rivaroxaban (Xarelto)

Indications

• DVT prophylaxis after arthroplasty
• superior to enoxaparin for DVT prophylaxis after total knee arthroplasty or total hip arthroplasty
• prevention of stroke in patients with atrial fibrillation
  • lower annual rates of ischemic stroke or systemic embolism than warfarin (3.0% vs 3.3%)
  • annual risk of death not different from warfarin (7.7% vs 8.5%)
  • superior to warfarin in Asians;
    • reduced risks for ischemic stroke/systemic embolism, intracranial hemorrhage, & all-cause mortality at 1 year
  • safe for patients with bioprosthetic mitral valves
• acute deep vein thrombosis (DVT)
• pulmonary embolism
• secondary prevention of myocardial infarction in conjunction with dual anti-platelet therapy (NICE)
• FDA-approved to reduce risk for major cardiovascular events in patients with oronary artery disease or peripheral artery disease

* safe & effective in the elderly

Contraindications

• hypersensitivity
• active bleeding
• ESRD; not recommended if creatinine clearance < 30 mL/min
• severe liver disease
• valvular heart disease
• morbid obesity (BMI >40 mg/kg)
• high-risk antiphospholipid antibody syndrome

* questionable

• pregnancy
• osteoporosis (GRS11: due to increased fracture risk relative to warfarin)
  • ref concludes decreased fracture risk relative to warfarin

Pregnancy category: C

Dosage

• prophylaxis for venous thromboembolism (VTE)
  • 10 mg PO QD (start 6-8 hours after surgery)
    • continue for 30-35 days after surgery
• stroke prevention for atrial fibrillation: 20 mg PO QD
• DVT or pulmonary embolism:
  • 15 mg PO BID for 3 weeks, then 20 mg PO QD
  • no need for bridging LMW heparin
• 2.5 mg PO BID (secondary prevention of MI)

• stop 24-48 hours prior to surgery (see perioperative anticoagulation)

Tabs: 10 mg

Dosage adjustment in renal failure

• 15 mg QD for creatinine clearance 15-50 ml/min (AF)
• do not use for VTE with creatinine clearance < 30 ml/min
  • no dosage adjustment treating VTE for creatinine clearance > 30 ml/min

Pharmacokinetics

• renal elmination:
  • 66%, 33% as active metabolite; 30%
• substrate of both CYP3A4 & P-glycoprotein
• time to maximum concentration: 3 hours
• 1/2life: 7-11 hours
• protein binding: 95%

Adverse effects

• bleeding most common adverse effect
  • clinically significant bleeding more common with rivaroxaban than LMW heparin in acutely ill hospitalized patients (4.1 vs 1.7%)
• major bleeding* < 1% of patients
• similar risk of GI bleed compared with warfarin
• risk of GI bleeding highest among direct oral anticoagulants
• less major bleeding than LMW heparin/warfarin when used to treat DVT
• higher risk of hospitalization for GI bleed & for intracranial hemorrhage than with dabigatran
• increased mortality (20-50%) relative to warfarin
• similar risks for ischemic stroke & bleeding as warfarin but lower risk for death in nursing home residents (RR=0.7-0.8)

* treatment of major bleeding

• stop rivaroxaban
• administer fresh frozen plasma until bleeding stops
• prothombin complex concentrate reverses anticoagulant effect of rivaroxaban; 70% effective
• neither prothrombin complex concentrate nor tranexamic acid limits bleeding
• andexanet reverses factor Xa inhibition
• a specific reversal agent is not yet licensed

• drug adverse effects of direct oral anticoagulants
• drug adverse effects of antithrombotic agent(s)

Drug interactions

• inhibitors of CYP3A4 may increase levels of rivaroxaban
• inducers of CYP3A4 may decrease levels of rivaroxaban
• rivaroxaban itself neither induces or inhibits CYP3A4

• drug interaction(s) of direct oral anticoagulants (DOAC) with NSAIDs
• drug interaction(s) of oral anticoagulants with selective serotonin reuptake inhibitor (SSRI)
• drug interaction(s) of diltiazem with rivaroxaban
• drug interaction(s) of aspirin, P2Y12 inhibitors & anticoagulants

Laboratory

• rivaroxaban in serum/plasma

Mechanism of action

• small molecule inhibitor of factor Xa

Clinical trials

• ROCKET AF trial
  • point-of-care device used to measure INR after dosing with warfarin in ROCKET AF trial later recalled by FDA because the device was prone to giving falsely low INR readings*
  • falsely low INR readings may have prompted higher doses of warfarin resulting in higher risks for bleeding making rivaroxaban seem comparatively safer
  • authors of ROCKET AF trial reanalyzed their data & concluded that use of the device had not significant clinical effect on the primary efficacy or safety outcomes in the trial
  • data not publically available

* Janssen, the pharmaceutical branch of Johnson & Johnson, knew that a point-of-care device used for measuring INR was giving falsely low readings during the ROCKET AF trial

* FDA concludes results of ROCKET AF trial not effected by faulty monitoring device

More general terms

• coagulation factor Xa inhibitor
• direct oral anticoagulant; novel oral anticoagulant (DOAC, NOAC)

Additional terms

• apixaban (Eliquis)

Database

• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=6433119
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=9875401