Xarelto (Rivaroxaban): FDA Approved for DVT and PE Treatment

Stephan Moll, MD writes…

Today is a very exciting day for patients and health care professionals: the oral anticoagulant Xarelto® (rivaroxaban) was FDA approved today (Nov 2^nd, 2012) for the use in patients with DVT and PE – for the acute treatment of DVT and PE, as well as for the secondary long-term prevention of recurrent venous thromboembolism (VTE). The FDA announcement can be read, here. Why is this exciting? Because therapy with Xarelto is much easier for patients and health care professionals than the often cumbersome therapy with warfarin.

 

A.     The Scientific Data that led to the FDA approval

Xarelto was compared with warfarin in three large phase 3 VTE treatment trials and was found to at least as effective and safe as warfarin [references 1,2]. Patient populations studied:

1)     Patients with acute DVT (EINSTEIN-DVT trial);

2)     Patients with acute PE (EINSTEIN-PE trial);

3)     Patients who had completed a standard course of anticoagulant therapy and were now considered for secondary VTE prophylaxis (EINSTEIN Extension trial).

 

B. The Advantages of Xarelto

1. No monitoring of anticoagulation level:  As Xarelto has a predictable anticoagulant effect and wide therapeutic window, no routine anticoagulation monitoring is needed and no dose adjustments: one dose fits all patients (patients with GFR < 30 ml/min or significant liver impairment should not be treated). The dosing regimens are:

• 15 mg twice daily with food for the first 3 weeks after an acute DVT or PE,
• 20 mg once daily with food after those first 3 weeks and for the long-term prevention of another clot.

2. No dietary interaction with vitamin K:  As Xarelto’s anticoagulant effect is independent of vitamin K, patients can eat what they want.

3. No need to bridge with LMWH or heparin when treating acute VTE:  Peak anticoagulant levels are reached 2-4 hours after oral Xarelto intake. The  phase 3 clinical trials studying Xarelto used the drug for the acute therapy of DVT and PE without the need for initial LMWH bridging therapy.

4. Short half-life:  The half-life of 5-9 hrs (given normal renal function) allows for the drug to be discontinued 24-48 hours before surgical procedures and makes pre-procedure bridging therapy with LMWH unnecessary. Details as to when to stop the drug prior to interventions can be found here, table 5.

5. Less drug interactions:  Rivaroxaban has markedly fewer drug interactions than warfarin. The main drugs that influence Xarelto metabolism (increase plasma levels) are certain antifungals, HIV and anti-seizure medications.  They are listed in the Xarelto package insert-prescribing information and the Xarelto Patient Guide.

6. Cost to the patient: Use of LMWH bridging therapy when initiating warfarin in the patient with acute VTE can be quite costly, as can a patient’s co-pay for INR monitoring clinic visits. Whether Xarelto is more, equally, or less expensive than warfarin therapy for an individual patient depends, of course, on a patient’s co-pay. The advice to a patient who is considering a switch to Xarelto is to contact his/her insurance carrier and inquire what the co-pay would be.

 

C.   The Disadvantages of Xarelto

1. Xarelto is still a relatively new drug.  However, it has been used (a) by more than 35,000 patients over the last several years in the clinical trials, and (b) by many patients worldwide since its approval in the various indications. Xarelto has been approved by the regulatory agencies as follows:

• for DVT prevention after orthopedic surgeries in Canada and Europe in September 2008, and in the U.S. in July 2011;
• for irregular heart beat (atrial fibrillation) in the U.S. Nov 2011, and in Europe in December 2011;
• for treatment of DVT in Europe in December 2011, and for DVT and PE in the U.S. today (Nov 2^nd, 2012).

2. There is no antidote or reversal strategy that is known to work if major bleeding occurs on Xarelto [ref 4].

 

D.   Which patient to treat with Xarelto?

1. First of all, patients who should NOT be treated with Xarelto:

• Patients with marked renal impairment  (GFR < 30 ml/min) or liver disease should NOT be treated with Xarelto, as the drug is renally cleared and metabolized by the liver.
• Patients who are on medications that interfere with Xarelto (some anti-seizure medications; certain antifungals and antivirals) should NOT be given the drug. These drugs are listed in the Xarelto package insert-prescribing information.

2. Patients who can be considered for Xarelto therapy fall into one of two categories:

I.  Patients with previous VTE, presently on short-term or long-term warfarin

• Xarelto is certainly an attractive option for the patient who is presently on warfarin for a history of DVT or PE and does not tolerate warfarin well or finds it cumbersome to take. This includes patients with fluctuating INRs or significant side effects (hair loss, fatigue) or difficulty getting to an anticoagulation clinic and monitoring the INR. In this situation the approved and appropriate dose of Xarelto is 20 mg once daily with food.
• However, Xarelto is also an attractive treatment option for any patient with DVT and PE and acceptable renal and liver function who is presently on warfarin therapy.
• The appropriate Xarelto dose in these patients is 20 mg once daily with food.

II. Patients with acute DVT or PE

One of the beauties of Xarelto is that it reaches peak plasma anticoagulant activity within 2-4 hours of oral intake and can be taken by the patient with a newly diagnosed DVT or PE right of the bat without the need for initial LMWH or heparin therapy.  This has the potential to be practice changing, as this will simplify VTE treatment significantly.
The appropriate Xarelto dose in these patients is 15 mg twice daily with food for the first 3 weeks, and then 20 mg once daily with food.

 

E.   REFERENCES

1. The Einstein Investigators: Oral Rivaroxaban for symptomatic venous thromboembolism. New Engl J Med 2010;363:2499-510.
2. The Einstein Investigators: Oral Rivaroxaban for the treatment of symptomatic pulmonary embolism. New Engl J Med 2012;366:1287-97.
3. Turpie AG et al. Rivaroxaban for the prevention of venous thromboembolism after hip and knee arthroplasty. Pooled analysis of four studies. Thromb Haemost, 2011;105:444-453.
4. Kaatz S et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol. 2012 May;87 Suppl 1:S141-5.

 

Disclosure:  I have consulted  for Janssen (U.S. distributor of Xarelto) and Boehringer-Ingelheim (company making Pradaxa).

Last updated:  Nov 2nd, 2012