ADD-ONS / MEDICATION / ANTICOAGULANTS

Rivaroxaban (Xarelto)

David Goldemund M.D.
Updated on 24/01/2024, published on 24/10/2022

Rivaroxaban (XARELTO) belongs to a group of drugs called direct oral anticoagulants (DOACs). It is a direct Factor Xa inhibitor and is used as an alternative to warfarin for the treatment and prevention of VTE and stroke prevention in people with nonvalvular atrial fibrillation (NVAF). Unlike warfarin, it does not require laboratory monitoring or special dietary restrictions.

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 after initial therapy with a non-heparin parenteral 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 of the ingredients)
  • pregnancy and lactation (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%) –  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 ulceration, presence of malignancy
    • a recent brain or spinal cord injury or surgery
    • eye surgery, vascular retinopathy
    • recent intracranial hemorrhage
    • known or suspected esophageal varices, AVMs, vascular aneurysms, or other vascular anomalies (relative contraindication)
    • bronchiectasis or history of pulmonary bleeding
    • uncontrolled severe arterial hypertension
  • spontaneous/pharmacologic (other anticoagulants) bleeding disorders
  • 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 associated with 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 RIVERtrial)
    • antiphospholipid syndrome (APS)
  • caution is recommended in patients ≥ 75 years of age due to an increased risk of GI bleeding compared to warfarin and reported rates with 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 independent of 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 clotting factors present in the plasma
Indirect anticoagulants
They affect clotting factors by reducing their liver production
Direct thrombin/factor Xa inhibitors
These drugs bind to thrombin/factor Xa and thereby block their function
Indirect thrombin/factor Xa inhibitors
These drugs activate antithrombin
  • vitamin K antagonists (VKAs)
  • hirudin (direct thrombin inhibitor – DTI)

Pharmacokinetics and pharmacodynamics

  • active drug with an easy and rapid absorption
    • maximum plasma concentration is reached within 2-4 hours after tablet intake
    • half-life: 5-9 hours in young subjects and 11-13hours in older adults ((Mueck, 2014)
  • must be taken with food
  • high bioavailability (80-100%) and high albumin binding
  • excretion is 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 is available (Adnexanet); rivaroxaban is not dialyzable
  • do not administer rivaroxaban to patients with CrCl < 0.25ml/s (15 ml/min)
  • prolongs INR and PT;  however, these tests can not be used to monitor the effect reliably
  • rivaroxaban does not inhibit cytochrome P450 enzymes or known drug transporter systems and has no clinically relevant interactions with most commonly prescribed drugs

Interactions

  • no significant interaction with atorvastatin, omeprazole, digoxin, or midazolam
  • patients at risk:
    • with renal insufficiency
    • with hepatopathy-related 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
    • dronedarone
  • 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 once daily (every 24 hours) with food
  • no dose adjustment is required in patients with CrCl >50 mL/min
  • 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 efficacy of 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 (trade name Andexxa) is an antidote for rivaroxaban and apixaban when reversal of anticoagulation is required
  • 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 of treatment 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

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

Overdose

  • if rivaroxaban 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 (due to ↑ risk of VTE)

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Rivaroxaban (XARELTO)
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