Rivaroxaban – a new oral anticoagulant

- May 1, 2013

Rivaroxaban (Factor Xa inhibitor) and dabigatran etexilate (a direct thrombin inhibitor) are alternatives to warfarin for oral anticoagulation, and to low-molecular weight heparins (LMWH) post-orthopaedic surgery. This bulletin discusses the use of rivaroxaban – important characteristics and potential issues – with a particular focus on treatment of atrial fibrillation (AF). A previous bulletin (005/12) has discussed the use of dabigatran etexilate.

Indications

Rivaroxaban is licensed for:

  • treatment of deep vein thrombosis (DVT)
  • prevention of recurrent venous thromboembolism (VTE)
  • thromboprophylaxis after total knee/hip replacement
  • thromboprophylaxis in non-valvular AF patients at moderate to high risk (e.g. congestive heart failure, hypertension, age ≥ 75 years, diabetes, prior stroke/transient ischaemic attack)

However, it is currently only funded via Special Authority for post- knee or hip surgery, for a course of up to 2 or 5 weeks, respectively.

Mechanism of action

Rivaroxaban is a direct Factor Xa inhibitor. Factor Xa is a key enzyme in the coagulation cascade that directly converts prothrombin to thrombin, leading to fibrin clot formation and platelet activation.

Pharmacokinetics

Rivaroxaban is well absorbed orally (66 -100%; increased with food). It has a terminal half-life of 5 – 13 hours, and is highly protein bound. Rivaroxaban is partially renally cleared (~30%) via active secretion, with ~50% of a dose hepatically cleared (~30% involving CYP enzymes, in particular CYP 3A4/5/7). Rivaroxaban is also a substrate of the efflux transporter protein, P-glycoprotein (P-gp).

Interactions

Rivaroxaban serum concentrations may be altered by drugs that inhibit/induce liver enzymes or P-gp, particularly if both are potently inhibited or induced (e.g. with ketoconazole or rifampicin), and the patient has renal impairment. Drugs that potently inhibit/induce both CYP 3A4/5/7 and P-gp should ideally be avoided (see the ‘Pink Book’).

Monitoring

Routine monitoring for rivaroxaban is not currently recommended. However, prothrombin time (PT) may be of use to determine patient adherence; or prior to a procedure, to ensure normal coagulation for surgery.

 

Dosing

  • Treatment of DVT/recurrent VTE: Week 1-3: 15mg Q12H, then 20 mg Q24H if prophylaxis required
  • Non-valvular AF: 20mg Q24H
  • Post-hip/knee-surgery: 10mg Q24H started 6-10 hrs post-op for 5 weeks (hip) or 2 weeks (knee)

Evidence for use in AF

This is mostly based on a double-blind, randomised, non-inferiority trial (Rocket AF Study; n=14,264) comparing rivaroxaban 15 or 20mg Q24H versus warfarin in patients with moderate-major risk of thrombosis, without valve abnormalities. Rivaroxaban was found to be non-inferior to warfarin in reducing stroke and systemic embolism in non-valvular AF patients. There appears to be no clear advantage over warfarin in adverse effects.

The incidences of overall mortality, systemic embolism or stroke, major bleeding and overall bleeding were not significantly different between the two arms. Rivaroxaban was associated with fewer intracranial bleeds, but more gastrointestinal bleeding, epistaxis and haematuria. (Note that a therapeutic INR was achieved in only 55% of the time in the warfarin arm).

Rivaroxaban has not been trialled head-to-head with dabigatran or other new anticoagulants.

Additional adverse effects

The most common non-bleeding adverse effects were peripheral oedema and dizziness. Others include gastrointestinal disorders (e.g. nausea, vomiting, diarrhoea, dyspepsia and abdominal pain), raised transaminases, syncope, anaphylaxis and kidney failure.

Management of bleeding

There is no specific antidote for rivaroxaban. Usual treatment measures should be instituted (e.g. compression, surgery, fluid replacement, blood products (e.g. packed red cells, fresh frozen plasma or platelets)). If the patient is still bleeding, procoagulants, such as activated prothrombin complex concentrate, prothrombin complex concentrate or factor VIIa can be considered, although data on use are limited. Discuss with Haematology. Neither protamine sulphate, vitamin K nor dialysis are expected to be beneficial. There are no data on administration of tranexamic acid.

Place in therapy

Rivaroxaban is an alternative to LMWHs for thromboprophylaxis after total knee or hip replacements. Rivaroxaban is expensive and not funded for AF. Therefore, use in this patient group is limited. It is reserved for patients unable to have warfarin e.g. adverse effects, and difficulty monitoring or achieving a therapeutic INR.

Table: Comparison of currently available oral anticoagulants in NZ

Anticoagulant Indications Advantages Disadvantages / Cautions Daily Cost
Rivaroxaban

(direct Factor Xa inhibitor)

DVT/recurrent VTE

Non-valvular AF

Prophylaxis post- hip/knee-surgery

No routine monitoring in most

Rapid onset

No antidote. Expensive.

Drug interactions. Rapid offset.

Anticoagulant effect not easily measured.

Caution in renal/hepatic impairment (contraindicated if GFR<15mL/min)

$10 – 20
Warfarin

(vitamin K antagonist)

Treatment and prevention of most thromboembolic conditions, including valvular AF and MI: Antidote available

Inexpensive

Anticoagulation effect easily measured

Vast experience

Regular monitoring and dose changes.

Drug interactions. Food interactions.

Warfarin resistance.

Slow onset.

Caution in hepatic impairment

< 20 cents
Dabigatran etexilate

(direct thrombin inhibitor)

Non-valvular AF

Prophylaxis post- hip/knee surgery

No routine monitoring in most

Quick onset

No antidote. Expensive.

Drug interactions. Rapid offset.

Anticoagulant effect not easily measured.

Dose reduce in renal impairment (contraindicated if GFR<30mL/min)

$5
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