Rivaroxaban (XARELTO) is an oral anticoagulant drug used to treat and prevent VTE and to prevent stroke in people with nonvalvular atrial fibrillation through directly inhibiting factor Xa. It is used as an alternative to warfarin, which does not require laboratory monitoring or dietary restrictions. Rivaroxaban belongs to a group of drugs called direct oral anticoagulants (DOACs)

Indications

  • Primary and secondary stroke prevention in non-valvular atrial fibrillation (NVAF) ROCKET AF a XANTUS trials
  • Treatment and prevention of venous thromboembolism (VTE)deep vein thrombosis (DVT) and pulmonary embolism (PE) EINSTEIN trial
  • A postoperative thromboprophylaxis in the knee and hip surgery
  • Secondary prevention after acute coronary syndrome (ACS) or peripheral arterial disease (PAD) – as a low-dose add-on to clopidogrel and aspirin therapy – COMPASS trial

Off-label use:

  • treatment of acute heparin-induced thrombocytopenia (HIT) as initial therapy in hemodynamically stable patients or following initial therapy with a parenteral non-heparin anticoagulant
  • post-percutaneous coronary intervention with stent placement (after stabilization with initial management) in patients with NVAF
  • acute, symptomatic superficial vein thrombosis

Contraindications

  • hypersensitivity to rivaroxaban (or any component of the formula)
  • pregnancy and breastfeeding (DOACs are not recommended)
    • not enough data are available to judge the safety and efficacy of DOACs used during pregnancy
    • the drug is excreted into milk (probably only <10%) –  it is not recommended
  • severe renal impairmentuse Cockcroft-Gault formula!
    • all xabans are contraindicated with CrCl <15 mL/min (0.25 mL/s) 
  • active bleeding
  • congenital or acquired lesions/conditions considered a significant risk factor for major bleeding:
    • active or recent GI ulcerations, presence of malignant tumors
    • a recent brain or spinal injury or surgical procedure
    • eye surgery, vascular retinopathy
    • recent intracranial hemorrhage
    • the known presence or suspected esophageal varices, AVMs, vascular aneurysms, or other vascular anomalies (relative contraindication)
    • bronchiectasis or history of pulmonary bleeding
    • uncontrolled severe arterial hypertension
  • spontaneous/pharmacological (other anticoagulants) disorders of hemostasis
  • liver disease
    • all DOACs are contraindicated in patients with liver disease associated with coagulopathy and clinically apparent risk of bleeding
    • avoid rivaroxaban in patients with moderate-severe hepatic impairment (Child-Pugh classes B and C) or patients with coagulopathy related to liver disease
    • no dosage adjustment is necessary for patients with mild hepatic impairment
  • concomitant therapy (especially potent P-glycoprotein inhibitors)
    • ketoconazole, itraconazole
    • macrolides
  • conditions requiring VKAs
    • avoid DOACs in patients with a mechanical valve or moderate-severe mitral stenosis (contraindication)
    • not recommended in patients with prosthetic heart valves or rheumatic heart disease (however, rivaroxaban is non-inferior to warfarin in bioprosthetic MI valves according to the RIVER trial)
    • antiphospholipid syndrome (APS)
  • caution is recommended in patients ≥ 75 years due to an increased risk of GI bleeding compared to warfarin and reported rates of other DOACs when used for long-term treatment

Mechanism of action

  • direct, competitive, highly selective inhibitor of activated factor Xa (fXa)
  • does not affect platelets
  • unlike indirect factor Xa inhibitors (heparin, LMWH), rivaroxaban inhibits both free and clot-bound factor Xa;  the effect is not dependent on the presence of AT III or other cofactors
  • prevents the progression of the coagulation cascade through the final common pathway, thus preventing thrombin generation
Direct anticoagulants
They inactivate the coagulation factors present in the plasma
Indirect anticoagulants
They affect coagulation factors by reducing their liver production
Direct thrombin/factor Xa inhibitors
These drugs are bound to thrombin/factor Xa and thereby block their function
Indirect thrombin/factor Xa inhibitors
These drugs act through the activation of antithrombin
  • vitamin K antagonists (VKAs)
    • warfarin (coumadin)
  • xabans (free and clot-bound factor Xa inhibitors)
    • apixaban
    • rivaroxaban
    • edoxaban
    • betrixaban
  • hirudin (direct thrombin inhibitor – DTI)

Pharmacokinetics and pharmacodynamics

  • active drug with an easy and rapid absorption
    • maximum plasma concentration: within 2-4 h after tablet intake
    • half-life: 5-9 in young subjects and 11-13h in elderly   ((Mueck, 2014)
  • must be taken with food
  • high bioavailability (80-100%) and high albumin binding
  • excretion occurs mainly via urine 66% and partially via feces 28%
    • 1/3 of the dose is excreted unchanged by the kidneys
    • and 2/3 is excreted in the kidneys and feces after metabolization in the liver (via CYP3A4, CYP2J2)
  • in case of an overdose, activated charcoal can affect the absorption + selective antidote exists (Adnexanet); rivaroxaban is not dialyzable
  • do not administer rivaroxaban to patients with CrCl < 0.25ml/s (15 ml/min)
  • prolongs INR and PT; tests, however, can not be used for reliable monitoring of the effect (unlike in warfarin)
  • rivaroxaban does not inhibit cytochrome P450 enzymes or known drug transporter systems and, because rivaroxaban has multiple elimination pathways, it has no clinically relevant interactions with most commonly prescribed medications

Interactions

  • no significant interaction with atorvastatin, omeprazole, digoxin, or midazolam
  • patients at risk:
    • with renal insufficiency
    • with hepatopathy-induced coagulopathy ⇒ avoid DOACs!
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P-glycoprotein
P-glykoprotein (P-gp) inhibitors
  • calcium channel blockers (verapamil, diltiazem, nifedipine)
  • dronedarone (strong inhibitor)
  • immunosuppressive drugs (cyclosporine A, tacrolimus)
  • macrolides (clarithromycin, erythromycin)
  • azoles (ketoconazole, itraconazole)
  • others (amiodarone, quinidine, dipyridamole, propranolol)
  • HIV protease inhibitors (nelfinavir, etc.
  • glekaprevir/pibrentasvir
  • statins
P-glykoprotein (P-gp) inducers
  • phenytoin, carbamazepine, phenobarbital
  • rifampicin
  • rifabutin
  • dexamethasone
CYP3A4
CYP3A4 inhibitors
  • strong
    • HIV protease inhibitors (nelfinavir, etc.)
    • azoles (ketoconazole, itraconazole)
  • moderate
    • dronedaron
  • weak
    • calcium channel blockers (verapamil, diltiazem, nifedipine)
    • macrolides (clarithromycin, erythromycin)
    • H2-receptor antagonist
  • unspecified potency
    • SSRI
    • amiodarone
    • quinolones
CYP3A4 inducers
  • phenytoin, carbamazepine, phenobarbital
  • rifampicin, rifabutin
  • dexamethasone
  • pioglitazone
  • reverse transcriptase inhibitors

Administration and dosing

  • rivaroxaban is administered orally with food once daily (every 24 hours)
  • in patients with CrCl >50 mL/min, no dosage adjustment is necessary
  • for patients with a BMI >40 or weight >120 kg, the International Society on Thrombosis and Hemostasis (ISTH) 2016 guideline suggests avoiding the use of rivaroxaban due to the lack of clinical data in this population. If used, ISTH suggests measuring peak and trough levels using an anti-factor Xa assay
rivaroxaban (XARELTO) stroke prevention VTE prevention and therapy
(no LMHW bridging required)
VTE prevention in the hip or knee surgery (THR, TKR)
CrCl > 0.83 ml/s (>50 ml/min) 20 mg once daily 2×15 mg for 3 weeks
then 20mg once daily
(after 6 months, continue with 10 mg once daily if needed)
10 mg once daily
CrCl 0.25-0.83 ml/s (15-49 ml/min)
15 mg once daily
2×15 mg for 3 weeks
then 15 mg once daily

Monitoring

  • clinical monitoring usual for all anticoagulated patients
  • specific laboratory monitoring is helpful in selected cases

→ monitoring of patients treated with DOACs

Complications, adverse events

Bleeding

  • bleeding (> 10%) is the most common AE: epistaxis, GI bleeding, hematuria or bleeding at the surgical site, puncture, or catheter site
    • intracranial bleeding is less common compared to warfarin
    • GI bleeding is more frequent compared to warfarin
  • risk factors for bleeding:
    • bacterial endocarditis
    • underlying congenital or acquired bleeding disorders
    • vascular retinopathy
    • thrombocytopenia
    • recent procedure/surgery, stroke, neuraxial procedures
    • uncontrolled hypertension
    • renal impairment
    • recent major bleeding
    • concomitant use of other drugs that affect hemostasis
    • advanced age

  • consider early (within 1-4h) administration of activated oral charcoal
  • there is no hard evidence regarding the antifibrinolytics (tranexamic acid, aminocaproic acid) or systemic hemostatic agents (desmopressin, aprotinin)
  • the antidote is still somewhat a theoretical possibility (price, availability) → andexanet alfa
    • andexanet alfa (sold under the trade name Andexxa) is an antidote for the medications rivaroxaban and apixaban when the reversal of anticoagulation is needed
  • antidote or substitution therapy should be reserved for severe bleeding or urgent surgery (↑ risk of VTE)
ROCKET AF trial (median duration of treatment 19 months, total duration 41 months)
rivaroxaban warfarin
principal safety point (major + non-major clinically relevant bleeding)
1475 (20.7%)
1449 (20.3%)
major bleeding
395 (3.6%) 386 (3.45%)
critical bleeding
91 (1.3%)
133 (1.9)
fatal bleeding
27 (0.4%) 55 (0.8%)
intracranial bleeding 55 (0.8%) 84 (1.2%)
decrease in hemoglobin ≥ 2g/dl
305 (4.3%) 254 (3.6%)
non-major bleeding
 1185 (16.7%) 1151 (16.2%)

Other adverse events

  • hematological:
    • anemia – often as a result of bleeding
    • mild, usually transient thrombocytopenia
  • GI disorders: abdominal pain
  • dermatologic: pruritus, skin blisters
  • CNS: dizziness, headache, insomnia, anxiety
  • hepatic: increased serum transaminases to >3 x ULN, cholestasis
  • neuromuscular & skeletal: back pain and muscle spasm
  • bronchiectasis and pulmonary hemorrhage
  • other adverse effects are minor and rare

Overdose

  • if the agent was administered within the past 2 hours consider activated oral charcoal (recommendation with unproven clinical benefit)
  • antidote or substitution therapy should be reserved for severe bleeding or urgent surgery (↑ risk of VTE)

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