highly effective for the prevention of stroke in patients with atrial fibrillation, with a reassuring safety profile;8 Xarelto® was approved in these indications in 2008 and 2011, respectively. Of the novel oral anticoagulants,

Xarelto® is approved across the broadest range of thromboembolic indications.

EINSTEIN PE: a Landmark Study

The EINSTEIN DVT and EINSTEIN PE studies were unique in that they evaluated an oral anticoagulant in separate DVT and PE populations.1,2 Both studies shared the same design but EINSTEIN PE included patients with symptomatic PE with or without DVT.1,2 EINSTEIN PE was an open-label, event-driven, non-inferiority study that compared a single-drug approach with oral Xarelto® with enoxaparin followed by a VKA (standard therapy). A regimen of Xarelto® 15 mg twice daily during the acute phase of the disease (first 3 weeks)

Xarelto®: Newly Approved for the Treatment of Pulmonary Embolism

followed by 20 mg once daily was studied. Patients were treated for 3, 6 or 12 months.2

Effectiveness and Reassuring Safety with Single-drug Xarelto® for the Treatment of PE

Xarelto® was non-inferior to (i.e. as effective as) enoxaparin followed by a VKA for the primary efficacy endpoint of symptomatic recurrent VTE. In the Xarelto® arm, 2.1% of patients had an event compared with 1.8% of patients in the standard therapy arm (p=0.003)2 - figure 3.

Xarelto® also had a favourable safety profile compared with standard therapy:

  • Similar incidence of clinically relevant bleeding
  • Significant reduction in the incidence of major bleeding, by approximately 50% compared with standard therapy - figure 4
  • Fewer critical-site bleeding events and fewer intracranial haemorrhages, one of the most-feared bleeding events2

The incidences of other adverse events in the Xarelto® arm were low and similar to standard therapy, including the occurrence of acute coronary events2.

Xarelto®: a Major Breakthrough in the Management of VTE

Oral Xarelto® is a highly effective treatment for acute DVT and life-threatening PE and protects patients against the risk of VTE recurrence. Xarelto® acts quickly – as fast as subcutaneous

Xarelto®: Newly Approved for the Treatment of Pulmonary Embolism

enoxaparin – and does not require routine coagulation monitoring or dose adjustments like the VKAs. Xarelto® also has a favourable safety profile compared with VKAs. The optimal dosing of Xarelto® for the treatment of PE is 15 mg bid for the first 3 weeks (acute phase) followed by 20 mg od for the remaining treatment period. The approval of Xarelto® for the treatment of PE is an important breakthrough that will provide physicians with a simple single-drug alternative to the complex dual-drug approach of enoxaparin and VKA for the treatment of VTE.

Featured In Next Issue

  • The Dual Pathway in Acute Coronary Syndrome
  • Diagnosis and treatment of pulmonary embolism
  • Updated ESC Guidelines recommend use of novel oral anticoagulants
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Reference List

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

  2. The EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287–1297.

  3. Kubitza D, Becka M, Voith B et al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct Factor Xa inhibitor. Clin Pharmacol Ther 2005;78:412–421.

  4. Eriksson BI, Borris LC, Friedman RJ et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008;358:2765–2775.

  5. Kakkar AK, Brenner B, Dahl OE et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a doubleblind, randomised controlled trial. Lancet 2008;372:31–39.

  6. Lassen MR, Ageno W, Borris LC et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008;358:2776–2786.

  1. Turpie AGG, Lassen MR, Davidson BL et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial Lancet 2009;373:1673–1680.

  2. Patel MR, Mahaffey KW, Garg J et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–891.

  3. Kubitza D, Becka M, Voith B, et al. Effect of enoxaparin on the safety, tolerability, pharmacodynamics, and pharmacokinetics of BAY 59-7939: an oral, direct Factor Xa inhibitor. J Thromb Haemost. 2005;3 (suppl 1). Abstract P1704 . The publication is expected Q1/2013.

Related Material

Converting to Xarelto® in Daily Practice Balancing the Benefits and Risks of Anticoagulation Xarelto®: Revolutionizing VTE Treatment with a New Single-drug Solution Xarelto®: Once-daily Oral Dosing Across Multiple Indications

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